Responsive Polymer Nanostructures

Biswas, Yajnaseni; Jana, Somdeb; Dule, Madhab; Mandal, Tarun K.

doi:10.1007/978-3-319-57003-7_6

Yajnaseni Biswas⁵,
Somdeb Jana⁵,
Madhab Dule⁵ &
…
Tarun K. Mandal⁵

Part of the book series: Engineering Materials and Processes ((EMP))

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2 Citations

Abstract

Here in this review, we describe recent advances and challenges toward the design and development of stimuli-responsive polymeric materials that are self-assembled to from nanostructured building blocks. A short introduction describing non-materials in general along with the different synthetic methodologies for making polymeric materials that are responsive toward several physical, chemical, or biochemical stimuli such as temperature, light, pH, redox reaction, ionic strength, glucose, CO₂, enzyme. A general discussion on the cause of thermoresponsivenes in polymers having either lower critical solution temperature (LCST) or upper critical solution temperature (USCT) transition is described. This followed by the detailed description of the nanostructured polymer materials, which are responsive to temperature. pH-responsive polymers are important materials in terms of their diverse range of applications, such as drug delivery, diagnostics. Thus, we describe the details of synthesis of different polymer and copolymer systems and their pH-responsive assembly into several types of nanostructures such as micelles, vesicles followed by their pH-triggered disassembly in aqueous solution. The polymeric nanomaterials responsive to light in particular has attracted much attention since light can be localized in time and space and can be applied from outside of the system. Therefore, it is indeed important to discuss the nanostructured polymer materials that are responsive to light followed by their potential applications. Polymeric nanomaterials that are responsive to other different stimuli such as redox reaction, CO₂, sugar are also described in this review. Finally, we also describe different multi-stimuli-responsive nanostructured polymer systems. The main goal of this chapter is to serve as a guideline to inspire future researchers toward the design and synthesis of stimuli-responsive materials so that novel applications and new generations of smart materials can be realized.

^✮These authors contributed equally to this chapter.

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Smart Stimuli-Responsive Nano-sized Hosts for Drug Delivery

Smart Polymers: Synthetic Strategies, Supramolecular Morphologies, and Drug Loading

Stimuli-Responsive Polymeric Systems for Smart Drug Delivery

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1 Introduction

Nanostructures are defined as having at least one dimension is in the size range of 1–100 nm. A great number of articles, reviews, and books about polymer nanostructures and their applications are available in the literature. Polymer nanostructures of different morphology (micelle, vesicle, cylindrical, worm-like micelle etc.) have been received great interest due to their wide range of potential applications such as encapsulates for drug [1], gene [2], enzyme [1], protein [3], catalyst [4] as dielectrics for electronics [5], as absorbent materials for sound and microwave [6], as nanocarrier for fabrication of nanodevices [7], and as label free chip sensor [8]. Among them, stimuli-responsive polymer nanostructures have attracted growing interest for their potential use in medicine, especially as drug delivery system and potential platform to mimic organelles as biological nanoreactors [9,10,11].

Over the past 25 years, responsive polymer-based nanostructured soft materials such as micelles, vesicles, polymersomes have gained increasing attention to the polymer research community because of the broad opportunities of these systems in vivo applications [12,13,14,15,16]. Responsive polymer nanostructured materials (Fig. 6.1) can also refer to as “environmentally sensitive” [17], “smart” [18], or “intelligent” [19] polymer materials that undergoes conformational and chemical changes on receiving an external signal [20] and made this class of materials very promising in the field of nanotechnology, nanoscience, and nanomedicine [21]. Mother Nature exhibits plentiful instances of responsive materials. Examples of such systems include sea cucumbers that change their stiffness by several orders of magnitude in the face of danger; the leaves of Mimosa Pudica collapse immediately upon touching; chameleons change their skin color according to their environment. The responsive materials present in these living systems are either biomacromolecules or biopolymers. Thus, researchers paid more attention toward the design and synthesis of responsive polymer materials to mimic the functions of several macromolecular organisms in living systems.

These responsive materials are generally derived from polymers and are proven its robustness in wide range of applications such as responsive biointerfaces that are mimic to natural surfaces [22], controlled delivery of drugs and its release to the desired site [23,24,25], tissue engineering [26, 27], “smart” optical systems [28], biosensors [29, 30], coatings [31, 32]. Responsive polymers mainly contain reactive functionalities that can show sharp responses to changes in external stimuli. Upon small changes in the environmental conditions, these materials can significantly change their properties such as shape, mechanical properties, phase separation, surface, permeability, optical properties, electrical, and chemical properties [33]. It is also known that different functional groups respond to different stimuli. The most common and frequently utilized stimuli are temperature [20, 34, 35], pH [36, 37], light [38,39,40], redox reaction [41], ionic strength [42] glucose [43], and carbon dioxide (CO₂) [44]. The pH, ionic strength, redox reactions can be categorized as chemical stimuli and temperature; light is indeed very important and promising physical stimuli in the responsive systems. However, biochemical stimuli can also be considered as another important category of stimuli that involve responses to enzymes, antigens, and other biochemical agents [20].

A detailed survey of the literature clearly tells that the number of scientific contributions to synthetic polymers with stimuli-responsive properties is increased epidemically in the last few decades [45, 46]. This is mainly ascribable to the fact that several new methods for the polymerization of various functional monomers are developed in last two decades. In this context, various controlled radical polymerization techniques such as the atom transfer radical polymerization (ATRP) [47], the reversible addition-fragmentation chain transfer (RAFT) [48], nitroxide-mediated polymerization (NMP) [49], ring-opening polymerization (ROP) [50], techniques have been used intensively to synthesize different stimuli-responsive polymers. Indeed, these polymerization methods show a high tolerance toward functional monomeric groups while providing the benefit to result in polymers and block copolymers with a narrow molecular weight distribution and well-defined end-groups. In addition, another new synthetic approach in polymer chemistry namely post-polymerization modifications [51] of polymeric precursors via “click” chemistry [52] is also found to be a very highly appealing tool to introduce responsive functional moieties into the polymer backbone. Thus, different stimuli-responsive polymeric materials with a variety of functionalities can be designed and prepared easily by using the above-mentioned polymerization techniques.

Smart macromolecular nanostructures are designated by their stimuli-responsive behavior, which is basically controlled by the presence of functional moieties within or on a polymer chain. Different functionalities respond to different stimuli and a broad library of such functionalities has been studied. Recently, synthetic smart polymeric materials may also respond to more than one or two stimuli [53, 54]. These materials are generally known as dual or multistimuli-responsive polymer systems and can be prepared by the successive introduction of different stimuli-responsive functional groups into one polymer chain. It is worth noting that these materials attracted significant and increasing attention toward academia as well as in industry because of not only their tunable physical and chemical properties but also their emerging potentiality toward biological application such as controlled release of drugs, tissue engineering, and responsive coatings.

This chapter is intended to present the recent developments as well as fabrication strategies of stimulus active polymer-based soft nanomaterials that are sensitive to heat, pH, redox, light, glucose, CO₂ etc. This chapter also deals with various methods and recent advancement toward dual as well as multistimuli-responsive polymers, bearing more than one or two responsive functional groups in one polymer chain. The breadth/target of this chapter is to demonstrate the current possibilities and chances as well as challenges toward the development of new generation of “smart” nanomaterials by comprehensively summarizing related interesting examples in this field, which have been published recently. Finally, wide applications and future perspective of these “smart” materials are summarized. We expect that this chapter will not only help the interdisciplinary readers to understand the recent stage of this area but also shed some light on future research directions in this important field.

2 Thermoresponsive Polymer Nanostructures

Thermoresponsive polymers are a class of “smart” materials that have the ability to respond to a change in temperature. Among all the studied responsive systems, thermoresponsive polymers are widely investigated because temperature stimulus can easily be tuned from outside, and it is easy to monitor the change in different properties, especially the change of solution properties and the adopted nanostructures morphologies (e.g., micelles, vesicles) of polymers with temperature. Thermoresponsive behaviors of polymers and biopolymers can be induced in a variety of settings, including in vivo [20, 35, 55], and potential benefits have been envisioned for a range of biologically relevant applications, including controlled drug delivery [56,57,58], bioseparations, [59, 60], filtration [61,62,63], making smart surfaces [64,65,66], and regulating enzyme activity [67].

Temperature-responsive polymers exhibit a volume phase transition at a certain temperature, which causes a sudden change in the solvation state. Polymers, which become insoluble upon heating, have a so-called LCST (Lower Critical Solution Temperature)-type transition and which become soluble upon heating have an UCST (upper critical solution temperature)-type transition. Polymers exhibiting LCST-type behavior were soluble in solution due to extensive hydrogen bonding interactions with the surrounding solvent molecules (such as water) and restricted intra- and inter-molecular hydrogen bonding between polymer chains. At LCST, upon heating, hydrogen bonding with solvent molecule is disrupted, and intra- and inter-molecular hydrogen bonding/hydrophobic interactions dominate, which results in the polymer to phase-separate from solution due to a molecular transition from a coiled, enthalpically favored structure to a dense globular, entropically favored structure (Fig. 6.2) [68]. This process will minimize the free energy of the system considerably.

Following this principle, the solution macroscopically starts to become turbid due to the phase separation of the polymer while heating [69]. Among different LCST non-ionic polymers, poly(N-isopropylacrylamide) (PNIPAAm) is indeed one of the most investigated LCST polymers in aqueous solution, as the phase transition temperature, which is also known as cloud point temperature of PNIPAAm (32 °C) is close to physiological temperature [35]. Other important classes of synthetic thermoresponsive non-ionic polymers featuring a LCST in aqueous solution includes poly(acrylamides), poly(vinyl methyl ether) (PVME) [70,71,72,73], polyoxazolines [26, 74, 75], as well as poly(oligoethylenenoxide)methacrylates [76,77,78,79]. Polymers with different cloud points have been summarized in Table 6.1. The LCST is further dependent on different parameters such as polymer chain length [80, 81] tacticity [82], and incorporation of comonomers [83], pressure [84], or even the chemical nature of the end group [85, 86].

Table 6.1 The chemical structures and transition temperatures of various temperature-responsive polymers in water

Full size table

Compared with polymers having LCST in aqueous media, polymers with UCST are relatively uncommon. A polymeric system comprising of poly(acrylic acid) (PAA)/poly(acrylamide) (PAm) is well-studied showing UCST-type of transition in water [87]. Later on, non-ionic poly(N-acryloylglutamineamide) (PNAGA) was found to be exhibit UCST-type of transition [88] in water. There are also many other polymers such as poly(sulfobetaine)s [89, 90], poly(6-(acryloxyloxy-methyl)uracil) [91], and ureido-derivatized polymers [92] that exhibits UCST-type transition. These polymers usually have a pair of interactive sites that cause the polymers to be insoluble at lower temperature due to intra-molecular and inter-molecular interactions(such as hydrogen bonding and electrostatic attraction) among polymer chains, which can be disrupted at higher temperature due to intensified molecular motion within the polymer chains, resulting in a hydrated polymer [93]. Since we are concerned here about the polymer nanostructures driven by external stimuli, we mainly focused here the self-assembly of amphiphilic block copolymers into various nanostructures, ranging from spheres, worms, to vesicles, and structures kinetically trapped as intermediate morphologies in solution.

“Living” radical polymerization (LRP) allows a wide variety of amphiphilic block copolymers to be synthesized in bulk or solution with excellent control over the block lengths and chemical compositions [48, 94,95,96]. It has been demonstrated that the presence of a thermoresponsive block in a di or tri block copolymers results in the rapid assembly into 3D structures upon heating a homogeneous polymer/water solution above its LCST [97, 98]. The assemblies form varieties of 3D nanostructures of different shapes and sizes depending upon the ratio of the hydrophilic to hydrophobic block lengths. These nanostructures are fully reversible in terms of morphology upon cooling [99, 100], unless crosslinked at temperatures above the LCST [98, 101,102,103,104,105,106,107]. For the sake of completeness, it should be mentioned that beside the solution state thermoresponsive phase behavior of polymers in solid-state film also exists as well that we are not going to review in this chapter. For a better understanding of the reader, we purposefully divided the thermoresponsive polymer into non-ionic and ionic categories.

2.1 Non-ionic Polymer Nanostructures

2.1.1 LCST-Type Polymer Nanostructures

2.1.1.1 Poly(N-substituted (meth)acrylamide)-Based Nanostructures

Poly(N-isopropylacrylamide) (PNIPAAm) was the first polymer showing LCST in aqueous solution, which was an important member of poly(N-(meth)acrylamide) polymer family [138]. The homopolymers and copolymers of PNIPAAm have gained significant attention [19, 20, 35, 56, 139,140,141,142,143,144] due to the sharp phase transition (soluble one phase to turbid two phase) around 32 °C (near room and body temperatures). However, the incorporation of comonomers containing hydrophilic groups makes PNIPAAm—copolymers of easily tunable LCST near body temperature, which promotes them as prominent candidates in biomedical applications [35, 69]. Above LCST, the unperturbed coil PNIPAAm chains turn into partially dehydrated globules. In this collapsed state, the amide groups of PNIPAAm lead to the formation of intra-molecular and inter-molecular NH···O=C hydrogen bonding interactions [145]. Hence, during the cooling process, the rehydration of PNIPAAm is hindered by these additional interactions, leading to a broad hysteresis during the cooling process.

It is known that the amphiphilic copolymers, synthesized by controlled polymerization techniques, have enabled the formation of a variety of nanostructures due the self-assembly among the copolymer chains. Incorporation of a polymer block into amphiphilic block copolymer that has stimuli-dependent miscibility and immiscibility in a given solvent provides a powerful method for reversibly changing the size and structure of the resulting assemblies. For example, thermomorphic PNIPAAm, which exhibit a LCST in water below which chains are miscible and above which chains are immiscible. This property has been utilized by many researchers to prepare thermoresponsive polymer nanostructures. For example, Convertine et al. have reported a series of thermally responsive di(AB)- and tri(ABA) block copolymers containing hydrophilic poly(N,N-dimethylacrylamide) (PDMAM) block of constant lengths and PNIPAAm blocks of variable lengths using room temperature RAFT polymerization to systematically study the temperature-dependent micellization behavior of these systems [146]. They demonstrate that these block copolymers are indeed capable of reversibly forming micelles in response to changes in solution temperature, and the micellar size and transition temperature are dependent on both the PNIPAAm block length and the polymer architecture (diblock vs triblock). In this context, it should be mentioned that not only amphiphilic block copolymers but also some double-hydrophilic block copolymers (DHBC)s having a thermoresponsive block (undergoes a transition from soluble to insoluble in water) shows various aggregated nanostructures [147]. Typically, most reports on such systems exploit the wide-spread occurrence of a LCST of non-ionic polymers in water. However, for DHBCs above the critical temperature, one of the hydrophilic blocks collapses, generating hydrophobic microdomain, which eventually aggregated into micro/nanostructure of various morphologies. Such aggregated micro/nanostructures are reversibly dissociated into unperturbed chain structure by lowering the temperature below a critical value. This strategy can be used to trigger the release of encapsulated materials, e.g., for controlled drug delivery [148].

A number of research groups have enhanced these pioneering examples of polymer systems that undergo stimulus-driven transitions between assemblies with well-defined structures. Grubbs and coworkers have been designed several ABC-type triblock copolymers that respond to a stimulus by transforming from one stable assembled form to another [100]. The triblock copolymer, PEO-b-PNIPAAm-b-poly(isoprene), comprised of hydrophilic end block, a thermally responsive central block, and a hydrophobic end block have been synthesized using the sequential nitroxide-mediated polymerization. They are designed to be largely hydrophilic at room temperature and largely hydrophobic above the LCST of PNIPAAm, thus forming small assemblies (spherical micelles) with a highly curved assembly-water interface at lower temperatures and larger assemblies (vesicles) with a less-curved interface at higher temperatures (Fig. 6.3) [100]. They have shown by transmission electron microscope (TEM) and dynamic light scattering (DLS) analysis the formation of large spherical micelles (D ∼ 9 nm) at room temperature and formation of large vesicular assemblies with a mean radius greater than 100 nm after heating at 65 °C for 4 weeks.

A number of other examples of polymers that exhibit similar behavior, which are discussed in more detail below, have also been recently described in the literature. Zhou et al. [149] reported a triblock copolymer, poly(ethylene propylene)-b-poly(ethylene oxide)-b-PNIPAAm, in which the hydrophilic block occupies the central position and the responsive block a terminal position (PEP₄₅-b-PEO₅₆₅-b-PNIPAAm_z, where z = 33, 83, 187), which assemble to form micelles having a PEP core with PEO and PNIPAAm blocks in the corona at room temperature in water. However, above the LCST of PNIPAAm, the outermost part of the corona became much less hydrophilic and the micelles are reorganizing, but under the experimental condition, it appears to be more favorable for micelles to aggregate through association of PNIPAM domains than to reorganize into other micellar forms. Further, Qiao et al. [150] synthesized a thermalresponsive fluorescent block copolymer comprised of temperature-responsive PNIPAAm unit, hydrophilic poly(maleic anhydride) (PMAn) unit, and fluorescent7-amino-4-methylcoumarin (AMC) groups by RAFT polymerization method. According to them, with increasing temperature, PNIPAAm chains become collapsed making the block copolymer more hydrophobic above the LCST resulting in larger aggregates. Thus, a part of the fluorescent groups would be embedded inside the enlarged block copolymer micelles, resulting in lower fluorescence intensity (Fig. 6.4).

However, PNIPAAm possesses some inherent drawbacks, such as controversial biocompatibility, phase transition hysteresis, and a significant end group influence on phase transition behavior [151, 152]. Other members of this family that have also been investigated as thermoresponsive polymers are poly(N-n-propylacrylamide) (PNnPAAm) and poly(N-cyclopropylacrylamide) (PNCPAAm) having phase transition behaviors significantly different from PNIPAAm, with LCST-type transition temperatures of 10 and 53 °C, respectively [108, 109, 153]. However, LCST transition of poly(N,N-diethylacrylamide) (PDEAAm) has been reported (~33 °C) near to that of PNIPAAm [110], though this value has been demonstrated to be tacticity-dependent [154]. In addition to the study of responsive behavior, several groups have reported applications of PDEAM that exploit its temperature-dependent solubility. For example, a well-defined amphiphilic polyisobutylene-b-poly(N,N-diethylacrylamide) (PIB-b-PDEAAm) diblock copolymers of varying compositions were synthesized by sequential living carbocationic and RAFT polymerization techniques, which self-assembled into large compound micelles in aqueous media. These compound micelles responded sharply to temperature as examined by UV–Vis and DLS studies. Above LCST, the transmittance decreased remarkably while hydrodynamic diameter (D _h) increased acutely. LCSTs of PIB-b-PDEAAm diblock copolymers were in the range of 29.0–31.8 °C which rose with elongating the length of hydrophilic PDEAAm segment [155]. Angelopoulos et al. have been synthesized a triblock copolymer PDEAAm-b-poly(acrylic acid)-b-PDEAAm (PDEAAm-b-PAA-b-PDEAAm) by sequential anionic polymerization led to reversible gelators. At high pH and temperatures above the cloud point of PDEAAm end block, a sol–gel transition of PDEAAm-b-PAA-b-PDEAAm was observed due to the formation of a three-dimensional transient network comprised of a PDEAAm hydrophobic physical crosslink interconnected by negatively charged PAA chains [156].

Further, Lowe and coworkers have reported numerous examples of PDEAM-based thermoresponsive systems [157, 158]. Recently, a series of new thermoresponsive polymers based on poly(N-(N′-alkylcarbamido)propyl methacrylamide) analogs have also been reported [111]. For instance, poly(N-(N′-isobutylcarbamido)propyl methacrylamide) exhibited a LCST phase transition at 13 °C, whereas the transition temperature of poly(N-(N′-ethylcarbamido)propyl methacrylamide) was reported to be 49.5–56.5 °C. These polymers have demonstrated potential in temperature-dependent chromatographic separations of peptides and proteins from aqueous mobile phases [111] l- and dl-forms of poly(N-(1-hydroxymethyl)propylmethacrylamide) (PHMPMAAm) have also been reported to be temperature-responsive [112,113,114, 159]. Several other novel thermoresponsive poly(N-alkylacrylamide)s have also been studied, including poly[N-(2,2-dimethyl-1,3-dioxolane)-methyl] acrylamide (PDMDOMAAm) (Table 6.1) [115], which exhibited a cloud point around 23 °C in water. Interestingly, this transition temperature can be easily tuned within the temperature ranges of 23–49 °C by the controlled degree of cleavage of the pendant dioxalane groups to form hydrophilic diol monomer units (Table 6.1). More recently, the same group tried to control precisely the LCST of poly(N-alkylacrylamide)s-based homopolymers and block copolymers by using controlled radical polymerization techniques such as RAFT or ATRP which allow one to obtain nearly the same structure sequence and length for each chain in the polymer sample [146, 160]. For instance, a detailed study on poly(N-alkylacrylamide)s family by tuning the N-alkyl substitution group has been conducted by Cao et al. [160]. They showed that the bulkier the N-alkyl substituent, the lower was the LCST, which can be understood by the enhancement of hydrophobic interactions between the polymer chains.

2.1.1.2 Poly(alkylene oxide)-Based Nanostructures

Poly(ethylene oxide) (PEO) is the most famous and widely studied members in poly(alkylene oxide) family, which is also known as poly(ethylene glycol) (PEG) for those of small molecular weights (below 10,000 Da). PEO is the simplest water soluble polymer. Its chemical structure (CH₂CH₂O)_n contains the right balance between hydrophobic and hydrophilic moieties, which allows PEO chains to be soluble in water in awide range of temperature and concentration. The LCST of PEO is above 100 °C for low molecular weight chains, e.g., LCST of 2000 Da PEO being 170–180 °C; it decreases to 100 °C with the molecular weight of M _n = 106 Da [161]. Another important member of this family is poly(propylene oxide) (PPO) [or poly(propylene glycol) (PPG)] which is also a well-known for its thermoresponsive behavior [56, 162]. In fact, a variety of copolymers consisting of different PEG and PPO compositions are commercially available under the names Pluronics, Poloxamers, and Tetronics [163]. Thermoresponsive polymers with significant PEG content have gained attention particularly from a biomedical perspective, because of their low toxicity/immunogenicity and high biocompatibility.

A wide varieties of shell-crosslinked (SCL) micelles have been reported from various PEG and PPO-based block copolymers [164, 165]. Shell-crosslinked (SCL) micelles with hydroxy-functional coronas have also been constructed in aqueous solution by exploiting the micellar self-assembly behavior of a new thermoresponsive ABC-type triblock copolymer, PPO-b-poly(dimethyl amino ethyl methacrylate)-b-poly(glycerol monomethacrylate)(PPO-b-PDMAEMA-b-PGMA), prepared via ATRP. The PDMAEMA block was crosslinked using 1,2-bis(2-iodoethoxy)-ethane. To create the SCL micelles, the solutions were heated to above the thermal transition of PPO, followed by the crosslinking of the PDMAEMA block. The size of the resulting SCL micelles could be controlled by changing the temperatures at which crosslinking occurs [165]. Further, Li et al. [164] demonstrated the formation of SCL micelle fromPEG-b-poly[(N,N-dimethylacrylamide)-stat-(N-acryloxysuccinimide)]-b-PNIPAAm, [PEG-b-P(DMA-stat-NAS)-b-PNIPAM], where the NAS block was crosslinked using cystamine. They showed by DLS that the SCL micelles increased in size upon cooling due to the swelling of the PEG core (Fig. 6.5).

Furthermore, thermoresponsive polymer nanoshells were generated by shell-crosslinking of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) dimethacrylate triblocks [166]. The PPO blocks aggregated, upon heating to 50 °C, leaving a methacrylate-functionalized PEG corona. Once cooled, the crosslinked triblock copolymers expanded to create a solvated nanoshell. Rank et al. have studied the formation of polymersomes made up of poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) block copolymer [167]. They reported that vesicles with a bilayer membrane of P2VP-b-PEO were formed spontaneously in aqueous solutions by polymer film hydration. Interestingly, the authors reported a cylinder to vesicle shape transition when the vesicles were subjected to a specific cooling/warming process. Upon cooling the vesicles to 4 °C, there was a transition from the vesicular structure to basket-like aggregates, which further disintegrate into worm-like micelles (Fig. 6.6). Warming back the suspension to 25 °C results in the recovery of unilamellar and almost monodisperse vesicles via intermediate discoid- and octopus-like structures. The reason for this thermoresponsive behavior lies in the temperature-dependent solubility of the PEO block. Upon warming, the solubility of PEO in water decreases and consequently the volume of the water-swollen PEO layer decreases. This reduces the interfacial area at the hydrophilic–hydrophobic interface.

In a pioneering work of Grubbs et al., an amphiphilic ABC triblock poly(ethylene oxide)-b-poly(ethylene oxide-stat-butylene oxide)-b-poly(isoprene) (E-BE-I) copolymers of varying compositions with narrow molecular weight distributions have been synthesized by the combination of sequential living anionic and controlled nitroxide-mediated radical polymerizations [168]. These block copolymers self-assembled into spherical micelles at room temperature which transformed to vesicles (polymersomes) at elevated temperatures as detected by them via DLS and TEM studies, for both with and without crosslinking of polymer assemblies (Fig. 6.7). The rate of transformation with E-BE-I systems is more rapid than that observed for poly(ethylene oxide)-b-poly(isoprene) assemblies reported earlier by the same group, suggesting that inter-chain hydrogen bonding of responsive blocks after dehydration plays an important role in the kinetics of aggregate rearrangement [169]. These results demonstrate that incorporation of a thermoresponsive block into an amphiphilic block copolymer results in discrete hydrophobic/hydrophilic volume ratios above and below the LCST of the thermoresponsive block, thus allowing the polymer assembly to be switched between large and small aggregates as a function of temperature.

“Schizophrenic” thermoresponsive copolymers are a special class polymer designed as double thermoresponsive polymers. Typically, one block possesses a LCST while the other displays an UCST. It has been reported that poly(acrylamide-co-acrylonitrile) poly(AAm-co-AN) block copolymer is one of the rare examples of uncharged polymers showing a UCST-type single phase transition in water and physiological medium, which was discussed later [136]. However, Agarwal et al. cleverly combined this poly(AAm-co-AN) block copolymer with PEG-based macro-azoinitiator to prepare a Schizophrenic” thermoresponsive copolymer using a simple conventional radical polymerization [170]. The copolymer showed dual thermoresponsivity of LCST- and UCST-type of transition in one system as investigated by turbidity and light scattering measurements in aqueous solution. The phase transition behavior and transition temperatures were found to depend on the PEG block length, polymer concentration, and ratio of AAm and AN monomers. The temperature-dependent change in the morphology from micelles to agglomerates and back to micelles was observed and correlating well with the phase transition behavior.

Poly(2-alklyl-2-oxazoline)- and Poly(2-oxazines)-Based Polymer Nanostructures

Poly(2-alkyl-2-oxazoline)s are another class of thermoresponsive polymers that are synthesized via living cationic ring-opening polymerization (CROP). Poly(alkyl oxazoline)s (PAOxs) (Fig. 6.8) are considered as pseudopolypepide and are being developed as alternatives to the famous water soluble thermosensitive polymers, PEG and PNIPAAm, for biological applications [80, 171]. The major disadvantage of PNIPAAm is the strong hysteresis during the thermal transition as discussed above, which makes PAOxs an interesting material for applications where the precipitation event is exploited [35]. In contrast, PAOxs show a LCST-type transition without hysteresis, which makes them more suitable for all applications (e.g., smart surfaces, thermoresponsive micelles) [80, 171]. Among the various PAOxs, poly(2-ethyl-2-oxazoline)(PEtOx) [122], poly(2-isopropyl-2-oxazoline) (PIPOx) [123, 124], and poly(2-n-propyl-2-oxazoline) (PnPOx) [125] are known to exhibit a thermal transitions in aqueous solution. PIPOx is another structural isomer of PNIPAM that exhibits a cloud point of approximately near 36 °C in aqueous solution, and the transition can be tuned by the addition of sodium chloride or surfactant [123, 124]. In these reports, they have also compared the thermoresponsiveness of PIPOx with that of PNIPAAm [123] PEOx, an isomer of poly(N,N-dimethylacrylamide) (PDMAAm) [172], that showed a LCST-type phase behavior approximately at around 62–65 °C in aqueous solution [122] Schubert, Hoogenboom, and coworkers reported a series of PEtOx-based thermoresponsive comb- and graft-shaped polymers from poly[oligo(2-ethyl-2-oxazoline) methacrylate]s (POEtOxMA) [126]. First, they have synthesized well-defined OEtOxMA macromonomers via CROP and subsequently homopolymerized and copolymerized with methyl methacrylate using RAFT polymerization to make such comb and graft polymers. It was observed that the LCST behaviors of the aqueous solutions of these polymers was dependent on the copolymer composition and could be tuned by varying the PMMA block composition. Rueda et al. have developed a doubly thermoresponsive polymer system by grafting PEtOx from a modified PNIPAAm backbone [173].

As discussed above, there have been many reports of studies of thermoresponsive behaviors of PAOxs and its copolymers. However, there were only very few reports that dealt with the thermoresponsive nanostructures made up of PAOxs- and PAOxs-based copolymers. In early 2000, a novel series of temperature- and pH-sensitive hydrogels based on poly(2-ethyl-2-oxazoline) and three-arm poly(d,l-lactide) were reported by Wang et al. The gel polymeric networks were prepared via photocopolymerization of two types of macromonomers, namely poly(2-ethyl-2-oxazoline) dimethacrylate and three-arm poly(d,l-lactide) trimethacrylate. As analyzed through SEM, the porous hydrogel network was composed of interconnected nanosized gel particles resulting in a material of high water retention capacity and exhibited reversible swelling–shrinking behavior in response to temperature and pH variations. According to them, these PEtOx-containing hydrogels are biodegradable and can be used as a potential thermoresponsive biomaterial [174].

In another study, Halacheva et al. have prepared a series well-defined, sparsely grafted, comb-like linear poly(ethylene imine)/poly(2-ethyl-2-oxazoline) (LPEI-comb-PEtOx) polymers with various degrees of polymerization [175]. Their aqueous solution properties were investigated by means of dynamic light scattering (DLS) and small-angle neutron scattering (SANS) over a temperature range of 25–65 °C. It has shown that the LPEI-comb-PEtOx polymer formed particles with typically bimodal distributions and featured smoother temperature variations in aqueous solution. They have also studied the shape and structure evolution of the small LPEI-comb-PEtOx aggregates (average radius ∼6 nm) with temperature. A variety of structures such as elongated aggregates, spherical core–shell were observed, depending upon the polymer composition and grafting densities of PEtOx [175].

2.1.1.3 Lactam/Pyrrolidone/Pyrrolidine-Based Polymers

Poly(N-vinylcaprolactam) (PVCL), poly(N-vinylpyrrolidone) (PVPy), and poly(vinylpyrrolidine) (PNVP) are the another few important non-ionic polymers which also exhibit thermoresponsiveness in aqueous solution. Therefore, it is important to include the discussion of their thermoresponsive properties in this chapter, although to the best of our knowledge there are no such reports formation of responsive nanostructures such as micelles based on these polymers. PVCL contains a seven-membered lactam ring with a repeat unit consisting of a hydrophilic heterocyclic amide ring, and it is water soluble and biocompatible exhibiting a LCST-type thermal transition around 32 °C as reported by Lau et al. and Tager et al. [127, 128]. PVCL. Apart from these properties, of potential interest for biomedical applications, PVCL offers benefits of low toxicity, water and organic solubility, high complexing ability, and good film-forming properties [129, 176,177,178]. A similar macromolecule, poly(N-vinylpyrrolidone) (PVPy), contains a five-membered lactam ring, as compared to PVCL seven-membered ring, it did not show any LCST in water. However, it exhibited LCST behavior in solutions containing a large amount of salt [129]. Maeda et al. found PVPy underwent a phase separation around 30 °C in aqueous 1.5 M potassium fluoride. Furthermore, poly[N-(2-methacryloyloxyethyl) pyrrolidone] (PNMP), a well-defined pyrrolidone-based polymer also exhibited a sharp LCST-type phase separation at 52 °C in water [130]. Poly(N-ethylpyrrolidinemethacrylate) (PEPyM), the pyrollidine analog of PNMP, exhibited a LCST-type cloud point in water at 15 °C [131]. They have shown that the LCST cloud point could be tuned up to 80 °C by copolymerizing PEPyM with a hydrophilic monomer, such as N,N-dimethylacrylamide (DMAM). Laschewsky and coworkers have synthesized thermoresponsive poly(N-acryloylpyrrolidine) (PAPR) via RAFT polymerization, with PAPR exhibiting a LCST-typecloud point at 51 °C [121].

2.1.1.4 Poly(aminoalkyl methacrylate)-Based Nanostructures

Poly(aminoalkyl methacrylate)s (see Table 6.1) represent a class of weak polybases, is another example of a temperature-responsive polymer, which has been studied extensively by many research groups recently [132, 133, 179,180,181,182,183,184]. One of the most renown members of this family is poly((N,N-dimethylamino)ethylmethacrylate) (PDMAEMA), which is also known for its LCST-type phase transition behavior in alkaline medium, since the tertiaryamine moieties can hydrogen-bond with water, while the gemini methyl groups exert hydrophobic effects. The amine functional group in the monomer is sensitive to pH and gets protonated below its pKa (between 7 and 10 depending on the substituents). This protonation, in turn, influences the polymer LCST: it delays the collapse of polymer chains during heating by increasing intra- and inter-chains repulsive electrostatic forces. As a consequence, a higher pH value promotes a lower cloud point. The reported cloud point of PDMAEMA ranges from 14 to 50 °C in pure water, depending on its molecular weight and other parameters [132, 133, 179,180,181,182,183,184].

Schubert and his coworkers utilized RAFT polymerization technique to prepare a series of statistical random copolymers of varying compositions by polymerizing N,N-(dimethylamino)ethyl methacrylate (DMAEMA) and poly(ethylene glycol) methyl ether methacrylate (PEGMA) monomers at 70 °C. The phase behavior of the pH- and temperature-sensitive copolymers was studied in aqueous solution by measuring the LCST-type transition by UV/vis spectroscopy. The measurements were performed at three different pH values (4, 7, and 10). At pH 7 and pH 10, it has been observed that the LCST linearly increased with the wt% of PEGMA in the copolymer feed. On the contrary, at pH 4, the hydrophilicity of the P(DMAEMA-stat-PEGMA) copolymers is too high due to the protonation of the DMAEMA units. Thus, no LCST has been detected for most of them. By varying the pH and the composition of the P(DMAEMA-stat-PEGMA) copolymers, the LCST can be easily tuned between 34.7 and 82.0 °C [183].

In another work, poly[2-(dimethylamino)ethyl methacrylate]-b-poly(glutamic acid) (PDMAEMA-b-PGA) double-hydrophilic block copolymers (DHBCs) can be readily synthesized from poly(γ-benzyl-l-glutamate)-b-poly[2-(dimethylamino)ethyl methacrylate] amphiphilic block copolymer precursors through alkali hydrolysis. Self-assembly in water of these PDMAEMA-b-PGA (DHBCs) can be selectively triggered by a variation of either the pH or the temperature [185]. Such doubly responsive DHBCs self-assembled into nanostructures of either electrostatic polymersomes or spherical polymeric micelles, depending on the pH of the solution and temperature (Fig. 6.9). The resulting morphologies also depend on the overall composition of the DHBCs. According to them, for pH values below and above the isoelectric point (IEP), the DHBCs behave as unimers owing to the high solubility of the PDMAEMA block. Close to the IEP, direct or inverse electrostatic polymersomes were generated by electrostatic interactions developing between the two charged blocks driving the formation of the hydrophobic membrane of the polymersomes, which was stabilized in water by uncompensated charges. The thermosensitivity of the DHBCs relates to the LCST behavior of PDMAEMA around 40 °C. Thus, at pH = 11 and below the LCST of PDMAEMA, free chains of DHBC unimers are evidenced, while above the LCST, the hydrophobicity of PDMAEMA drives the self-assembly of the DHBCs in a reversible manner. In this case, spherical polymeric micelles or polymersomes were observed, depending on the PGA block length.

Muller and coworkers studied the aqueous solution phase behavior of both star-shaped and linear PDMAEMA and showed that the cloud point can be readily tuned by changing the pH of the solution, molecular weight, and the concentration of the polymer [133]. Furthermore, a dual thermo- and photoresponsive densely grafted molecular brushes have been prepared from DMAEMA monomer and trans-4-methacryloyloxyazobenzene (MOAB), a monomer containing a light-sensitive azobenzene group using successive ATRP technique. Incorporation of these two monomers allowed for control of the temperature-responsive behavior by photoirradiation [186]. The copolymer brush with trans-azobenzene units demonstrated LCST-type phase transition behavior, while the less hydrophobic cis-azobenzene isomer did not respond within the examined temperature range.

Since PDMAEMA itself could be deemed as a weak polyelectrolyte to a certain extent, the effect of pH and ionic strength of aqueous media may impose significant influence on the phase transition of its aqueous solution. Therefore, the aqueous PDMAEMA systems might exhibit a multidimensional stimuli-responsive behavior. Moreover, the amines of PDMAEMA could undergo N-alkylation (quaternization or betainization), to result in cationic polyelectrolytes or zwitterionic polybetaines, respectively. The final ionic polymers also exhibited a different stimuli-responsive phase transition behavior which will be discussed later in the other Sect. 6.2.2.1 of this chapter.

2.1.1.5 POSS-Based Polymer Nanostructures

Polyhedral oligomeric silsesquioxane (POSS) has attracted a great deal of attention because of the unique nanoscale cage-shaped structure and good solubility in organic solvents [187]. Thus, POSS can be easily incorporated into polymeric matrices to prepare novel polymer hybrids by physical blending or chemical modification through copolymerization with POSS-based vinyl monomers or growing of polymer from POSSend-functionalized initiator [188,189,190,191,192,193]. Some novel POSS-containing polymers with well-defined structures have been synthesized using living/controlled radical polymerization techniques, and the self-assembly behavior of these hybrid polymers has also been attracted great attention. The self-assembly behavior of POSS-containing block copolymers is quite dependent on the rigidity of POSS blocks, strong intra-chain association, and their miscibility with organic sub-chains. Thus, the self-assembly behavior of POSS-containing hybrid block copolymers could be modulated by controlling the nature of the inorganic sub-chains, the architecture of the block copolymers and the types of organic polymer blocks connected to the POSS block, which may create a variety of nanostructures. These POSS-based nanostructures can exhibit stimuli (temperature, pH, light, etc.)-responsiveness if some responsive functional groups are present in the organic polymer block.

For example, Zheng et al. have reported the synthesis of organic-inorganic, amphiphilic ABC–type triblock copolymer PEO-b-poly(MA-POSS)-b-PNIPAAm triblock copolymers via ATRP. The hybrid triblock copolymers PEO-b-P(MA-POSS)-b-PNIPAAm were composed of one highly hydrophobic mid block (i.e., P(MA-POSS)) and two water soluble end blocks (viz., PEO and PNIPAAm blocks). Furthermore, the PNIPAAm block is thermoresponsive and is capable of undergoing the coil-to-globule transition with a change in temperature. The hybrid triblock copolymers were microphase-separated above LCST. Both TEM and DLS showed that all the triblock copolymers can be self-organized into micellar aggregates in aqueous solutions. The sizes of the micellar aggregates can be modulated by changing the temperature [194].

Zhang et al. synthesized tadpole-shaped hybrid PNIPAAm using a POSS-containing RAFT agent [195]. The tadpole-shaped POSS-PNIPAAm hybrid self-assembled into core–shell nanostructured micelles with uniform diameter. Furthermore, an amphiphilic fluorescent polymer containing asymmetric perylenebisimide was designed and synthesized by combining reaction of perylene anhydride with amino functional POSS and ATRP of NIPAAm [196]. The self-assembly of this amphiphilic POSS-polymer hybrid into hybrid nanoparticles in aqueous solution was investigated by DLS and TEM. The hybrid nanoparticles exhibited attractive high red fluorescence at 645 nm due to the significant effect of the bulky POSS moieties. Moreover, based on the thermoresponsive PNIPAAm coronas, the fluorescence intensity of the self-assembled hybrid nanoparticles can be further enhanced and tuned by changing temperature (Fig. 6.10).

2.1.2 Non-ionic UCST-Type Polymers

Non-ionic polymers showing an upper critical solution temperature (UCST) in water are rare. Hence, it is really hard to find any nanostructures (e.g., miclelles, vesicles) made up of polymers that exhibit UCST-type thermoresponsiveness in aqueous solution. But, it is worthy to discuss the polymeric system that exhibits UCST-type transition as these UCST-type polymers exists as nanosized globules or nanogels in aqueous solution below a particular temperature. In this context, recently, the non-ionic homopolymer, poly(N-acryloyl glycinamide) (poly(NAGA)), has been shown to exhibit a sharp UCST-type transition in pure water as well as in electrolyte solution [136, 197]. Although, the polymer poly(NAGA) is known for decades and was first synthesized by Haas and Schuler in 1964 [198], but the UCST behavior had not been reported earlier. They only observed a gelatin-like thermoreversible gelation of concentrated aqueous solutions.

In further studies, they concluded that the gelation is based on physical crosslinking by hydrogen bonding [199, 200]. However, in the aforementioned publications, no UCST behavior was reported until Agarwal et al. reported such property of this polymer in 2010 [88]. Failure to notice the UCST-type transition in the past by Hass et al. was because ionic groups have been introduced unintentionally by either acrylate impurities in the monomer, hydrolysis of the polymer side chains, and/or usage of ionic initiators or chain transfer agents. The presence of traces of ionic groups in the polymer prevented phase separation. The proof for these conclusions along with a procedure to obtain stable aqueous solutions of non-ionic poly(NAGA) so that the UCST behavior can be exploited in pure water as well as in physiological milieu was recently published by the same group [201]. The UCST phase transition temperature of a 1 wt% aqueous solution of poly(NAGA) is about 22 °C.

Not only poly(NAGA) homopolymer, but also its copolymer, poly(acrylamide-co-acrylonitrile), exhibited a UCST as demonstrated by Agarwal and coworkers [136]. Controlled increase of the UCST by copolymerization of acrylamide with varying amounts of acrylonitrile was shown, and it could be varied between 6 and 60 °C. The hysteresis between the cloud point upon cooling and heating was very small with only 1–2 °C in most cases. The cloud points of these polymers in pure water were similar to that measured in phosphate buffered saline solution.

Maruyama et al. demonstrated that polymers with ureido groups undergo UCST-type phase transitions under physiologically relevant conditions [202]. Poly(allylurea) copolymers showed UCST-type behavior at pH 7.5 in 150 mM NaCl even at the low polymer concentration of 0.13 mg/mL. Their phase separation temperatures could be controlled up to 65 °C. Similar thermosensitivity was also observed by them with copolypeptides consisting of L-citrulline having an ureido group.

2.1.3 Polymer Nanostructures in Water-Alcohol Cosolvent System

Ethanol/water solvent mixtures are environmentally friendly solvents that exhibit interesting abnormal properties due to the presence of hydration shells around the ethanol molecules [203, 204]. The addition of cosolvent or co-nonsolvent also strongly influences the thermoresponsive behavior of a polymer. Here, we describe few polymeric system that exhibits some abnormal responsive behavior in cosolvent system, which has been recently reviewed by Zhang and Hoogenboom [205]. Poly(methyl methacrylate) (PMMA) is insoluble in both water and ethanol at ambient temperature, although a UCST-type transition was reported for PMMA in pure methanol as well as in pure ethanol at ∼87 °C or above [206]. The polymer, however, showed a decreased in its UCST when adding water to the alcohol [207,208,209,210,211]. UCST behavior of PMMA in other lower aliphatic alcohols, e.g., methanol, 1-propanol, 2-propanol, and t-butanol has also been reported, exhibiting increased solubility, i.e., lower cloud point, with increasing size of the alkyl group [207, 208]. Due to the structural similarity of poly(methyl acrylate) (PMA) and PMMA, it is not surprising that PMA also exhibits a UCST transition in ethanol/water solvent mixtures [212]. Thermoresponsive micelles were then obtained in ethanol/water solvent mixtures for polystyrene-b-PMA (PS-b-PMA) block copolymers of various compositions above the UCST of PMA.

It was shown by DLS and TEM that these block copolymer micelles transformed into thermoresponsive micellar aggregates when the solution was cooled below the UCST transition temperature of the PMA block (Fig. 6.11a). But, the temperature above UCST, the micellar aggregates dissociated into unit micelles. It was further shown in another study that the double hydrophobic block copolymer, PS₈₈-b-PMMA₈₀ was self-assembled into micelle in an ethanol/water solvent mixture containing 80 vol% of ethanol [209]. At a polymer concentration below 0.2 wt%, spherical unit micelles were obtained from BCP with equal block sizes due to the relatively large radius of gyration (Rg) of the fully hydrated PMMA chains as shown by small-angle neutron scattering (SANS) study. A thermoresponsive micellar gel was formed by a polymer concentration of 1 wt%, ascribed to the large Rg of the PMMA block facilitating interactions between the formed unit micelles (Fig. 6.11b).

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) having short side chains are either totally soluble or show LCST-type phase transition in pure water or in ethanol/water solvent mixtures. However, extending the hydrophobic side chain length to a butyl group induces UCST-type phase behavior depending on the content of ethanol in the mixture [213]. The amount of ethanol required to induce a UCST-type transition increased with increasing hydrophobicity of the polymer side chains. Furthermore, PAOx with aromatic substituents, PPhOx, and PBnOx also exhibited UCST-type behavior in ethanol/water mixture [213]. The higher hydrophobicity of the PBnOx is clearly evidenced by the higher UCST cloud points as well as a clear shift in the transition temperature with higher ethanol content. Solution phase behavior of the BCPs, PMeOx-b-PPhOx, and EtOx-b-PhOx showed that both of the two series of copolymers exhibit UCST behavior at high content of PPhOx block in ethanol/water mixture with high content of ethanol [214]. The solubility maxima of those copolymers occurred at an ethanol content of around 80 wt%. In addition, a remarkable observation was made for the PEtOx₅₀–PPhOx₅₀ copolymer in an aqueous solution with 40 wt% ethanol content showing both a LCST and a subsequent UCST, so-called closed-loop coexistence (Fig. 6.12).

Furthermore, Fustin et al. have been reported the pathway-dependent micellization behavior of tri- and tetra block copoly(2-oxazoline)s composed of solvophilic PEtOx and/or PMeOx blocks and a solvophobic poly(2-nonyl-2-oxazoline) (PNonOx) block, as well as a PPhOx block, of which the solubility can be switched from solvophilic in ethanol/water mixture with 60 wt% of ethanol to solvophobic in ethanol/water mixture with 40 wt% of ethanol [215]. They claimed that the size and morphology of the self-assembled nanostructures can be tuned depend on the solvophobic content of the copolymers and the block order as well as the solvent composition. In particular, triblock copolymer (MPN) containing PMeOx, PPhOx, and PNonOx blocks form spherical micelles together with larger, irregularly shaped, nanoaggregates in ethanol/water (60/40) mixture, while coexistence of spherical micelles and cylindrical micelles was observed in ethanol/water (40/60) mixture. Interestingly, dilution with water of the MPN micellar solution in ethanol/water (60/40) to (40/60) resulted in a collapse of the PPhOx block onto the PNonOx core leading to a core–shell structure indicating a pathway-dependent self-assembly behavior (Fig. 6.13).

2.2 Ionic Polymer Nanostructures

Not only non-ionic polymer but also some polymers carrying ionic functional groups, namely ionic polymers also shows response toward external stimuli such as temperature, pressure, ionic strength of solution, light, redox. Ionic water soluble polymers are a diverse class of polymers, ranging from biopolymers such as nucleic acids and proteins that mediate life processes to commercial polymers with applications in water remediation, drag reduction, and formulation of pharmaceutics, cosmetics, and coatings. Charged polymers can be arbitrarily divided into two classes: polyelectrolytes and polyzwitterions. The former have ionizable functional groups that are either anionic or cationic in nature. The charges may be along or pendent to the macromolecular backbone, and charges are balanced by small counterions. Zwitterionic polymers have both cationic and anionic charges along or pendant to the backbone and they are charge-neutral. Polymers containing cationic and anionic functionality on different monomer units are designated as polyampholytes while those having both charges on a single monomer unit are called polybetaines [216]. Because of their zwitterionic character, these ionic polymers exhibit markedly different behavior than polyelectrolytes in aqueous solutions [217,218,219]. The charge–charge repulsions along the polyion backbone resulting from counter ion mobility are responsible for chain extension and the large hydrodynamic volume of polyelectrolytes in water at low ionic strength.

However, polyelectrolytes usually exhibit decreases in the hydrodynamic volume and solution viscosity upon the addition of electrolytes such as inorganic salts. This polyelectrolytes effect is due to conformational changes that occur when the added electrolytes shield the electrostatic repulsions of like charges along the polymer chain, causing the polymer coils to contract [220]. On the other hand, polymers with charge balance, trend to adopt collapsed or globular conformations in salt-free solution because of the electrostatic attractions between opposite charges [219, 221, 222]. Indeed, the electrostatic associations are so strong among polyzwitterion molecules that it may phase-separate in solution even in the absence of low MW electrolytes such as inorganic salts. However, as simple electrolytes are added to polyzwitterions solution, the electrostatic interactions are shielded, and the polyzwitterions can adopt random-coil conformations, called the “antipolyelectrolyte effect.” The globule-to-coil transition that occurs upon the addition of electrolytes results in increased polymer hydrodynamic volume and solution viscosity [219, 223, 224]. Many factors govern the solution properties of polyzwitterions, including the charge density, charge asymmetry (i.e., degree of charge imbalance), and chemical properties of the ionizable groups [219, 225, 226]. The polyzwitterions solubility and magnitude of the globule-to-coil transition (i.e., change in the hydrodynamic size) exhibited by polyzwitterions are typically determined by the charge density of the system. As the polyzwitterion charge density increases, greater concentrations of electrolytes are required to promote coil expansion and the relative increase in the hydrodynamic size upon electrolyte addition tends to be greater. Unbalanced polyzwitterions (i.e., polyzwitterions with a net charge) usually exhibit a combination of polyzwitterions and polyelectrolytes solution behavior according to the degree of charge imbalance. Polyzwitterions generally tend to exhibit behavior more characteristic of conventional polyelectrolytes with increasing charge asymmetry. For polyzwitterions bearing weakly acidic and/or weakly basic functional groups (i.e., carboxylic acids and/or tertiary amines), the charge density and charge asymmetry are dominated by the level of functional group incorporation and the solution pH. Thus, reversible transitions between polyelectrolytes and polyzwitterions behavior can be triggered by changes in the solution pH. Further, polybetaines have been classified as polycarboxybetaines, polyphosphobetaines and polysulfobetaines (Fig. 6.14).

Another important member in the family of ionic polymers is the poly(ionic liquid)s (PILs) or polymerized ionic liquids (ILs), which is referred to a subclass of polyelectrolytes that feature an IL species in each monomer repeating unit, connected through a polymeric backbone to form a macromolecular architecture. Some of the unique properties of ILs are incorporated into the polymer chains, giving rise to a new class of polymeric materials. PILs expand the properties and applications of ILs and common polyelectrolytes. As an emerging interdisciplinary topic among polymer chemistry and physics, materials science, catalysis, separation, analytical chemistry, and electrochemistry, PILs are attracting increasing interest among the scientific community [227].

2.2.1 Zwitterionic Polymer Nanostructures

Zwitterionic polymers such as carboxybetaine methacrylate (CBMA), sulfobetaine methacrylate (SBMA), and phosphorylcholine-based polymers have been widely utilized as superhydrophilic and ultra-low fouling biomaterials [228, 229]. It is known that commercially available low fouling non-ionic PEG resists non-specific protein adsorption via hydration forces, which are formed via hydrogen bonding between water molecules and PEG [230]. Zwitterionic materials, with their strong intra- and inter-molecular electrostatic interactions, can bind water molecules strongly and form electrostatically induced hydration [231,232,233], which resists non-specific protein adsorption over a long period. Polyzwitterions, specifically polysulfobetaines usually exhibit a UCST-type phase transition, i.e., they are water-insoluble at lower temperature due to the electrostatic attraction. Zwitterionic moieties can form associations through the electrostatic interactions between the cationic and anionic groups. Heating promotes the water molecules to diffuse into the network, leading to the disruption of the network at a critical temperature. As a result, the solution undergoes an emulsion–dissolution phase transition. Chang and coworkers reported a detailed investigation of solution properties of zwitterionic poly(sulfobetaine methacrylate)s (polySBMAs) [234].

It has been reported that the aqueous solution of polySBMAs exhibited an UCST-type transition that is attributed to the charge–charge or dipole–dipole interactions among the zwitterionic sulfobetaine groups [89, 235, 236]. The insoluble–soluble phase transition of polySBMA in aqueous solution was due to inter-molecular associations and dissociation of polyzwitterion molecules, which depend strongly on the stimuli-responsive control of solution pH and ionic strength (Fig. 6.15). It has been found that polySBMAs of increasing molecular weights had enhanced mutual intra- and inter-chain associations of the sulfobetaine groups in aqueous solution, resulting in the increase of their UCST-type cloud point associated with the non-fouling nature of polySBMA’s suspension.

Afterwards, Laschewsky and coworkers reported a block copolymer consisting two hydrophilic blocks, PNIPAAm, and the zwitterionic Poly (3-[N-(3-methacrylamidopropyl)-N,N dimethyl] ammoniopropane sulfonate) (PSPP) exhibiting double thermoresponsive behavior in water. This BCP formed PNIPAAm-cored micelles above the LCST of PNIPAAm (29–35 °C) and PSPP-cored micelles below the UCST of PSPP (8–20 °C) (Fig. 6.16) [134].

Sulfobetaines derived from acrylamide and methacrylates are two of the prominently used monomers for making a wide variety of zwitterionic polymers [237, 238]. However, these monomers are hydrolytically unstable [239]. To overcome such difficulty, Vasantha et al. reported a hydrolytically stable vinyl benzene substituted imidazole-based sulfobetaine-type zwitterionic polymers. These imidazole-based polysulfobetaines exhibited many unusual solubility characteristics. Unlike the acrylate and acrylamide-derived polysulfobetaines which were soluble in water, the benzimidazole-based polysulfobetaines were only soluble in concentrated brine solution (22.6 wt% NaCl) and also swell in deionized water. Further, they exhibited reversible phase transitions due to the formation of expanded chains at elevated temperature and aggregates below the UCST cloud point as studied by DLS, turbidity, and viscosity measurements. The unique thermoreversible gelling properties as well as unusual solubility characteristics make them interesting materials for a wide range of applications.

Shao and coworkers compared thermo- and salt-responsive behaviors of sulfobetaine and carboxybetaine polymers by examining their rheological properties as a function of temperature and their hydrodynamic sizes as a function of salt concentration [240]. In this work, they investigated the structure and dynamics of associations among cationic and anionic groups present in these two zwitterionic polymers. Results showed that the difference in the charge density of cationic and anionic groups of zwitterionic moieties dictates associations among moieties: the less difference results in more and stronger associations. These different interaction behaviors lead to the diversified properties of zwitterionic materials. Thus, carboxybetaine polymers do not exhibit stimuli responses as expected from the antipolyelectrolyte behavior of zwitterionic polymers as observed in sulfobetaine polymers.

Zhao et al. [241] also observed similar phenomenon in their work. In their work, they copolymerized temperature-responsive NIPAAm monomer with zwitterionic monomers, carboxybetaine methacrylate (CBMA) and sulfobetaine methacrylate (SBMA), and synthesized the statistical copolymers, poly(NIPAAm-co-CBMA) and poly(NIPAAm-co-SBMA), respectively. Above the LCST of PNIPAAm, a clear sol–gel transition was observed, accompanied by an increase in the turbidity and elastic modulus of the copolymer solution. The hydrophilic sulfobetaine group present in the PSBMA block was strongly influenced by elevated temperatures, which counter affected the thermal properties in the pure PNIPAAm-based polymer at temperatures higher than its LCST. While the carboxybetaine group in PCBMA is weakly affected by temperatures, poly(NIPAAm-co-CBMA) solution is able to preserve its thermoresponsive nature. In addition, CBMA moiety acted as stronger ionic bridges in poly(NIPAAm-co-CBMA) to form reinforced elastic networks with superior recovery features when compared with poly(NIPAAm-co-SBMA). Thus, incorporation of PCBMA block with the thermoresponsive PNIPAAm provides a tractable and facile way to introduce non-fouling property with thermoresponsive characters, without compromising with the mechanical properties.

Further, zwitterionic polymers have been investigated as surface coating materials due to their low protein adsorption properties, which reduce immunogenicity, biofouling, and bacterial adsorption of coated materials. Most zwitterionic polymers, reported so far, are based on (meth)acrylate polymers which can induce toxicity by residual monomers or amines produced by degradation. Jeong et al. [242] demonstrated a zwitterionic polymer consisting of phosphorylcholine (PC) and biocompatible poly(propylene glycol) (PPG) blocks as a new thermogelling material. The aqueous solution of PC-PPG-PC BCP undergone unique multiple sol–gel transitions with increasing temperature. A heat-induced unimer-to-micelle transition, changes in ionic interactions, and dehydration of PPG block are involved in the sol–gel transitions (Fig. 6.17). Based on the broad gel window and low protein adsorption properties, the PC-PPG-PC thermogel can be utilized for sustained delivery of protein drugs and stem cells over 1 week. Further, a novel triblock copolymer based on PPO, poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC), and PNIPAAm have also been synthesized via ATRP [243]. Two architectures were created: an ABC triblock and an ABA triblock copolymer, with the A-block being PPO, the B block being PMPC, and the C block being PNIPAAm. At reduced temperatures, all three blocks are water soluble, while PPO became insoluble between 15 and 31 °C, and the PNIPAAm block became insoluble above 31 °C. Between 15 and 31 °C, the PPO blocks aggregated creating micelles, and above 31 °C the PNIPAAm blocks aggregated creating a gel.

2.2.2 Poly(Ionic Liquid) Nanostructures

Yuan and Men and coworkers were the first to report an anionic PIL, poly(4-tetrabutylphosphonium styrene sulfonate) (PTPSS) exhibiting an LCST-type phase transition in aqueous solution [244]. Very interestingly, the experiments indicated that cloud point temperature can be shifted to either higher or lower temperature, depending on the type of the added foreign salts such as potassium bromide, tetrabutylphosphonium bromide (TPB), and the salt of TPSS monomer. This PIL also exhibited a very high stabilizing power for carbon nanostructures and can readily synthesize environment-sensitive graphene dispersion. The same group also discovered a new type of gemini PILs, poly[(1,8-octanediyl-bis(tri-n-butylphosphonium) 4-styrenesulfonate], synthesized via conventional free radical polymerization of a dicationic IL monomer in DMF [245]. This PIL presented a LCST-type phase transition in aqueous solution. Copolymerization of this gemini dicationic IL monomer with divinyl benzene crosslinker in water resulted in the formation of hydrogel, which exhibited a temperature-triggered volume change in water. Recently, the same group reported a cationic PIL, poly(tributyl-4-vinylbenzylphosphonium pentanesulfonate) that showed a similar LCST-type transition in aqueous solution [246]. This phase transition occurred in a wide temperature range in terms of PIL concentration as well as type and concentration of externally added salts. According to them, anion exchange and salting out effects are responsible for the flexible phase transition temperatures.

Very recently, we have discovered a new cationic phosphonium PIL, poly(triphenyl-4-vinylbenzylphosphonium chloride) (P[VBTP][Cl]), exhibiting responsiveness in water [247] RAFT polymerization technique have been employed to synthesize (P[VBTP][Cl])s of varying and controllable molecular weights (Fig. 6.18), which exhibited an UCST-type phase transition in aqueous solution in the presence of externally added halide ions. The addition of halide ions transformed the transparent aqueous PIL solution into a turbid two-phase solution, forming insoluble microgel aggregates (D = 2.5 µm) owing to the screening of the positively charged phosphonium groups of PILs and eventually forms intra- and/or inter-chain crosslinking among the PIL chains through halide ion bridges.

Further, this turbid solution exhibits a distinct UCST-type phase transition and transformed into a one-phase transparent solution due to the disruption of ion bridges upon heating (Fig. 6.19). The rate of aggregation of P[VBTP][Cl] increased sharply with an increase of the size of the added halide ions in this order I⁻ > Br⁻ > Cl⁻. The cloud point temperature increased linearly with increasing halide ion concentration as well as with increasing molecular weights of the PIL. The phase diagram of aqueous PIL solution shows the highest cloud point at 6 wt%. This PIL exhibits very good stabilizing ability for carbon nanotubes in water, whose dispersion state can be switched from dispersed to agglomerate and vice versa by adding halide ions and increasing the temperature, respectively. The crosslinked hydrogel of P[VBTP][Cl] also shows dual responsiveness toward both halide ions and temperature.

Tenhu and coworkers also observed UCST-type phase behaviors of imidazolium- and DMAEMA-based polycations in aqueous solution in the presence of both LiNTf₂ and NaCl salts [248]. Moreover, there are also some reports of amphiphilic block copolymers in the literature consisting of cationic/anionic polymer as one of the blocks. These block copolymers are able to self-assemble into a range of 3-dimensional morphologies in aqueous solution, whose characteristics and size can be readily tuned by the block copolymer’s chemical composition and physical properties [249, 250].

O’Reilly and coworkers reported a BCP containing charged end group can undergo a relatively fast and fully reversible transition between micelle and vesicle morphologies (Fig. 6.20) [99]. Initially, the diblock copolymer PMA₂₇-b-PNIPAAm₄₇ synthesized using sequential RAFT polymerization techniques employing a “head-group” functionalized RAFT CTA. Here, the block copolymer system studied employed a chain end functional charged “head-group,” to act as a permanently hydrophilic group to stabilize the structures when the block copolymer becomes completely hydrophobic above the LCST of the copolymer. Thus, at room temperature, the amphiphilic block copolymer formed micelle and above the LCST, vesicular morphology was created generating a tuneable and reversible morphology switching copolymer system.

Li et al. [251] explored the improved thermoresponsiveness of PNIPAAm hydrogels by using poly(sodium p-styrenesulfonate) (PSSNa), a strong anionic polyelectrolyte (i.e., a permanently water soluble polymer); PSSNa was incorporated into PNIPAAm network as the blocky sub-chains. To achieve this, a sequential RAFT polymerization approach was employed to access the blocked PNIPAM networks. The morphologies of BCP networks were studied by means of TEM and small-angle X-ray scattering (SAXS). The thermoresponsive properties of the hydrogels were examined in terms of swelling, deswelling, and reswelling tests. According to them, such improvement thermoresponse was attributable to the formation of the PSSNa nanophases, which promoted the transportation of water molecules into the crosslinked networks.

3 pH-Responsive Polymer Nanostructures

One other stimulus that has been explored extensively within the scientific community is the change of pH of the solution [36, 139, 252]. The incorporation of ionisable monomer units containing –COOH/–NH₂ into polymer backbones enables pH-dependent phase transitions and solubility changes. pH-responsive polymeric systems are polymers whose solubility, volume, configuration, and conformation can be reversibly manipulated by changes in external pH [253, 254]. The adjustment in pH alters the ionic interaction, hydrogen bonding, and hydrophobic interaction, resulting in a reversible microphase separation or self-organization phenomenon. pH-responsive polymers have drawn attention as an intelligent material, in drug delivery due to their abilities to sense changes and rapidly stimulate structural or morphological responses [139, 255]. Such pH-triggered delivery system could be achieved by the following: (a) incorporation of pH-responsive moiety to the polymer structure; (b) destabilization of self-assembled polymeric aggregates; or (c) chemical conjugation of pH-liable linkage between polymers and drugs [256, 257]. Herein, we categorized our discussion into two parts that based on pH-responsive non-ionic and ionic polymers.

3.1 Non-ionic Polymer Nanostructures

It is known that amphiphilic block copolymers, consisting of at least one block that is hydrophilic and at least one block that is hydrophobic, undergo self-assembly into polymeric nanostructurs in aqueous media to minimize the unfavorable interactions between the hydrophobic block and the surrounding water. Introduction of a pH-responsive functionality into an amphiphilic BCP capable of generating polymer nanostructures responsive to pH. The core–shell pH-responsive microgel particles containing PMMA core and poly(methacrylic acid-co-ethyl acrylate) P(MAA-co-EA) shell crosslinked with di-allyl phthalate (DAP) have been synthesized [258]. PMMA core was first synthesized through conventional seeded emulsion polymerization, and the second pre-emulsified monomers and small amounts of initiator were introduced slowly under monomer-starved feeding conditions to grow the pH-responsive shell layer.

Other systems, such as those composed of poly(methacrylic acid) (PMAA) and poly(N,N-diethylaminoethyl methacrylate) (PDEAM) chains, have recently been reported [259]. In contrast to the PMAA or poly(acrylic acid) (PAA) based systems, such latex was swellable at low pH due to the protonization of amino segments of PDEAM. Polymer scaffolds bearing activated ester pentafluorophenylacrylate (PFPA) groups were successfully synthesized by Doncom et al. utilizing RAFT method [260]. The PFPA groups were easily substituted with N,N-diisopropylethylenediamine and the RAFT end group modified with either a charged tertiary amine acrylate or triethylene glycolmethyl ether acrylate, to achieve pH-responsive block copolymers with the same backbone but different end-groups. These polymers were self-assembled into vesicles at basic pH to and there was a morphology transition to a micelle upon lowering the solution pH (Fig. 6.21). The large block copolymers took longer to stabilize after a morphology switch than the smaller block copolymers. In addition, the encapsulation and control release of a hydrophilic dye, Rhodamine B, was demonstrated.

In another study, a series of pH-sensitive micelles were generated from poly[(ethylene oxide)-b-glycerolmonomethacrylate-b-2-(diethylamino) ethylmethacrylate] P(PEO–GMA–DEA) and poly[(ethylene oxide)-b-2-hydroxyethyl methacrylate-b-2-(diethylamino)ethylmethacrylate] P(PEO–HEMA–DEA) triblock copolymers [261]. These triblock copolymers were synthesized via ATRP of GMA or HEMA followed by DEA monomers using a PEO-based macroinitiator. These copolymers were totally soluble in water at low pH but deprotonation of the DEA layers above pH 8 led to the formation of the three-layer micelles. At pH 8, the micelle contained DEA cores with GMA or HEMA innershells and PEO chains as the outer surface layer (corona). Selective crosslinking of the hydroxy-functional innershell was carried out with divinyl sulfone [DVS] under alkaline conditions retaining the DEA at the core of the micelle resulting in SCL micelles. These SCL micelles exhibited reversible pH-dependent swelling behavior upon protonation of the DEA cores at low pH.

The same group also prepared a series of pH-responsive “schizophrenic” AB-type diblock copolymers via ATRP that formed two types of micelles in aqueous solution depending on pH [262,263,264]. The first diblock copolymer, P(VBA-b-DEA), was comprising of 2-(diethylamino)ethyl methacrylate (DEA) and 4-vinyl benzoic acid (VBA) monomer unit [262]. They observed the formation of both conventional micelles and inverted micelles from P(VBA-b-DEA) in aqueous solution at ambient temperature, by controlling the solution pH (Fig. 6.22). According to them, at low pH, VBA-core micelles were formed, but at high pH DEA-core micelles were formed, and at neutral pH, the system precipitated from the solution. In another work, a similar type of diblock copolymer, poly[4-vinylbenzoic acid-b-2-N-(morpholino)ethyl methacrylate] P(VBA₆₃-b-MEMA₁₂₃), was synthesized via ATRP (Fig. 6.23) [263]. This copolymer also self-assembled into similar conventional micelles and inverted micelles at two different pHs (Figure). The key to this behavior was in choosing the correct polymer block, i.e., the use of PVBA (pKa ~7.1) as one block and the other block, poly(2-N-(morpholino)ethylmethacrylate) (PMEMA) (pKa of the conjugate acid ~4.9) ensured that precipitation did not occur during pH variation across the isoelectric point.

In the literature, there are several other examples of polymeric system that exhibits “schizophrenic” behaviors [56, 181, 265, 266]. One of such example involved poly(propylene oxide)-based (PPO) macroinitiator for the polymerization of 2-(diethylamino)ethyl methacrylate (DEA) by ATRP technique in alcoholic media at 55 °C [181]. The resulting P(PPO-b-DEA) diblock copolymer dissolved in cold water at pH 6.5. DEA-core micelles were formed at 5 °C in mildly alkaline solution (pH 8.5) and PPO-core micelles were obtained at pH 6.5 at elevated temperatures (40 ± 70 °C).

Zhang and coworkers have developed an efficient way to achieve nanoparticle-to-vesicle transition of an ABC-type triblock copolymer by in-to-out switch of the pH-sensitive core-forming C block [267]. A well-defined triblock copolymer, poly(N,N-dimethylacrylamide)-b-polystyrene-b-poly[N-(4-vinylbenzyl)-N,N-dibutylamine] (PDMA-b-PS-b-PVBA) was synthesized by seeded dispersion RAFT polymerization, which self-assembled into corona–shell–core nanoparticles at a particular pH. They observed the nanoparticle-to-vesicle transition of this pH-sensitive ABC triblock copolymer to form unsymmetrical ABC triblock copolymer vesicles through the in-to-out switch of the pH-sensitive core-forming C block.

It was found that the length of the core-forming C block of PVBA greatly affects the morphology transition of the ABC triblock copolymer nanoparticles. The triblock copolymers of varying compositions, PDMA₃₈-b-PS₁₆₇-b-PVBA₁₉ and PDMA₃₈-b-PS₁₆₇-b-PVBA₃₇, containing a short core-forming PVBA block, formed nanoparticles with sizes 29 and 33 nm, respectively, whose sizes did not change upon changing the pH of the solution suggesting no morphology transition of the two triblock copolymers. Whereas, when the DP of the core-forming C block of PVBA increased to 76, the nanoparticle-to-vesicle transition occurred and 39 nm petal-like vesicles of PDMA₃₈-b-PS₁₆₇-b-PVBA₇₆ with an etched shell were formed. When the DP of the core-forming PVBA block increased to 114, the nanoparticle-to-toroid transition occurred and the PDMA₃₈-b-PS₁₆₇-b-PVBA₁₁₄ toroids with sizes ranging from 60 to 80 nm were observed. Interestingly, some of the ABC triblock copolymer toroids were disjointed into worm-like rods.

Yang et al. have designed a series of amphiphilic 4- and 6-armed star triblock copolymers based on poly(ε-caprolactone) (PCL), poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA), and poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) blocks. The star-armed polymer has been synthesized by a combination of ROP and continuous activators regenerated by electron transfer ATRP (ARGET ATRP) [268]. The star copolymers self-assembled to form micelles in aqueous solution, which showed pH-responsive behavior owing to the tertiary amine groups of DEAEMA. Upon changing the pH, one can protonate or deprotonate DEAEMA groups that eventually induce the swell or shrink of the formed micelles (Fig. 6.24). As the pH decreased from 10 to 3, transmittance was almost unchanged at lower concentrations of 0.1 and 1 mg/mL, but sharply increased at concentrations of 10 mg/mL. The hydrodynamic diameter (D _h) and zeta potential exhibited almost the same tendency, which slightly increased with the concentration increased and increased rapidly as the pH decreased from 7 to 4 followed by a slight decrease at pH < 4.

A simple, new, two-step method was introduced for preparing hollow pH-responsive poly(methyl methacrylate-co-methacrylic acid) particles (Fig. 6.25). The hollow particles swelled at moderate pH values, formed gels in concentrated dispersions and can be disassembled by adding reducing agents. The pH-responsive particles have enabled preparation of space filling gels with microporous (inter-connected) porosity (Fig. 6.26). The main advantage is that these particles are prepared without the use of small molecule surfactants [269].

Zhang and coworker have been constructed pH-dependent flexible nanostructures by the self-assembly of two kinds of hyperbranched polymers and then validated its potency as the controllable siRNA/drug co-delivery vehicle for the combination of chemotherapy with RNA interfering (RNAi) therapy [270]. They have shown that pH-reversible phenyl boronate linking phenylboronic acid-tethered hyperbranched oligoethylenimine (OEI600-PBA) and1,3-diol-rich hyperbranched polyglycerol (HBPO) spontaneously interlinked together to form a core–corona nanostructure (Fig. 6.27). The special build-up of compactly clustering OEI600-PBA units around hydrophobic HBPO aggregate offered significant advantages over parent OEI600-PBA, including strengthened affinity to siRNA, ability of further loading anticancer drug, easier cellular transport, and acidity-responsive release of payloads. To evaluate the co-delivery capability, Beclin1 siRNA and antitumor DOX were used as the therapeutic models in order to suppress the post-chemotherapy survival of tumor cells caused by drug-induced autophagy. The nanoassembly-mediated co-delivery of siRNA together with DOX can effectively silence Beclin1 gene, suppress DOX-induced autophagy, and consequently provide strong synergism with a significant enhancement of cell-killing effects in cultured cancerous cells. The in vivo combinational treatment was shown to make the tumor more sensitive to DOX chemotherapy while displaying substantially improved safety as compared with the monochemotherapy.

3.1.1 POSS-Based pH-Responsive Polymer Nanostructures

As we mentioned above in the section of POSS-based thermoresponsive polymer, the responsive nanostructures made up of inorganic/organic hybrid polymer containing POSS have gained lot of attention recently. Furthermore, responsive polymeric micelles have been widely studied because of their potential use in nanocontainers and nanocarriers. A tadpole-shaped inorganic/organic hybrid containing poly(tert-butyl acrylate) (P^tBA) was prepared by RAFT polymerization using a POSS-containing chain transfer agent (CTA) [271]. POSS-P^tBA was further hydrolyzed into amphiphilic, tadpole-shaped POSS-poly(acrylic acid) (POSS-PAA) hybrid nanostructures. The self-assembly of POSS-PAA in aqueous solution at pH 8.5 resulted in the formation of a simple core–shell micellar nanostructures with POSS molecules as the core and PAA as the shell (Fig. 6.28). Apparently, micellar aggregates were formed where the POSS moieties are dispersed in the particle. The aggregates were pH-responsive, and the size contraction occurred upon decreasing the pH from 8.5 to 4.

Ma et al. [272] have developed a POSS end-capped PDMAEMA (POSS-PDMAEMA) organic/inorganic hybrid polymer, a stimuli-responsive (both pH and salt) hybrid synthesized via ATRP technique. The POSS-PDMAEMA hybrid molecules self-assembled into a single unit micelles with the POSS molecules forming a crystal core and the PDMAEMA chains stretching as a corona in aqueous solution. The unit single micelles were then acting as building blocks to reversibly form a hierarchical micelle-on-micelle structure (complex micelle) under external stimuli (Fig. 6.28).

3.2 pH-Responsive Ionic Polymer Nanostructure

There are only very few recent reviews that discussed different aspects of pH-responsive ionic polymers [216, 273]. As mentioned above, ionic polymers can be classified as polyelectrolyte, polyzwitterions, poly(ionic liquid)s, etc. Thus, we have separately discussed these different types of ionic polymers in terms of their pH-responsive nanostructure formation in this chapter below.

3.2.1 Zwitterionic Polymer Nanostructures

As mentioned above, polyzwitterions can be categorized into two groups (a) polyampholytes and (b) polybetaines. In these types of polymers, the pH-responsiveness arises due to the presence of ionizable cationic or anionic functional groups of zwitterions.

3.2.1.1 Polyampholytes

Polyampholytes, i.e., the copolymers of anionic and cationic monomers could form a homogeneous solution when dissolved in acidic or alkaline solution to achieve a high charge asymmetry, characteristic of common polyelectrolyte. However, the phase transition from a solution to an emulsion could be triggered by adjusting the pH around its isoelectric point (IEP), in which there is no net charge in polyampholytic chain [226, 274]. The typical polyampholytes, including poly(acrylic acid)-co-poly(vinylpyridine) (PAA-co-PVP) and poly(acrylic acid)-co-poly((N,N-dimethylamino)ethylmethacrylate) (PAA-co-PDMAEMA), have been intensively investigated for a detailed understanding on their phase transition behavior and conformational change in solution [226, 274,275,276]. Liu et al. [262] have demonstrated a new zwitterionic AB diblock copolymer that undergoes spontaneous self-assembly in aqueous solution at ambient temperature to form both micelles and reverse micelles, simply by switching the solution pH, which has been discussed above in detail in Sect. 6.3.1. It should be mentioned here that the P(VBA-b-DEA) diblock copolymer is a more hydrophobic analog of the extensively reported ampholytic poly(2-(dimethylamino)ethyl methacrylate)-b-(methacrylic acid)) (PDMAEMA-b-PMA) diblock and poly(2-(dimethylamino) ethyl methacrylate)-b-(methyl methacrylate)-b-(methacrylic acid)) (PDMAEMA-b-PMMA-b-PMA) triblock copolymers [277,278,279,280,281,282,283,284,285,286]. In these cases, a series of diblcok PDMAEMA-b-PMA and triblock PDMAEMA-b-PMMA-b-PMA copolymers of varying compositions have been synthesized by Patrickios et al. [285] via group transfer polymerization (GTP). These block polymers showed a strong tendency to precipitate near the isoelectric point. The presence of the hydrophobic block (PMMA) in the triblock copolymer resulted in formation of micelles in water.

Later on, Chen and coworkers reported that the structure of the micelles is such that the hydrophobic PMMA block is always in the center of the micelle, irrespective of the net charge born by the other ionic blocks in the triblock copolymer. Thus, if the PMMA block is between the acid and basic blocks, the micelle diameter is restricted to be about the copolymer contour length, while if the PMMA block is at the end of the molecule, the micelle radius is determined by the polymer contour length [277]. In this connection, it is worthy to mention that Armes and coworkers also synthesized zwitterionic poly(2-(dimethylamino)ethyl methacrylate-b-methacrylic acid) (PDMAEMA-b-PMAA) copolymers by group transfer polymerization [283, 284]. They further demonstrated that these copolymers underwent reversible micellization in aqueous media as examined through DLS and variable temperature ¹H NMR spectroscopy [283, 284].

In an another work, Armes and coworkers first synthesized poly(2-(dimethylamino)ethyl methacrylate-b-2-tetrahydropyranyl methacrylate) (PDMAEMA-b-PTHPMA) diblock copolymer precursor, which upon hydrolysis readily converted into ampholytic poly(2-(dimethylamino)ethyl methacrylate-b-methacrylic acid) (PDMAEMA-b-PMAA) block copolymer [287]. Depending on the reaction sequence, two types of zwitterionic SCL micelles were generated from the PDMAEMA-b-PTHPMA block copolymer precursors using the 1,2-bis-(2-iodoethoxy)ethane (BIEE) crosslinker (Fig. 6.29). For the synthesis of the Type-I SCL micelles, which have anionic PMAA cores and cationic PDMAEMA coronas, conventional micelles of the PDMAEMA-b-PTHPMA precursor were initially prepared in aqueous solution using 5 vol% THF followed by its hydrolysis with HCl. PDMAEMA-b-PMAA copolymer self-assembled into micelles with PDMAEMA cores and PMAA coronas, which upon crosslinking with BIEE produced Type-II SCL micelles (cationic cores and anionic coronas) [287]. In contrast, the P(VBA-b-DEA) diblock copolymer reported here to form compact, well-defined PVBA-core micelles at low pH and PDEA-core micelles at high pH [262].

3.2.1.2 Polyzwitterion

Among the different biomimetic zwitterionic groups, such as functional groups of phosphorylcholine (PC), sulfobetaine (SB), and carboxybetaine (CB), CB group is found to be pH-responsive due to the simultaneous presence of the positive quaternary amine group and the negatively charged carboxylate group in the each repeating unit. Zwitterionic polycarboxybetaine materials have attracted noticeable interest for biomedical applications, such as wound healing/tissue engineering [288, 289], medical implants [290], and biosensors [291, 292], due to their excellent antifouling properties and design flexibility. Antifouling materials with buffering capability are particularly useful for many biomedical applications.

A pH- and salt-responsive carboxybetaine monomer, 4-(N,N-diallyl-N-methylammonio)-butanoate (DAMAB), was first prepared and then cyclocopolymerized with the cationic monomer N,N-diallyl-N,N dimethylammonium chloride (DADMAC) in 0.5 M NaCl aqueous solution (pH 7.0) using 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959) as the free radical photoinitiator [216]. As per their report, the formed copolymer, PDAMAB-co-PDADMAC with a large excess charge exhibited typical polyelectrolyte behavior, while those with balanced charge exhibit “antipolyelectrolyte” behavior reported for zwitterionic copolymers. Unlike solutions of sulfobetaine-containing polymers [293], PDAMAB-co-PDADMAC remains soluble in water at very low ionic strength even up to 100% incorporation of PDAMAB block. Additionally, the solution of PDAMAB-co-PDADMAC exhibited a pH-dependent viscosity. PDAMAB-co-PDADMAC copolymers with more than 28 mol% of PDAMAB block showed viscosity responsiveness between pH values of 2.5 and 4.5. The maximum pH response was achieved for the solution of PDAMAB-co-PDADMAC containing 37 and 56 mol% of the PDAMAB block containing carboxybetaine monomer.

Zhang et al. [294] prepared five different polycarboxybetaines brushes, including one polycarboxybetaine methacrylate (polyCBMA) and four polycarboxybetaine acrylamides (polyCBAAs), with different spacer groups from gold surface covered with initiators using surface-initiated ATRP technique. This polymer-coated gold surface was then incubated with fibrinogen, and their adsorption was measured as a function of ionic strengths and pH values using surface plasmon resonance sensors. The responsive protein adsorption on four polyCBAAs brushes was mapped out. Their results showed that most of these surfaces exhibited high protein resistance in a wide range of ionic strengths and are more effective than zwitterionic self-assembled monolayers. Although the protein adsorption tends to increase at low ionic strength and low pH value, it is still very low for polycarboxybetaines with a methylene, an ethylene, or a propylene spacer group but is more evident for polyCBAA with a longer spacer group (i.e., a pentene group). The responses to ionic strengths and pH values can be attributed to the antipolyelectrolyte effect and protonation/deprotonation properties of polycarboxybetaines, respectively. It has been believed that since sulfonic acid is a strong acid, no hydrolysis or association occurs for aqueous polysulfobetaine systems. Consequently, pH-sensitive properties could only exist in aqueous polycarboxybetaines systems, and it was absent or rather weak at least, in aqueous polysulfobetaine systems [295, 296]. However, several research groups have systematically investigated the pH-sensitive properties of aqueous polysulfobetaine systems. It was revealed then that even aqueous polysulfobetaine systems can exhibit a series of pH-sensitive solution properties [286, 297].

In continuation with polycarboxybetaines, Thayumanavan et al. have been reported a one-pot synthesis of acrylamide-based zwitterionic amphiphilic homopolymers with hydrophilic and hydrophobic components placed orthogonally in every repeat unit (Fig. 6.30) [298]. Here, they have introduced glycinebetaines unit as charge-neutral, zwitterionic, hydrophilic moieties in amphiphilic homopolymers. Due to the presence of zwitterionic hydrophilic glycinebetaines component in the polymer, it reversibly switched between cationic, zwitterionic, and anionic forms depending on the pH of the solution. These zwitterionic polymers spontaneously self-assembled into micelle-like and inverse micelle-like assemblies depending on the solvent environment and act as hydrophilic and hydrophobic nanocontainers in apolar and polar solvents, respectively (Fig. 6.30). Moreover, they have shown pH-responsive surface charge and size variations of the micelles.

Recently, Cheng and coworkers designed and synthesized an integrated zwitterionic polymeric material, poly(2-((2-hydroxyethyl)(2-methacrylamidoethyl)ammonio)acetate) (PCBMAA-1T), to investigate its many interesting properties such as antifouling, switchability, and buffering capability [299]. A tertiary amine was used to replace quaternary ammonium as the cation to endow the materials with buffering capability under neutral pH (Fig. 6.31). The tertiary amine cation does not compromise antifouling properties of zwitterionic materials. The amount of adsorbed proteins on PCBMAA-1T polymer brushes is less than 0.8 ng/cm² for fibrinogen and 0.3 ng/cm² (detection limit of the surface plasmon resonance sensor) for both undiluted blood plasma and serum. It was reported that the tertiary amine was favorable to obtain good lactone ring stability in switchable PCB materials. Titration study showed that PCBMAA-1T could resist pH changes under both acidic (pH 1–3) and neutral/basic (pH 7–9) conditions. To the best of our knowledge, such an all-in-one material has not been reported earlier. We believe this material can be potentially used for a variety of applications, including tissue engineering, chronic wound healing, and medical device coating.

3.2.1.3 Amino Acid-Based Zwitterionic Polymer

Incorporation of biologically active amino acid moieties into the polymer main chain or side chain induces better biocompatibility of the resulting biopolymers [300]. This has drawn to the focus of polymer scientists in recent times for synthesizing stimuli-responsive amino acid-based polymer architectures [301, 302]. In these cases, the pH-responsiveness arises due to the presence of ionisable zwitterionic functional groups (–COOH and –NH₂) of amino acids. Although, zwitterionic amino acid-based polymers are interesting, but are less investigated class of ionic polymers [303, 304]. There are some excellent recent reviews discussing the developments of amino acid-based polymers with stimuli-responsive properties [305,306,307]. Furthermore, several different zwitterionic polymers based on lysine, cysteine, ornithine, aspartic acid, and glutamic acid have been developed and investigated their potential protein and bacterial resistivity [303, 308,309,310].

Recently, Liu et al. [311] have reported synthesis of zwitterionic poly(serine methacrylate) brushes from gold surface via a surface-initiated photoiniferter-mediated polymerization with good antifouling property which has comparable protein resistivity with zwitterionic poly(sulfobetaine). Lu et al. [312] have designed a l-histidine-based zwitterionic polymer which exhibited soluble–insoluble phase transition depending upon pH of the solution in addition to its antiprotein-adsorptionability. Furthermore, there is another report of synthesis of two different types of methacrylic polybetaines bearing trans-4-hydroxy-l-proline connected via its hydroxyl group, one with an aliphatic spacer of 6 carbon atoms and the other without any spacer [313]. These two polyzwitterions showed pH sensitivity in aqueous media having an isoelectric point (IEP) close to 3. Swelling of networks prepared from these two monomers exhibited reversible pH sensitivity; the largest the pH distance from the IEP, the higher the net charge (positive or negative) and the higher the swelling. At basic pH and an ionic strength of 0.15, maximum swelling degrees of around 11 and 24 (water/gm of polymer) have been found for these systems with and without spacer, respectively [313].

Our group had reported a l-lysine-based zwitterionic polymer which showed Cu(II) ion-induced pH-responsive nanogel aggregate formation [314]. A convenient and water-based approach was described for the synthesis of an l-lysine-based zwitterionic polymer, poly(ε-l-lysinyl acrylamide) (PLAM), by conventional radical polymerization technique. PLAM contained both amine and carboxylic acid groups in each repeating unit, which can either be protonated or deprotonated just by altering the pH of the solution to obtain overall positive or negative charge in the polymer chain. PLAM is tested for its applicability as a zwitterionic polymeric buffer in water. Spherical nanogel aggregates were formed at pH 9.5 due to aggregation of PLAM through its complexation with Cu(II) ion. Spherical aggregates appeared to dissociate via breaking of the complexation at a pH < 5.5 resulting in molecular dissolution of PLAM. The aggregation process was pH-reversible. The Cu(II)–PLAM aggregates are used as a template for generations of CuO and CuS nanoparticles (Fig. 6.32) [314].

Furthermore, we have extended this approach to synthesize l-serine-based zwitterionic polymers, poly(l-serinyl acrylate)s, which exhibited an interesting dual-responsive behavior with respect to pH and temperature in aqueous solution [315]. The details of this responsive system will be discussed in the Sect. 6.10.1.

3.2.1.4 Poly(ionic liquid) Nanostructures

Another important class of ionic polymer is the PILs. Recently, our group has demonstrated pH-dependent self-aggregation behavior of an imidazolium-based PIL hybrids [316]. Here, we have synthesized semitelechelic POSS-poly(vinyl imidazole) (POSS-PVim) hybrid via simple radical polymerization technique using thiol-functionalized POSS as initiator as well as chain transfer agent (Fig. 6.33). Amphiphilic POSS-PVim hybrid molecules self-assembled into primary micelles in water as well as in DMF. These primary micelles further aggregated into hybrid nanospheres in an aqueous solution of pH 6. It was observed that there was a complete transformation of morphology from spherical aggregates to large cube, pyramid, and even chain-like aggregates composed of polygons with delicate variation of solution pH. It was proposed that such higher order aggregated structures were formed due to the ionic secondary interactions among the polymer in the outer layer of the spherical primary micelles. Surprisingly, it was also found that the addition of Zn(II) ion in the solution of POSS-PVim hybrid produced dendritic nanostructures composed of primary spherical micelles. Furthermore, two different POSS-PIL hybrids are prepared by post-modification of pendent imidazole groups of PVim block of POSS-PVim hybrid with different 1-bromoalkanes of varying chain lengths. POSS-PIL hybrid molecules also self-aggregated in water to generate cubic hybrid nanostructures (Fig. 6.34). The combined zeta potential and XRD analyses provided further evidence in favor of secondary aggregation of initially formed spherical primary micelles.

Recently, a new pH-sensitive PIL has been designed by Matini and coworker [317], through incorporating pH-responsive imidazolic units at varying distance in a polymer backbone to generate materials that can be tuned to exploit specific local conditions for therapy. Variation in comonomer content, molar mass, and block ratios/compositions affected the pH-responsiveness of this PIL. As a result, the PIL molecules were undergone reversible self-assembly into either micelles and/or polymersomes (Fig. 6.35). These transitions can be tuned to achieve environmental responses in a pH range from 5 to 7, as shown by turbidimetric analysis, NMR, and dynamic light scattering measurements (DLS). Further characterization by TEM indicated that polymersomes with diameters of 100–200 nm can be formed under certain pH ranges where the weakly basic side-chains were deprotonated. The ability of the systems assembled with these polymers to act as pH-responsive containers was shown by DNA encapsulation and release studies, and their potential for application as vehicle for drug delivery was proved by cell metabolic activity and cell uptake measurements.

In another study, the hydrophobically associating cationic polyacrylamides (C-HAPAM), containing a major part of hydrophilic polyacrylamide backbones and a minor part of ionic hydrophobic groups, i.e., N,N′-dimethyloctadeyl allyl ammonium chloride (DOAC), were synthesized via free radical polymerization by Lu et al. [318]. They have investigated the self-assembling behaviors of the C-HAPAM molecules in water under different concentrations and pH values [318]. The critical aggregate concentration (CAC) for C-HAPAM was about 0.42 wt% and a solution-sol–gel transition has been observed for C-HAPAM aqueous solutions with increasing concentration. Rheological tests demonstrated a pH-reversible sol–gel transition when the pH was regulated from its original value of 7.45 to the weak alkaline value of 9.87 by adding NaOH and then switched back to 5.28 by adding HCl. The sol–gel transition was actually attributed to the fiber-network aggregate structure transition as shown by SEM, AFM, and DLS analyses. The mechanism of above-mentioned pH-responsive self-assembling behavior was explained by the remarkable counter ion effect of OH⁻. Specifically, they proposed that the OH⁻ ion was additionally capable of H-bonding with surrounding water molecules which promoted the solvation of C-HAPAM and induced thick hydration layer. The strong counterion effect of OH⁻ ion and the inter-molecular hydrophobic association interactions of C-HAPAM collectively triggered the formation of joints and hence the network structure transition, i.e., sol–gel transition.

4 Light-Responsive Polymer Nanostructures

The polymeric materials responsive to external stimuli such as light has attracted much attention since light can be localized in time and space and can be applied from outside of the system [144]. Indeed, photo processes usually start or stop when the light is switched on or off and generates only very limited amount of byproducts as there are no additional reactants [39]. In addition to this, a lot of parameters such as wavelength as well as intensity of light can also be tuned for achieving good control over the reaction. In these contexts, the wavelength of light ranging from hard UV right up to the deep infrared can be applied that allow a high diversity in tuning the light-responsive polymer system which cannot be offered by any other stimulus. The use of light as an external stimulus to control the properties of polymer nanostructures such as micelles, vesicles has started being mostly exploited since 2004. Developing polymer systems that can undergo micellization/demicellization upon light irradiation is an attractive idea that would allow external control of drug encapsulation and release.

Different kinds of photochromic units shown in Fig. 6.36 such as o-nitrobenzyl [319], azobenzene [320], coumarinyl [321], pyrenylmethyl [322], spiropyran [323] spirooxazine [324], and fulgide [53] can be introduced into the polymers or block copolymers of different amphiphilicity to make them photoresponsive. The first demonstration of photocontrollable nanostructured polymeric micelles was reported in 2004 by Zhao and coworkers [325]. Since then, there has been growing interest in designing and developing polymer nanomaterials whose aggregation states and functions can be controlled by light irradiation. Matyjaszewski and coworkers showed that the light can be employed as an effective tool to release encapsulated substance from light-responsive block copolymer micelles [326].

Zhao et al. [327] recently wrote an excellent review on different types photoresponsive polymer and block copolymer systems. As compare to other stimuli, light enables more temporal and positional control over photoprocess, and we can trigger the secondary structure formation, function, and properties of polymer systems simply by shining light from outside of the system; these materials have potential application in diverse field including light triggered controlled delivery of drugs, “smart” optical systems, biosensors, and responsive coatings. Here, we should mention that even one light-responsive unit can be sufficient to influence the properties of the whole polymer chain within a light-responsive polymer system [328]. The summary of different photosensitive groups that have been incorporated so far into the polymer and block copolymer systems as well as their potential applications are discussed in the following section.

4.1 o-Nitrobenzyl Functional Group Containing Polymer Nanostructures

In this regard, o-nitrobenzyl ester (NBE) is a promising class of photoresponsive group and is used diversely in synthetic polymers or block copolymers to make them photosensitive. Photolysis of o-nitrobenzyl moieties proceeds irreversibly via Norrish II type intra-molecular rearrangement (Fig. 6.37) in the presence of UV light of wavelength 365 nm as well as near infrared light of wavelength 700 nm, and it does not require any solvents [329]. Zhao and coworkers are the first to describe how to obtain a photosensitive amphiphilic block copolymer containing o-nitrobenzyl ester (NBE) functionality [319]. They used ATRP technique to synthesize diblock copolymer with PEO as a hydrophilic block and a hydrophobic block of poly(2-nitrobenzylmethyl methacrylate) (PNBMA) (Fig. 6.38). As shown in Fig. 6.38, the block copolymer self-aggregated into well-dispersed spherical micelles in an aqueous medium. Upon UV irradiation (λ = 350 nm), the photocleavage of the PNBMA block of the PEO-b-PNBMA BCP takes place, and that leads to the formation of the doubly hydrophilic poly(ethylene oxide)-b-poly(acrylic acid) (PEO-b-PAA) BCP causing the rupture of core–shell micelles (Fig. 6.38), and the release of the encapsulated guest molecules have been observed.

We have also involved in designing photoresponsive block copolymer. We have prepared a novel amphiphilic BCP namely poly(2-ethyl-2-oxazoline)-b-poly(2-nitrobenzyl acrylate) (PEtOx-b-PNBA) via combination of microwave-assisted cationic ring-opening polymerization CROP and ATRP [330]. The amphiphilic nature of this BCP causes them to self-assemble into primary micelles in THF/H₂O, which further undergo secondary aggregation into nanostructured micellar agglomerates (Fig. 6.39). Upon UV light (λ = 360 nm) irradiation, the photolysis reaction of 2-nitrobenzyl ester group takes place which results in the cleavage of 2-nitrosobenzaldehyde from the polymer, which transformed the hydrophobic PNBA into the hydrophilic poly(acrylic acid) (PAA) and triggered the micellar dissociation (Fig. 6.39). Photocontrolled release of a loaded hydrophobic dye, Nile Red (NR), from an aqueous micellar solution of PEtOx-b-PNBA upon UV light irradiation was investigated by monitoring the fluorescence emission of NR (Fig. 6.39). As a result of the photocleavage of NBE moiety of PNBA block upon UV irradiation, there was a disruption of NR-loaded BCP micelles/micellar agglomerates, consequently leading to the release of NR from hydrophobic micellar core to water medium outside the micelles. However, the NR is insoluble in water, which results in the decrease of the fluorescence intensity of NR present inside the micellar core with increasing UV irradiation time that, in turn, proves the release of NR dye (Fig. 6.39).

As mentioned above that even one light-responsive unit can be sufficient to influence the properties of the whole polymer chain. In this context, Kang and Moon described the synthesis of an easily cleavable polystyrene-b-poly(ethylene oxide) (PS-ONB-PEO) block copolymer by ATRP technique in which a photochemically sensitive o-nitrobenzyl (ONB) group was installed as a linker (Fig. 6.40) [331]. According to their report, the BCP cleaved into individual PS block and PEO block upon exposure to UV light at 350 nm in solution (Fig. 6.40). Cleavage upon irradiation with UV light was also shown to be successful in solid state. The as-cast PS-ONB-PEO film showed vertically aligned cylindrical morphology which transformed completely into nanoporous structure after UV light irradiation followed by washing with MeOH/H₂O (Fig. 6.40).

Recently, Fustin and coworkers developed a more versatile synthetic route using one pot combined ATRP and “click” reaction techniques to prepare a series of BCPs such as PEO-ONB-PS, poly(ethylene oxide-ONB-poly(^tbutyl acrylate) (PEO-ONB-P^tBA), and polystyrene-ONB-poly(methyl methacrylate) (PS-ONB-PMMA), with narrow dispersities containing a single photocleavable ONB junction (Fig. 6.41) [332]. Photocleavage of this diblock copolymer by UV light (λ = 300 nm) was demonstrated for PEO-ONB-PS in solution to be complete after 15 min, as proven by size-exclusion chromatography (SEC) and UV-visible spectroscopy (Fig. 6.41). Their synthetic procedure avoids the preparation of a macroinitiator (PEO-ONB-Br in Fig. 6.40), which is often more difficult to synthesize than small molecule initiators (Fig. 6.41).

Coughlin and coworkers extended this synthetic strategy to prepare PS-ONB-PEO containing single photocleavable ONB junction (Fig. 6.42) by the combination of RAFT polymerization and a subsequent intermacromolecular azide-alkyne “click” reaction, providing more flexibility in synthesis of photocleavable block copolymers [333]. A highly ordered thin film was prepared from this photocleavable BCP and after photoetching the resulting nanoporous film was used to prepare highly ordered array of silica nanodots by the treatment of PDMS and oxygen plasma (Fig. 6.42). This was the first example of preparation of silica nanostructures from a photocleavable polymer template. Block copolymers having photocleavable junction recently attracted much attention toward research community to prepare nanoporous thin films for nanopatterning, separation membranes, and sensors.

Apart from the fabrication of well-ordered nanoporous thin film application, block copolymers with a ONB junction also have some use in the encapsulation/release of guest molecules through, for example, a polymersome-micelle transition. In this regard, Meier and coworkers reported the synthesis of a new amphiphilic BCP, poly(γ-methyl-ε-caprolactone)-ONB-poly(acrylic acid) (PmCL-ONB-PAA), with a ONB junction by ring-opening polymerization and ATRP techniques [334]. Here, a dual initiator based on ONB was synthesized and used for the preparation of doubly hydrophobic poly(γ-methyl-ε-caprolactone)-ONB-poly(^tbutyl acrylate) (PmCL-ONB-P^tBA) (by sequential ring-opening polymerization (ROP) of mCL and ATRP of ^tBA (Fig. 6.43). Afterward, the P^tBA block was hydrolyzed, resulting in the formation of amphiphilic diblock copolymer and PmCL-ONB-PAA (Fig. 6.43).

The amphiphilic BCPs were shown to self-assemble into different nanostructures including micelles and vesicles that can be degraded by light, as demonstrated by a decrease in the size of the aggregates after UV irradiation (Fig. 6.44). These BCP systems can be applied as efficient light-responsive nanocarriers for hydrophilic as well as hydrophobic guest molecules.

PCL-based BCP having an ONB photocleavable junction have also been investigated by Nojima et al. They synthesized a PS-ONB-PCL diblock copolymer with an ONB-based junction. They clearly showed that this synthesized BCP possesses a nanostructured cylindrical morphology and the crystallization behavior of the PCL chains behaves very differently before and after irradiation with UV light, as a result of the cleavage of the PCL chains [335]. An alternative synthetic strategy was reported by Zhao and his coworkers where they incorporated a photodegradable polyurethane block (PUNB) in the middle of an amphiphilic triblock copolymer, PEO-b-PUNB-b-PEO (Fig. 6.45) [336]. Here, the short polyurethane middle block was composed of multiple ONB units that allowed a fast photodegradation of the micelles in solution (Fig. 6.45). The release of a model hydrophobic guest, Nile red (NR) from aqueous BCP micellar solution upon photoinduced disintegration of the micelle core was also investigated in this study.

However, light-responsive BCP has been largely used for micelle disruption and drug release but only few examples of light-induced micellization have been reported [325, 326]. Gohy and his coworkers reported a different synthetic approach to synthesize ONB group containing BCP composed of a poly(4,5-dimethoxy-2-nitrobenzyl acrylate) block and of a polystyrene block (PDMNBA-b-PS) [337]. This BCP has been synthesized by grafting a derivative of 4,5-dimethoxy-2-nitrobenzyl onto poly(acrylic acid)-b-polystyrene precursor copolymers (PAA-b-PS) prepared by ATRP. Upon light illumination, cleavage of the side chromophores takes place, and consequently, PDMNBA block is turned into a fully hydrophilic PAA block which is insoluble in the chloroform) (Fig. 6.46). Self-assembly of PAA-b-PS thus takes place, forming micelles made of a PAA core and a PS corona (Fig. 6.46). In addition, they have also demonstrated the ability of their system to act as a trapping agent by the encapsulation of coumarin 343 into the micellar core produced during the irradiation of the block copolymers in solution (Fig. 6.46).

Light-induced micellization could be very promising in the field of encapsulation, notably because the trapping process can start whenever it is needed and have some robust application such as in situ product removal [338] or product separation by micellar extraction [339]. ONB side chain functional group can also be introduced into the polymer for thin film patterning application. Doh et al. designed a terpolymer poly(o-nitrobenzyl methacrylate-co-methyl methacrylate-co-(ethylene glycol) methacrylate) (P(o-NBMA-co-MMA-co-EGMA)) to prepare thin film patterns on the micrometer scale [340]. They showed that for a terpolymer with composition of 43 wt% of o-NBMA, 38 wt% of MMA, and 19 wt% of EGMA, the exposed areas of a thin film could be dissolved by phosphate-buffered saline (PBS) after UV irradiation (Fig. 6.47). Bowman, Khire, and coworkers immobilized ONB acrylate functional moieties on the surface of silica nanoparticles simply by acid amine coupling and used them to grow linear polymers by thiolene “click” chemistry. Upon exposure to UV light, the graft copolymers are released and analyzed and they were found to be similar to polymers formed in bulk [341].

4.2 Azobenzene-Based Polymer Nanomaterials

Azobenzene containing polymers and block copolymers (BCPs) have attracted much attention in the active research field mainly because of the reversible cis–trans photoisomerization of azobenzene present in the system upon UV light irradiation [40]. In this process of photoisomerization, the apolar trans-isomer can be converted to the polar cis-isomer upon UV irradiation, and the process is reversible with respect to visible light irradiation. Indeed, morphology and related self-organized nanostructures of azobenzene containing BCPs can be easily tuned reversibly by simple exposure of UV light in solution. Previously, azobenzene containing polymers synthesized via anionic polymerization or post-functional modification was mainly used as a mesogen for liquid crystalline polymers (LCPs) [342,343,344]. In recent years, the interest in azo-BCPs has been stimulated by the accessibility of several controlled radical polymerizations techniques such as ATRP [47] and RAFT polymerization [345]. Thus, a growing number of studies on azobenzene containing BCPs have been reported by many researchers. It should be noted that trans-cis photoisomerization of Azo-BCPs may affect the nanostructure morphology of the system. Kadota et al. demonstrated a novel ABA-type triblock copolymer, where A and B correspond to azobenzene (Azo) containing poly(methacrylate) and PEO, respectively, was synthesized by ATRP [346]. Here, an Azo-containing methacrylate monomer was polymerized from both ends of a PEO-based ATRP macroinitiator using CuBr/HMTETA catalyst systems to synthesize the triblock copolymer (Fig. 6.48). The monolayer thin film on mica with trans-Azo groups displayed morphology with a mixture of dot- and rod-shaped microdomains of the Azo polymer block (Fig. 6.48). However, they observed morphology transformation to long stripes of the microdomains when the trans-Azo film was exposed with UV light irradiation due to conversion into its cis-isomer (Fig. 6.48).

This photoinduced change of morphology from trans to cis-form was ascribed to an anisotropic expansion of the microdomains with Azo groups in the cis-form, as the more polar cis-isomer became in contact with the water surface. The microdomain expansion was also followed in reduction of the height difference from 1.70 ± 0.25 nm for the film with the trans-isomer to 1.05 ± 0.250 nm for the film with the cis-isomer. Reversible photoisomerization process of azo benzene system has also been utilized by Zhao and coworkers to design a micellar system that is disrupted upon UV irradiation and reforms itself when irradiated with visible light [325, 347]. They reported a diblock copolymer containing on one side a hydrophilic random poly(^tbutyl acrylate-co-acrylic acid) (P(^tBA-co-AA)) block and on the other side a poly(methacrylate) bearing azobenzenes as pendent groups (PMAzo) (Fig. 6.49).

Spherical micelles and/or vesicles have been observed from this BCP when it is dissolved in a dioxane/water mixture depending on the amount of water content (Fig. 6.49). Upon UV light irradiation, the azobenzene side-chain groups in the apolar trans-form were converted into the polar cis-form resulting in an increase of polarity of the PAzoMA block followed by disruption of the micellar aggregates (Fig. 6.49). Afterwards, when the visible light was applied, azobenzene chromophores isomerized back into the trans-form and the micellar aggregates reformed (Fig. 6.49). In addition to the reversible micelle formation and disruption, azobenzene containing photoresponsive BCPs can also induce the morphological transitions for the irradiated micellar agglomerates [34, 348, 349]. For example, Li and coworkers reported a new BCP, poly(N-isopropylacrylamide)-b-poly{6-[4-(4-methylphenyl-Azo) phenoxy] hexylacrylate}(PNIPAM-b-PAzoM) synthesized by RAFT polymerization [350]. Amphiphilic PNIPAM-b-PAzoM is shown to be self-assembled into giant micro-vesicles (Fig. 6.50). Upon photoirradiation at 365 nm, fusion of the vesicles was taken place, as observed directly through optical microscope (Fig. 6.50). The associated surface expansion increases the surface-free energy and fusion of vesicles appears to be the most likely way to reduce that excess of free energy and thus stabilizes the objects.

A fascinating application of azobenzene-based photoresponsive BCP was reported by Hoffman and Stayton [351], where they synthesized a light-responsive BCP namely poly(N,N-dimethylacrylamide)-b-poly(N-4-phenylazophenyl acrylamide) (Fig. 6.51) by radical polymerization in the presence of a functional chain transfer agent. They demonstrated that the photoinduced changes in the size and hydration of this BCP chain due to its transformation from coil to globule can be used to regulate substrate access and enzyme activity when conjugated to the enzyme at a specific point just outside the active site. The “smart” photoresponsive polymer can act as a molecular antenna and actuator to reversibly turn the enzyme endoglucanase 12A (EG 12A) activity on and off in response to distinct wavelengths of light (Fig. 6.51).

The above highlighted works on BCPs containing azobenzene moiety are good examples of generating specific functionality by making use of the photoisomerization of azobenzene. It should also be noted that azobenzene remains the chromophore of choice toward many polymer research community for the photocontrolled ordering of BCP nanostructures where an efficient and controllable photoinduced molecular orientation and/or motion is the key condition.

4.3 Pyrenylmethyl Polymer-Based Nanomaterials

Upon UV light irradiation, esters of pyrenylmethyl undergo a photolysis reaction requiring the presence of a protonic solvent such as H₂O (Fig. 6.52). In the pioneering work by Jiang et al. [322] ATRP was used to synthesize a novel amphiphilic BCP composed of hydrophilic PEO and a hydrophobic block of poly(1-pyrenylmethyl methacrylate) (PPyMA). Upon UV light irradiation on aqueous micellar solution of BCP (PEO-b-PPyMA), the photolysis of pyrenylmethyl esters takes place, which cleaves 1-pyrenemethanol from the polymer and, consequently, the hydrophobic PPyMA block of this BCP converts into hydrophilic PMA block as depicted in Fig. 6.52. They have shown by FESEM that core–shell micelles (D = 15 nm) obtained from aqueous solution of PEO₄₇-b-PPyMA₇₂ BCP were disappeared after 15 min of UV light irradiation (λ = 365 nm, Intensity ~2 W). They have also proposed that this BCP can be a good candidate for biological application especially in photoinduced drug delivery by demonstrating the photoinduced release of a model hydrophobic dye, Nile red (NR). NR dye was encapsulated into the micellar core of aqueous micellar solution formed by the BCP (PEO-b-PPyMA). Upon UV light irradiation, the photocleavage of pyrenylmethyl groups disrupts the micellar association and, consequently, the release of encapsulated NR taken place as shown by fluorescence emission spectroscopy (Fig. 6.52).

4.4 Spiropyran Polymer-Based Nanomaterials

Photresponsive spiropyran moiety can respond to light and undergo a reversible isomerization between colorless spiropyron (SP) and colored mecrocyanine (ME) (Fig. 6.53) [352]. The reversible photochromic behavior of spiropyran polymer-based material has led to their consideration in several useful applications such as optical and electrical switching, [353] data recording [354], and light-actusted-nanovalves [355]. Matyjaszewski and coworkers proposed the use of photoresponsive spiropyran (SP) moieties toward reversible photoinduced micellar association-dissociation process [326]. They synthesized amphiphilic PEO-b-poly(spiropyran) (PEO-b-PSP) copolymer where methacrylate block bears spyropyran side chain functionality (Fig. 6.53).

This BCP self-assembled in aqueous solution to form micelles in which the hydrophobic spiropyran containing block forms the inner core and the hydrophilic PEO block forms the outer shell (Fig. 6.53). Irradiation with UV light (λ = 365 nm) led to the photoisomerization of hydrophobic spiropyran (SP) into hydrophilic zwitterionic mecrocyanine (ME) which completely disrupted the micelles due to the formation of doubly hydrophilic PEO-b-PME copolymer (Fig. 6.53). Reversible micellization was also triggered by photochemical inversion from ME to SP, which occurred as a result of visible light irradiation (λ = 620 nm) into the disrupted micellar solution (Fig. 6.53). They have also studied the encapsulation of coumarin 120 into the micellar solution formed by the BCP (PEO-b-PSP), and its photocontrolled release upon UV light irradiation was demonstrated by fluorescence emission measurements. Moreover, the authors described the partial re-encapsulation of the fluorescent dyes on regeneration of the micelles which can be achieved by visible light irradiation.

4.5 Coumarin Containing Polymer Nanomaterials

Another important class of photochromic group that can be introduced to design photoresponsive BCP material is coumarin. The beauty of coumarin is that it is sensitive toward UV and near-infra red (NIR) light equally and efficiently. The light-responsive BCP micelles that have been reported till now are mainly activated by UV and visible light. There is only one reported example where photocleavage of o-nitrobenzyl group containing BCP occurs upon NIR light irradiation at 700 nm, but the sensitivity was low because of inefficient two-photon absorption [319]. However, NIR light having the wavelength within the range of 700–1000 nm is more suitable for biomedical application compared to UV or visible light. The reason is that at this longer wavelength, the irradiation is less harmful to healthy cells. Therefore, the BCP micelles that are sensitive to NIR light are essentially more promising candidate toward biomedical applications.

Babin et al. [321] reported a novel coumarin chromophore-based amphiphilic BCP namely poly(ethylene oxide)-b-poly([7-(diethylamino)coumarin-4-yl]methyl methacrylate) (PEO-b-PDEACMM) whose micellar disruption can effectively be triggered by two-photon NIR absorption at 794 nm. According to them, upon NIR or UV light irradiation, photosolvolysis of 7-(diethylamino)coumarin-4-yl]methyl ester moieties of the BCP was taken place which resulted in the cleavage of 7-(diethylamino)-4-(hydroxyethyl)coumarin from the polymer, and consequently, the hydrophobic PDEACMM block converted into hydrophilic PMA as presented in Fig. 6.54. Thus, photosolvolysis of the PEO-b-PDEACMM upon NIR or UV light irradiation leads to the formation of the doubly hydrophilic PEO-b-PMA BCP causing the rupture of initially formed micelles (Fig. 6.54). A hydrophobic dye, NR was also encapsulated, and its release upon UV or NIR light irradiation was monitored by fluorescence emission measurements (Fig. 6.54).

However, light-responsive BCP micelle-drug conjugates are highly unplumbed and may represent an exciting future research direction. Recently, an anticancer drug, 5-fluorouracil, was linked covalently to coumarin side group on the hydrophobic block of a diblock copolymer namely (poly(ethylene oxide)-b-poly(n-butyl methacrylate-co-4-methyl-[7-(methacryloyl)-oxyethyloxy]coumarin)) (PEO-b-P(BMA-co-CMA) through UV-induced cycloaddition at comparatively larger wave length (>320 nm) and subsequent release from the micelles formed by the drug conjugated BCP under shorter wave length UV light (254 nm) [356].

5 Redox-Responsive Polymer Nanostructures

Among the available chemical stimuli, redox reaction is one of the most popular stimuli employed to trigger sharp changes in the properties of a polymer material. Recently, the design and fabrication of redox-responsive polymeric drug delivery systems based on the tumor microenvironment have received immense attention. Redox reaction is particularly promising because the disulfide bonds can be cleaved to the corresponding thiol units in the presence of reducing agents [357]. In these aspects, glutathione (GSH) is a thiol-containing tripeptide which is capable of reducing disulfide bonds in the biological environment. The concentration of GSH in the cytoplasm (1–10 mM) is much higher than that in blood plasma (2 μM). Moreover, in vivo research has demonstrated that the concentration of GSH in the tumor tissue can be many-fold higher than that in normal tissue [358,359,360]. Therefore, this kind of dramatic concentration incline of GSH provides an opportunity for designing the redox-responsive drug delivery systems for cancer treatment.

Many research studies introduce polymeric drug delivery vehicles having GSH-responsive disulfide bonds into the backbones or side groups of the polymeric carriers where drugs are encapsulated or covalently conjugated with the polymer [361,362,363]. The polymeric drug delivery systems containing GSH-cleavable disulfide bonds are stable during the blood circulation, while they will disassemble rapidly and give burst drug release triggered by the intracellular redox stimuli at the tumor sites [364, 365]. Thus, it is noteworthy that drug delivery vehicles based on disulfide functionalities can potentially facilitate extracellular stability and intracellular release of the encapsulated drug molecules.

Recently, there was a report of a novel redox-responsive micellar drug nanocarrier formed by the self-assembly of single disulfide bond-bridged block polymer consisting of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) (PCL-SS-PEEP) [366]. Such polymeric carriers can rapidly release the encapsulated doxorubicin (DOX) in response to the intracellular reductive environment and therefore significantly enhanced the cytotoxicity of DOX to multidrug resistance (MDR) cancer cells. Here, it should be mentioned that MDR is a major restriction to the success of cancer chemotherapy. The intracellular accumulation of drug and the intracellular release of drug molecules from the carrier could be the most important barriers for nanoscale carriers in overcoming MDR. Redox-responsive micellar nanoparticles based on PCL-SS-PEEP block polymer can act as a drug carrier and also can significantly overcome the two barriers in overcoming the MDR of cancer cells, thus reversing the multidrug resistance of cancer cells.

On the one hand, nanoparticles bearing PEEP shell exhibit a high affinity to cells and are more efficiently internalized by cells, which help the drug escape from the pump-off by P-glycoprotein (P-gp) and lead to high levels of cellular drug accumulation. On the other hand, it is known that MDR in cancer cells is often associated with an elevation in the concentration of reductive glutathione (GSH) [367]. Such shell-detachable nanoparticles are sensitive to the intracellular glutathione of MDR cancer cells, resulting in significantly enhanced intracellular drug release and rapid accumulation of free drug in MDR cancer cells (Fig. 6.55).

In biomedical applications, the thiol-disulfide exchange reaction [368] is exploited extensively for constructing redox-responsive gene and drug carriers [362, 369] For example, Meng and Zhong’s group demonstrated a facile way to prepare the disulfide-linked dextran-b-PCL amphiphilic block copolymer using the thiol-disulfide exchange reaction between dextran orthopyridyl disulfide (Dex-SS-py, 6000 Da) and mercapto PCL (PCL-SH, 3100 Da) under mild conditions (Fig. 6.56) [370]. It was observed that the as-synthesized BCP self-assembled into micelles with an average size of 60 nm in phosphate buffer solution (Fig. 6.56) and, interestingly, these micelles formed large aggregates rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the dextran shells through reductive cleavage of the intermediate disulfide bonds. The effective shedding of dextran shells and almost zero-order release of DOX in response to 10 mM DTT, analogous to the intracellular redox potential, was observed. It was shown by confocal laser scanning microscopy (CLSM) that the DOX was rapidly released to the cytoplasm as well as to the cell nucleus. These redox-responsive biodegradable micelles have appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy (Fig. 6.56).

Not only disulfide linkage, many researchers introduced redox-sensitive inorganic metal-metal bond to design redox-responsive polymer materials. Selenium has similar kind of chemical properties like sulfer because they are present in the same group of the periodic table and also diselenide bond energy is very less (E _Se–Se = 172 kJ mol⁻¹). Therefore, researchers paid attention toward diselenide linkage to fabricate redox-responsive polymeric nanostructures for controlled drug delivery. Normally, Se–Se bond can be cleaved and oxidized to seleninic acid in the presence of oxidants and reduced to selenol in a reducing environment. The selenium containing polymer was, however, still unexplored due to the lack of efficient synthetic methods to overcome its poor solubility. In 2010, Xu and Zhang’s group reported a dual diselenide containing redox-responsive polyurethane (PU) triblock copolymer, PEG–PUSeSe–PEG, using toluene diisocyanate as the chain extension agent (Fig. 6.57) [371]. This amphiphilic triblock copolymer (PEG–PUSeSe–PEG) self-assembled into micellar structure in aqueous environment. They investigated that the redox-responsive PEG-PUSeSe-PEG micelles were quite stable under ambient conditions but disrupts very rapidly in the presence of external redox stimuli (oxidants or reductants) due to the destruction of Se–Se bonds (Fig. 6.57). The release of encapsulated Rhodamine B from the aqueous micellar solution of the following triblock copolymer (PEG–PUSeSe–PEG) upon addition of suitable oxidants (e.g., H₂O₂) or reductants (e.g., GSH) were also investigated and the results indicated that the diselenide was much more sensitive: Even under 0.01 mg mL⁻¹ of GSH, the encapsulated Rhodamine B could still be released almost entirely in only 5 h, while they were stable without redox stimuli.

To confirm its use in drug delivery and tumor inhibition, Liu et al. introduced the diselenium bond into a hyperbranched structure and found that the hyperbranched polydiselenide could not only be used as a biocompatible drug carrier but itself had the ability to inhibit tumor proliferation [372]. Another interesting redox-active couple in polymeric systems is the ferrocene/ferrocenium system. Ferrocene containing polymers are one of the well-studied oxidation-responsive polymers with promising applications ranging from biomedicine, biosensors, batteries, and liquid crystals to electronics and other related areas [373,374,375,376]. As per the position of ferrocene in the polymer, these polymers can be roughly classified into three categories: polymers with ferrocene in the backbone, polymers with ferrocene on the side chain, and polymers with ferrocene as the terminal group. Staff et al. successfully designed poly(vinylferrocene)-b-poly(methyl methacrylate) (PVFc-b-PMMA) nanocapsules with ferrocene on the side chain [377]. Microphase separation in the nanoparticles led to a patchy assembly, where PVFc patches are surrounded by the PMMA phase (Fig. 6.58). Furthermore, the PVFc nanopatches could be selectively oxidized into hydrophilic ferrocenium, thereby inducing a transition from a purely hydrophobic patchy object to a hydrophobic object with swollen hydrophilic nanopatches (Fig. 6.58). The hydrophobic to hydrophilic transition of the PVFc nanopatches was advantageously utilized to release a hydrophobic payload upon selective oxidation of the nanopatches. Polymers with terminal ferrocene group are usually used to construct more complex polymeric systems utilizing ferrocene related host-guest chemistry. Depending on the redox state of ferrocene, the inclusion complexation between ferrocene and cyclodextrin has already been established to associate and disassociate reversibly.

Yan, Yin, and coworkers synthesized a pseudo block copolymer via orthogonal assembly between cyclodextrin-modified poly(styrene) (β-CD-PS) and ferrocene end-functionalized poly(ethylene oxide) (PEO-Fc) in aqueous solution (Fig. 6.59) [378]. The following supramolecular block copolymer can self-assembled into vesicles with voltage-responsiveness. The association-dissociation balance of the supramolecular vesicles could be reversibly addressed by electro-stimuli. For example, upon application of +1.5 V voltage stimulus, the vesicles disassembled into small pieces in less than 5 h, while under a −1.5 V voltage, the fragments could reassemble into vesicles (Fig. 6.59). Additionally, from the controlled release experiments, they claimed that the release rate can be well-controlled by slightly tuning the voltage strength, exhibiting great potential in electrochemical therapeutic applications [379].

Further, Xiong et al. recently fabricated redox-responsive nanogels by radical copolymerization of an ionic liquid (IL)-based monomers, 1,n-butanediyl-3,30-bis-1-vinylimidazolium dibromide ([C_nVIm]Br, n = 4, 6), and disulfide dimethacrylate (DSDMA) monomer in selective solvents [380]. The sizes of PIL-based nanogel particles can be tuned by the feed ratio of the IL monomer and DSDMA. Moreover, the redox-response performances of these nanogels were evaluated through the size variation in the presence of dithiothreitol (DTT) and benzoyl peroxide (BPO). The capability of PIL-based nanogels for controlled release was also investigated by using rhodamine B (RhB) as prototype model drug. It was found that DTT-triggered release of RhB could be achieved. Only less than 50% RhB could be released in the absence of DTT, while over 80% RhB could be released with the addition of DTT. This high cargos release was attributed to the cleavage of disulfide bonds in reducing environments. Thus, the redox-responsive nanogel particles could selectively increase intracellular drug release and potentially used as controlled carrier in biological medicine [380].

6 Glucose-Responsive Polymer Nanostructures

Polymeric micelles (PMs) formed by the self-assembly of block copolymers have also attracted immense interests for their potentiality to control the release of insulin and fast response to glucose levels, as well as other advantages, such as small size and defined core–shell structures [381,382,383]. Phenylboronic acid-containing materials have been most widely studied and used in construction of glucose-responsive system. As shown in Fig. 6.60, phenylboronic acid (PBA) exists in equilibrium between the undissociated (neutral trigonal) and dissociated (charged tetrahedral) forms in an aqueous milieu. An increase in the glucose concentration induces a shift in the equilibrium, increasing the fraction of total borate anions (B and C) and decreasing the fraction of the uncharged form (A) [384]. This kind of shift in the direction of the charged phenylborates results in an increased hydrophilicity. Thus, the change in the glucose concentration should have a significant effect on the solubility of amphiphilic polymer strands having pendant phenylborate moieties [385].

Shi and his coworkers reported PBA-based polymer micelles formed through the self-assembly of poly(ethylene glycol)-b-poly(acrylic acid-co-acrylamidophenylboronic acid) (PEG-b-(PAA-co-PAAPBA)) BCP exhibiting glucose-responsive release of insulin under physiological conditions [386]. They claimed that these monodisperse micelles were sensitive to pH and glucose in aqueous solutions. The micelles swelled and dissociated in the presence of glucose at pH = 7.4 which was caused by the conjugation of PAAPBA segments with glucose unit and the resultant increases in hydrophilicity of the PAAPBA core (Fig. 6.61). They have also demonstrated that the insulin-loaded micelles disaggregated at a faster rate in the solution with higher concentration of glucose, and the cumulative amount of insulin released from the micelles gradually increased with time.

Kataoka and his coworkers have made excellent contributions to the synthesis and application of PBA-based glucose-responsive polymeric materials. Their magnificent work was the synthesis of a complex gel based on the reversible complexation between PBA moiety of poly(N-vinyl-2-pyrrolidone)-co-poly(phenylboronic acid) (P(NVP-co-PBA)) and diols moiety of poly(vinyl alcohol) (PVA) [387]. Afterwards, glucose-responsive release of insulin using this complex gel was established successfully [388].

Recently, Liu et al. [389] developed a glucose-responsive complex polymeric micelle (CPM) through the self-assembly of two types of diblock copolymers, poly(ethylene glycol)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PEG-b-P(Asp-co-AspPBA)) and poly(N-isopropylacrylamide)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PNIPAM-b-P(Asp-co-AspPBA)). The complex micelles had a common P(Asp-co-AspPBA) core and a mixed PEG/PNIPAM shell (Fig. 6.62). Upon increasing the temperature up to 37 °C, PNIPAM chains collapsed on the glucose-responsive P(Asp-co-AspPBA) core, forming a novel core–shell–corona structure (Fig. 6.62). The complex micelles exhibited a reversible swelling in response to changes in the glucose concentration, enabling the repeated on–off release of insulin regulated by the glucose level (Fig. 6.62). Additionally, the formation of a continuous PNIPAM shell (membrane) around the micellar core could provide fruitful insulin protection against protease degradation. This kind of the biocompatible complex polymer micelle could be very effective for constructing self-regulated insulin delivery systems to control diabetes.

Sumerlin and his coworkers synthesized a BCP, namely poly(N,N-dimethylacrylamide)-b-poly(3-acrylamidophenylboronic acid) (PDMA-b-PAPBA) by RAFT polymerization and elementarily investigated the sensitivity of PNIPAM-b-PBA micelles to pH and glucose [382]. It should be mentioned that the boronic acid-acyclic diol complexes are less stable and can easily dissociated in the presence of appropriate saccharide molecules because, the rigid cis-diols found in many saccharides generally exhibits higher binding affinities with organoboronic acid through reversible boronate ester formation [390]. However, this kind of competition mechanism between sugar molecule and acyclic diol toward organoboronic acid provides an excellent opportunity for unfolding/developing novel type of sugar-responsive macromolecules. Inspired by this competition concept, Yuan and his coworkers recently reported the synthesis of an amphiphilic BCP namely poly(ethylene glycol)-b-poly[(2-phenylboronic ester-1,3-dioxane-5-ethyl) methylacrylate] (PEG-b-PPBDEMA) which contains phenylborate ester as a leaving group in response to glucose in the hydrophobic block (Fig. 6.63) [391]. They showed that BCP self-assembled into core–shell micelles in aqueous solution with hydrophobic PPBDEMA segments as the core and hydrophilic PEG units as the shell (Fig. 6.63). Upon addition of sugar into aqueous micellar solution, the marked pinacol phenylboronate moieties present on the hydrophobic part of the BCP were combined with sugar molecules because of its predominant binding force with organoborane and resulting in the detachment of phenylborate ester from the BCP as phenylboronate-saccharide complex (Fig. 6.63). The detachment of phenylboronate groups from the BCP changes the polarity of the BCP from amphiphile to double hydrophile, and thus leading to the disruption of the initial nanoaggregates formed via self-assembly of the amphiphilic PEG-b-PPBDEMA BCP (Fig. 6.63). Additionally, glucose-responsive release of encapsulated insulin from these BCP micelles at neutral pH was also successfully investigated in this report (Fig. 6.63).

7 CO₂ Responsive Polymer Nanostructures

In recent years, majority of scientific reports on stimuli-responsive polymers have focused on some particular stimuli including pH, light, and temperature. However, pH, light, and temperature-responsive polymer systems have some kind of limitations. For example, repeated switchable cycles of pH-responsive polymer systems require repeated addition of acids and bases to the solution, which may contaminate the system and weaken the switch ability due to salt accumulation [392, 393]. On the other hand, the light-responsive BCP micelles that have been reported till now are mainly activated by UV light. However, light and pH as stimuli are harmful to biological tissues in some cases and therefore not widely applicable. The penetration depth of UV light in tissue is very short because of its small wavelength, and extended irradiation of high-energy UV light can also lead to the damage of biological tissues [321]. Therefore, investigation of alternative stimuli is highly recommendable for the utilization of responsive polymers in biomedical applications. Carbon dioxide (CO₂) can be considered as a kind of “green trigger” and plays an important role as an endogenous metabolite [394]. In addition, CO₂ is a non-toxic, inexpensive, and abundant gas. It is, therefore, an attractive stimulus toward responsive polymeric systems in biological applications such as drug or gene delivery, tissue engineering. Furthermore, CO₂ can react with different responsive functional groups such as amines or amidines resulting in the generation of hydrophilic compounds [44]. We can also recover original compound upon removal of CO₂ simply by purging with inert gases or heating. Therefore, using CO₂ as a stimulus can lead to many switching cycles without the accumulation of any byproducts. Another appealing feature of CO₂-responsive polymeric materials is their ability to capture CO₂. The pathway to utilize and capture CO₂ is really a crucial issue to minimize the greenhouse gas [395, 396].

In the past years, there has been immense interest in possibilities to capture CO₂ from the atmosphere and ensure a safe storage. Recently, Yuan, Yan, and his coworkers designed amidine containing BCP to fabricate CO₂-responsive vesicles having biomimetic “breathing” feature [394]. Here, they have synthesized poly(ethylene oxide)-b-poly((N-amidino)dodecyl acrylamide) (PEO-b-PAD) amphiphilic BCP using PEO-based macroinitiator by ATRP (Fig. 6.64). Amidine can transform into a charged amidinium species upon reaction with CO₂, and this reaction is reversible upon exposure to argon (Fig. 6.64) [397]. The conductivity of the PEO-b-PAD solution rose dramatically from 3.4 to 26.9 µS cm⁻¹ accompanied with a decrease of the pH value from approximately 6.94 to 5.68 was observed when CO₂ passed through the solution indicating that a number of protonated species formed in the BCP solution because of the formation of amidinium ion. However, the original low conductivity of this BCP solution was regained upon treatment with Ar gas owing to an opposite deprotonation effect. Due to its amphiphilic nature, this BCP can self-assemble into vesicles in aqueous solution (Fig. 6.64). The notable finding was that these vesicles can swell and expand its size when CO₂ is passed through the BCP solution (Fig. 6.64). It was noted that upon CO₂ treatment only 37% amidine side groups are protonated, this probably the reason behind why vesicles are still remaining in solution. Therefore, CO₂ can tune the size of these vesicles over a wide range by controlling the degree of protonation of amidine side chains of this BCP. They have also investigated that these vesicles can return to their initial size upon removal of CO₂ by bubbling Ar gas through the solution. This kind of reversible expansion and contraction phenomena of polymeric vesicles in response to CO₂ or Ar gas is called “breathing” vesicles. Based on this “breathing” phenomenon, Yuan and his coworkers further extended their investigation toward membrane permeability of these vesicles [398].

First report on CO₂-responsive polymer brushes was highlighted in 2013 by Kumar, Zhao and his coworkers [399]. The brushes were prepared by grafting PDEAEMA from a surface under ATRP conditions. This polymer brushes can be switched between extended (hydrated) and collapsed (dehydrated) chain conformational states just by passing CO₂ gas and an inert gas like N₂ in solution, respectively. At room temperature, PDEAEMA chains are generally hydrophobic in nature at neutral pH, and therefore, the respective PDEAEMA brushes are insoluble in water and exist in the collapsed state (Fig. 6.65) under these conditions. Upon passing CO₂ through the solution, tertiary amine groups of PDEAEMA unit gets protonated to form charged ammonium bicarbonates (Fig. 6.65), and consequently, PDEAEMA brushes become hydrophilic and adopting the chain extended state (Fig. 6.65). However, the reverse process can also be achieved by the introduction of N₂ through the solution to remove CO₂. Under N₂ purging, PDEAEMA brushes became hydrophobic and insoluble in water and regained the collapsed state from the extended state due to deprotonation. This kind of CO₂ triggered expansion and collapsed state of polymer brushes has some promising application in gas-controlled reversible capture and release of protein where repeatable repelling and adsorption of protein occurred on the extended brush and the collapsed brush, respectively.

8 Cyclodextrin Inclusion Complexation-Based Responsive Polymer Nanostructures

Cyclodextrins (CDs) are a class of cyclic oligosaccharides that have molecular-compatible cavities. These semi-natural compounds commonly comprise several D-glucopyranoside units linked together by a 1,4-glycosidic bonds. The most common ones are α-, β- and γ-CDs, consisting of six, seven, and eight glucopyranose units, respectively. The exterior of the cavity is highly polar, because of the bristling hydroxy groups, while the interior is nonpolar. The inclusion complexation between CDs and various guests has been extensively investigated in supramolecular and polymer chemistry resulting in a broad scope of guest molecules available under different conditions [400] One of the most investigated pairs, i.e., the complexation between β-CD and adamantane (ADA) has been widely employed in macromolecular assembly as it has strong binding ability with an association constant around 1 × 10⁵ M⁻¹ in water [400]. Many host-guest pairs with a binding ability that is adjustable to external environment, such as temperature, pH, light, and voltage, have drawn great attention, as they could be used in constructing stimuli-responsive assemblies. Furthermore, as the interaction strength of different pairs covers a very broad range, and it provides a good opportunity to realize reversibility of self-assembly just by competition between different pairs. This includes amphiphilicity adjustment and various structures built by inclusion complexation. In this chapter, we focus on the stimuli-responsive polymer-based inclusion complex assemblies.

The use of amphiphilic macromolecules as building blocks has drawn increasing interest because of their controllable self-assembly, and the morphology transformation of the assemblies can be realized by tuning the amphiphilicity [401]. CDs are particularly valuable and extensively employed in tuning the amphiphilicity of macromolecules. Generally, once part of a macromolecule containing a guest moiety is connected to CDs via inclusion complexation, the part will become more hydrophilic, and thus, the amphiphilicity of the macromolecule as a whole is turned. For example, the block copolymer composed of two hydrophobic blocks, i.e., polystyrene and adamantyl polyphosphazene, could be converted to an amphiphilic copolymer when the adamant units enter the cavities of the added β-CDs. This resulted amphiphilic copolymer then self-assembled into micelles with polystyrene as the core and β-CD-modified polyphosphazene as the shell [402]. Kim et al. reported that a dendron amphiphile with a pyrene apex formed vesicles in aqueous solution. There is another example of nanostructure formation, where the amphiphilicity of the dendron was significantly altered by capping the dendron with β- or γ-CDs due to inclusion complexation between pyrene and CD, which made the vesicles convert into nanotubes [403]. However, when the binding ability of a host–guest pair is rather strong, it can be employed to link two linear polymers with respective host and guest groups at the chain ends into a pseudo block copolymer.

Shi et al. reported that ADA end-functioned PNIPAAm and β-CD end-functioned poly(4-vinylpyridine) (P4VP) formed a pseudo block copolymer via the ADA/b-CD interaction [404], which formed micelles in aqueous solution of pH 2.5 and at 60 °C, with a hydrophobic PNIPAAm core and a hydrophilic P4VP shell. When the condition was switched to pH 4.8 at 25 °C, PNIPAAm became hydrophilic and P4VP slightly hydrophilic, then vesicles with a radius around 80 nm were formed, in which a P4VP layer is sandwiched between the two PNIPAAm layers.

Following their systematic study on double-hydrophilic block copolymers (DHBC), Liu et al. achieved non-covalently linked DHBC containing β-CD terminated PNIPAAm and ADA-terminated poly(2-(diethylamino)ethyl methacrylate) (PDEA) [405]. At room temperature, the polymer pair molecularly dissolved at pH <6 but formed PDEA-core micelles at pH >8 with PNIPAAm as the hydrophilic outer layer of the micelles. In acidic media, above the LCST of PNIPAAm, vesicular nanostructures were formed with a PNIPAAm layer sandwiched by the hydrophilic PDEA layers.

Very recently, Zhang et al. [406] designed and synthesized a β-CD core four-arm PNIPAAm and functionalized PEGs with ADA groups at one or both of its ends. Thus, they obtained non-covalently linked block copolymers with different architectures by inclusion complexation (Fig. 6.66). They found that the thermosensitive behavior of the β-CD-core star PNIPAAm in the block copolymers was changed significantly, i.e., LCST of these self-assembling systems was greatly increased depending on the ratio of ADA moiety to β-CD core and/or the length of the PEG blocks. When the PEG chain with ADA groups on both of its ends was used for complexation with β-CD-core star PNIPAAm, the LCST of linked block copolymer system reached to 39.2 °C. This method of combining short PEG chains to PNIPAAm by inclusion complexation provided an efficient way to control the LCST avoiding the conventional copolymerization of NIPAAm with hydrophilic monomers. So this supramolecular approach might be promising for the production of intelligent systems for biomedical and pharmaceutical applications.

Wang and Jiang used the concept of the inclusion complexation between β-CD and adamantyl group (ADA) as a driving force in constructing polymeric micelles [407, 408]. For this they have synthesized hydrophobic linear polymer PtBA-ADA and hydrophilic poly(glycidyl methylacrylate)) containing β-CD (PGMA-CD). The two polymers were dissolved in DMF, where their interaction was weak. Water was then added as a selective solvent, in which inclusion complexation came to dominate. Thus, micelles with PtBA-ADA as core and PGMA-CD polymer as shell were formed. The core and shell were non-covalently linked by inclusion complexation between β-CD and ADA. Moreover, when the shell was crosslinked and then the core was dissolved by switching the solvent from water to DMF, the micelles were converted into hollow spheres of PGMA-CD (Fig. 6.67) [407, 408].

Inclusion complexation could induce thermoresponsive assembly, because the binding ability of CD with different guests has its own entropy or enthalpy driven nature. Amphiphile containing a bipyridinium head and a bulky tail was taken to study the thermoresponsiveness of micelles [409]. The amphiphile formed a water soluble pseudorotaxane with α-CD below 60 °C. Since this structure is more entropy dependent, after heating, the amphiphile slid out of the α-CD cavities and formed micelles accommodating pyrene in the core. The whole process was fully thermoreversible accompanying the release or load of the pyrene moiety, which was monitored by the absorption spectra of pyrene. It was very interesting that in this system, if the ^tBu group at the end was replaced by −OMe, α-CD was very stable on the chain of the amphiphile and could not be removed after heating. It is worth noting that this reversible thermoresponsiveness of the assembly is based on the thermal reversibility of inclusion complexation rather than the well-investigated thermal behavior of polymers such as PNIPAAm chains. Further, Ritter et al. observed that PIL, poly[1-butyl-3-vinylimidazolium bis(trifluoromethanesulfonyl)-imide] showed a pseudo-LCST effect in aqueous solution in the presence of cyclodextrin due the temperature-sensitive formation/disruption of its inclusion complex [410].

AZO and Ferrocene (Fc) are the two most popular guests for reversible inclusion complexation with CDs. The trans-AZO binds strongly with α- or β-CD, while the binding capacities of cis-AZO with these CDs are very poor. With a few exceptions, CD normally binds to neutral or anionic compounds only. So the oxidized state of Fc binds very weakly to CDs because of its cationic nature, while the reduced state of neutral iron of Fc binds properly [378]. Recently, Wang et al. [411] reported the formation of micelles by inclusion complexation of two block copolymers. They synthesized two copolymers based on PEG-b-PAA with respective β-CD and AZO modifications on the PAA blocks, which were self-assembled into micelles driven by inclusion complexation between β-CD and AZO groups. After crosslinking, the assembly structure was capable of loading/unloading pyrene, which is photoswitchable by the inclusion complexation of CD/AZO. Further, Yuan et al. reported that β-CD end-capped PS(β-CD-PS) and Ferrocene (Fc) ended polyethylene oxide (PEO) (Fc-PEO) formed pseudo block copolymers of PS and PEO due to the inclusion complexation of β-CD and Fc [378]. The block copolymer formed stable vesicles in water. The vesicles were dismantled by positive electro-stimulation (+1.5 V) for 5 h, which oxidized Fc into Fc⁺. This voltage-dissociated inclusion complexation was proved by a half-wave potential (E_1/2) decrease of 0.11 V accompanying an increase in the peak currents. Further negative electro-stimulation (−1.5 V) reassembled the vesicles by reduction of Fc⁺ to Fc after 5 h (Fig. 6.68). Therefore, this work proved that voltage is also a good choice of clean stimuli for reversible association/disassociation based on inclusion complexation.

Further, a POSS-based supramolecular amphiphile prepared from the host–guest inclusion complexation between a mono adamantane-functionalized POSS (AD-POSS) and a β-cyclodextrin oligomer [Poly(β-CD)] have been reported by Jiang et al. [412] (Fig. 6.69). Assisted by the interface of H₂O/toluene, the obtained supramolecular hybrids self-assembled into stable hollow nanospheres with thick walls. These hollow nanospheres aggregated together into a sphere layer through a spin coating technique, which then further transformed into a thin porous film containing nanometer-sized scaleholes.

9 Mechano-responsive Polymers

There is growing interest in the use of mechanical energy to alter the molecular and supramolecular structure of polymers to create stress-responsive materials [413, 414]. Chemical reactions that are accelerated by force remain poorly understood, and there is a need for the rapid discovery of new mechanophores (i.e., stress-sensitive units). Many specimens of chemically, thermally, electrically, optically, or otherwise responsive materials are known, but comparably few materials have been studied, which respond in a useful and controlled manner to the exposure of mechanical stress. Therefore, a discussion regarding these types of mechano-reponsive polymer materials is highly important in the context of the present review, although, to the best of our knowledge there are no such reports formations of nanostructures such as micelles, vesicles that are responsive to mechanical energy.

In order to successfully design mechano-responsive materials, researchers are trying to draw inspiration from nature, especially biological systems, because most of them are mechano-responsive to their environment [415,416,417]. As for example, titin, (Fig. 6.70a) a giant protein in muscles, which own a remarkable combination of strength, toughness, and elasticity, is essential for the assembly and elasticity of the sarcomere. In other words, titin has good mechanical properties and is sensitive to mechano-stimulus. Generally, polymers do not have such a combination of properties.

However, Guan and coworkers described the synthesis of a titin’s prototype modular polymer by incorporating the quadruple hydrogen bonding 2-ureido-4[1H]-pyrimidone (UPy) motif within a macrocycle that reveals a rare combination of high modulus, toughness, and elasticity, while demonstrating smart mechanical properties [417]. The target polymer (P1 in Fig. 6.70) (M _n = 18.0 kDa, PDI = 1.7) was obtained by acyclic diene metathesis (ADMET) with a Grubbs Gen-2 catalyst, which did not aggregate in solution as shown by DLS. This polymeric material showed very intriguing mechanical properties. It is a relatively stiff kind of material with a Young’s modulus of about 200 MPa and undergoes large deformation (maximal strain >100%) with a relatively small increase in stress, resulting in the absorption of a large amount of energy (Fig. 6.70b). The continuous unfolding of UPy dimer modules at the molecular level upon stretching bestows high toughness behavior on the material. In further studies, it was observed that the plastic deformation is not permanent and could gradually self-recover with time (>18 h) or upon heat treatment (about 30 s at 80 °C).

In addition to the self-healing process, the material also showed an interesting shape-memory behavior in spite of no permanent or physical crosslinks within the polymer. The unusual molecular topology can contribute to the formation of stable entanglements, thereby resulting in the shape-memory effect. Upon strain-induced breaking of the macrocyclic UPy dimer, inter-molecular UPy dimers form, fixing the material in a temporary state (Fig. 6.71). Once the UPy dimer reverts back to the preferred intra-macrocyclic dimer, the material recovers to its original state. The stress–strain behavior and the shape-memory effect show good mechanical properties found in titin and fascinating adaptive behavior. However, when the UPy units were protected to prevent dimer formation, the material was brittle and fractured at 7% strain, while lacking extensibility or any adaptive properties.

Ultrasonication has proven to be one of the most efficient mechanical stimuli to induce chain scission of polymers in solution [414, 418, 419]. Paulusse and his coworkers demonstrated an excellent example about sonication-induced reversible mechanochemistry of a Pd^II coordinated supramolecular polymer [414]. The following metallo-supramolecular polymer (P2 in Fig. 6.72, M _w = 1.70 × 10⁵) was developed by stirring a solution of diphenylphosphine-terminated poly(tetrahydrofuran) (M _n = 7300, PDI = 1.11) with a small excess of palladium dichloride (PdCl₂) in toluene for 2 days. After sonicating the polymer solution in the presence of toluene for 1 h, M _w of the as-synthesized polymer was shown to decrease from 1.70 × 10⁵ to 1.02 × 10⁵ while the original molecular weight of the polymer was recovered nearly quantitatively on removal of the sonication for 1 day (Fig. 6.72). The procedure was repeated five times without irreversible polymer abasement, showing that sonication-induced mechanical forces are highly selective for the metal-coordination bonds. Furthermore, it has been found that the sonication can also lead to an increase in polymeric material of a more specific length (after 5 min of sonication, the greatest increase was found at M _w = 1.90 × 10⁵) and ultrasonic chain scission is a non-random process that acts specially on longer chains. Afterwards, the same research group has also employed the similar technique to access an ultrasound-responsive metallo-supramolecular polymer gel [420] and moved on this concept to fabricate ultrasound-induced catalysis [421]. These valuable results and distinguished examples represent a novel methodology for exploring the reversible mechanochemistry of supramolecular polymer materials toward useful applications.

10 Dual Stimuli-Responsive Polymer Nanomaterials

In recent years, there have been lots of developments in the area of responsive polymers not only with respect to single stimulus but also show a responsive behavior to dual or multiple stimuli. Dual or multiresponsive polymer systems are of great interest and attracted notable attention in academia because of the possibility to tune their properties in multiple ways [320, 422,423,424]. For example, temperature-responsive polymers can be tagged with light-responsive chromophores to fabricate temperature and light-responsive polymers, and temperature-responsive polymers can be combined with pH-responsive functional group to build temperature- and pH-responsive polymers.

10.1 Temperature- and pH-Responsive Polymer Nanostructures

Temperature- and pH-responsive polymer nanomaterials have been extensively studied in drug delivery because these two parameters often differ from the normal value in diseased tissue [425,426,427]. Dual thermo- and pH-responsive polymers typically contain a PNIPAM or PEG unit as the thermoresponsive block and a polyamine or poly(carboxylic acid) unit as the pH-sensitive block. Hydrophilicities of both blocks undergo a substantial change in response to these stimuli and resulting in shifting of hydrophilic-lyophilic balance (HLB) of the polymer, and it can act as a driving force to umpire the assembly and disassembly process. Very recently, Liu, Chen, and his coworkers reported the self-assembly behavior of pH- and thermoresponsive hydrophilic ABCBA-type pentablock copolymer, consisting of PEG, PNIPAM, and poly(2-(diethylamino)ethyl methacrylate) (PDEA) [428]. This copolymer, PDEA-b-PNIPAM-b-PEG-b-PNIPAM-b-PDEA, was synthesized by consecutive RAFT polymerization technique. Solution properties of the copolymer (PDEA-b-PNIPAM-b-PEG-b-PNIPAM-b-PDEA) can be manipulated easily because of its multicomponent and multifunctional nature. For example, the copolymer was molecularly dissolved in acidic solution at room temperature because at this condition, pH of the solution is below the pK _a value of PDEA block and the temperature is below the LCST of PNIPAAm block (Fig. 6.73). However, in alkaline medium at room temperature, the copolymer can self-assembled into core–shell–corona micelles, with the hydrophobic PDEA block as the core, the thermoresponsive PNIPAAm block as the shell and the hydrophilic PEG block as the corona (Fig. 6.73). Upon increasing the temperature above the cloud point of PNIPAAm block in acidic medium, the copolymer self-assembled into hydrophobic PNIPAAm-core micelles with mixed hydrophilic PEG and pH-responsive PDEA coronas (Fig. 6.73). These properties of the thermo- and pH-responsive micelles open up new opportunities in the field of intelligent drug delivery systems.

We have also involved in the synthesis of amino acid-based dual thermo- and pH-responsive zwitterionic polymer. We have synthesized l-serine-based zwitterionic polymers (PSAs) of controllable molecular weights and low dispersities via RAFT polymerization technique in water (see Fig. 6.74) [315]. PSAs exhibited an isoelectric point at around pH 2.85 and within the pH range of 2.3–3.5, the aqueous PSA solution became a two-phase system due to the formation of insoluble aggregated structure of PSA through the electrostatic attraction between the pendent cationic ammonium and anionic carboxylate groups of PSA (Fig. 6.74). Furthermore, within this pH range of 2.3–3.5, the PSAs exhibited reversible UCST-type phase transition due to the formation of aggregated globular nanostructures below cloud point and transformed into soluble coils above the cloud point (Fig. 6.74). Finally, fluorescent labeling of PSA was carried out with FITC, and the final conjugate retained its dual-responsive nature (i.e., temperature and pH) for its future potential application in sensors and bioimaging. The work in this direction is currently underway in our laboratory.

Liu et al. reported a polypeptide hybrid double-hydrophilic poly(N-isopropylacrylamide)-b-poly(l-glutamic acid) (PNIPAAm-b-PLGA) BCP, which was synthesized via the ring-opening polymerization of γ-benzyl-l-glutamate N-carboxyanhydride using monoamino-terminated PNIPAAm as the macroinitiator [429]. It is noteworthy that the as-synthesized BCP contains a thermoresponsive PNIPAM block and pH-responsive PLGA block. However, the obtained polypeptide hybrid diblock copolymer molecularly dissolves (Fig. 6.75) in aqueous solution at alkaline pH, and at room temperature but supramolecularly self-assembled into PNIPAAm-core micelles (Fig. 6.75) at alkaline pH and at an elevated temperatures. Further at acidic pH and at room temperature, the PMIPAM-b-PLGA copolymer formed PLGA core micelles with coil-to-helix transition of the PLGA sequence.

A poly(ethylene glycol)-b-poly(n-butyl methacrylate)-b-poly(N,N′-dimethylamino ethyl methacrylate)(PEG-b-PnBMA-b-PDMAEMA) triblcok copolymer with a dual pH- and thermoresponsive PDMAEMA as end segment was developed via sequential RAFT polymerization [430]. The PEG-b-PnBMA-b-PDMAEMA triblock copolymer molecules self-assembled into spherical micelles in acidic solution but transformed into cylindrical micelles in alkaline solution. This pH-induced shape transformation was reversible. Moreover, this triblcok copolymer underwent a pathway-dependent re-assembly from cylinder to toroid or to vesicle upon programmed variation of solution pH and temperature in dilute aqueous solution. It was found that the re-assembly from cylinder to toroid or to vesicle was apparently irreversible as confirmed through DLS and cryogenic transmission electron microscopy (cryo-TEM).

Zhang et al. [431] have demonstrated a new approach based on using UCST polymers to develop assemblies that are able to undergo a solubility transition in aqueous solution at room or body temperature (37 °C) in response to a small pH change. Here, two copolymers, P(AAm-co-AN-co-AAc) or P(AAm-co-AN-co-4VP)), were synthesized by incorporating either acrylic acid (AAc) or 4-vinylpyridine (4VP) comonomer units in the random copolymer of acrylamide and acrylonitrile, P(AAm-co-AN) through RAFT technique. As mentioned above that this random copolymer, P(AAm-co-AN)), exhibited an UCST-type phase transition [136]. The pH-induced shift of UCST cloud point was investigated by them by monitoring the solution cloud point. Their results revealed an unusually large shift of the cloud point upon pH variation over a small range.

In particular, one P(AAm-co-AN-co-4VP) sample exhibited a cloud point drop from 72 °C at pH 4.75–15 °C at pH 4.50, and its transition from soluble to insoluble state at room temperature was visually observable over a pH change as little as 0.05 unit. Using P(AAm-co-AN-co-4VP) as macromolecular chain transfer agent to polymerize dimethylacrylamide (DMAAm) through RAFT, an ABA-type triblock copolymer of P(AAm-co-AN-co-4VP)-b-PDMAAm-b-P(AAm-co-AN-co-4VP) was prepared, which showed an even larger cloud point switch from 71 to 10 °C with pH decreasing from 4.75 to 4.50. Consequently, the micelle formed by this block copolymer was stable at 37 °C with pH from 7.00 down to 4.75 but abruptly dissolved at pH 4.50 due to the water solubility switch [431]. This study demonstrated a new UCST polymer-based approach to polymer assemblies that can sense a very small pH change by undergoing straightforward water solubility switch.

In another example, an ionically assembled nanoparticles (INPs) have been prepared from poly(ionic liquid-co-N-isopropylacrylamide) composed of poly(ethylated 4-vinylpyridine) and PNIPAAm with deoxycholic acid through electrostatic interaction (Fig. 6.76) [432]. The assembled complex nanoparticles were disrupted under acidic conditions, where DA is protonated leading to a decrease in electrostatic interactions which are the driving force for the assembly. Appreciable release of guest molecules was observed at pH 5.2 at 37 °C, elevating the temperature enhanced the release percentage at the same pH. When heated above the LCST at pH 7.4, PNIPAAm presumably became less hydrophilic causing inter-particle aggregation, which likely caused the guest molecules to be squeezed out [432].

Zuo et al. [433] have been demonstrated a facile strategy for the preparation of thermo- and pH-responsive nanogels particles through RAFT crosslinking copolymerization of ionic liquid-based monomers. The use of chain transfer agents (CTAs) containing carboxyl group in the RAFT polymerizations is the key to producing highly thermoresponsive nanogel particles. It was demonstrated that the critical gelation temperature of the as-prepared nanogels can be tuned by adjusting the feed ratio of monomer and CTA. It was proposed based on the results of temperature-dependent FTIR and other control experiments that the hydrogen bonding interactions between the carboxyl groups of CTAs are responsible for the thermoresponsive behaviors of PIL-based nanogel nanoparticles. Furthermore, PIL-based nanogels are also found to be pH-sensitive and can be further decorated by PNIPAAm via surface-grafting polymerization. PNIPAAm-grafted nanogel aqueous suspensions can be reversibly transformed into macrogel particles upon a change in temperature [433]. A oral delivery copolymeric system consisting of thermoresponsive zwitterionic poly(sulfobetainemethacrylate) (polySBMA) and pH-responsive poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) was synthesized via free radical polymerization [434]. This copolymer self-aggregated into nanogel particles via electrostatic attraction between ammonium cation and sulfo-anion of poly(SBMA) and successfully encapsulate anticancer drug, curcumin. The stimuli-responsive phase transition behaviors of P(SBMA-co-DPA) copolymers at different pH buffer solution showed pH-dependent UCST-type transition attributed to the influence of protonation/deprotonation of the pH-responsive PDPA segments. Through the delicate adjustment of the poly(SBMA)/PDPA molar ratios, the stimuli-responsive phase transition could be adjusted to physiological environment [434].

10.2 Temperature- and Light-Responsive Polymer Nanostructures

There are several arresting reports that allow for a fine-tuning of the LCST/UCST-type cloud point of a polymer or block copolymer by light irradiation or enable the controlled formation of nanoaggregates by combining temperature and light. The first example of a temperature and light-responsive polymer system was random copolymers of NIPAAm with N-(4-phenylazophenyl)acrylamide of varying compositions. The objective of their work was to control the phase transition temperature of aqueous solution of PNIPAAm by incorporating photochromic azobenzene moieties [435]. They have demonstrated that there was a clear shift in the LCST-type phase transition temperature from initially 21 to 27 °C after UV light irradiation (λ = 360 nm) was observed for the copolymer system containing 2.7 mol% of azobenzene group. This change was explained by the change in the dipole moment due to the trans-to-cis isomerisation of the azobenzene moieties upon UV light irradiation. As mentioned above that the isomerization of azobenzene upon UV/visible light irradiation is accompanied by a strong polarity change. This polarity change is a direct consequence of the change in the dipole moment from 0 Debye for the trans-isomer to 3 Debye for the cis-isomer [435]. However, the initial phase transition temperature of 21 °C was re-obtained after visible light (λ = 440 nm) exposure because at this wavelength, cis-form re-isomerizes into trans-form.

Another report based on thermo- and light-responsive copolymers was the work of Ravi and his coworkers [424]. The authors synthesized a copolymer, poly(2-(dimethylamino)ethyl methacrylate-co-poly(azo-methacrylate) (PDMAEMA-co-PAzM), via ATRP in which the PDMAEMA block exhibits a LCST behavior (Fig. 6.77). LCST of the PDMAEMA-co-PAzM BCP increased upon UV irradiation from 41 °C for the trans-form to 44 °C for the cis-form (Fig. 6.77). The LCST of the copolymer (PDMAEMA-co-PAzM) increased upon irradiation by UV light due to the cis conformers being more hydrophilic. In addition to this, the following copolymer (PDMAEMA-co-PAzM) can self-assembled into core–shell micelle as evident from TEM image (Fig. 6.77).

Another synthetic illustration of thermo-and light-responsive BCP was described by Kakuchi and his coworkers with the combination of ATRP and “click” chemistry. In this context, an azide terminated PNIPAM was conjugated to an alkyne terminated poly(6-[4-(4-methoxyphenylazo)phenoxy]hexyl methacrylate) by CUAAc technique, resulting in the formation of BCP consisting of one thermoresponsive block and one photoresponsive block [436]. They observed that upon UV light irradiation, LCST-type cloud point of the BCP increases up to 4.1 °C from trans- to cis-form of the BCP containing only 1.4 mol% of azobenzene. Another pioneering work in this area was on the synthesis of thermo- and light-sensitive BCP namely poly(ethylene oxide)-b-poly(ethoxytri(ethylene glycol) acrylate-co-o-nitrobenzyl acrylate) (PEO-b-P(ETEGA-co-NBA)) (Fig. 6.78) via ATRP and the investigation of the micellization/dissociation transitions in water in response to temperature changes and UV light irradiation [437]. The PETEGA sequence confers the thermosensitivity into the BCP, (PEO-b-P(ETEGA-co-NBA)) which displays a cloud point at around 25 °C (LCST₁). Upon UV light irradiation, the irreversible photocleavage of o-nitrobenzyl ester moieties into carboxylic acid increases the hydrophilicity of the BCP and consequently, increases the cloud point by more than 10 °C (LCST₂ = 36 °C). The PEO-b-P(ETEGA-co-NBA) BCP was molecularly dissolved in water at low temperature. But at higher temperature above LCST₁, the BCP can self-assemble into polymer micelles where the thermoresponsive PETEGA block forms the core and PEO block forms the corona (Fig. 6.78). Upon UV light irradiation, photolysis of o-nitrobenzyl ester units taken place and therefore, cloud point of thermosensitive block (PETEGA) was increased, causing the dissociation of micelles into unimers (Fig. 6.78), leading to the release of encapsulated fluorescent dye NR into water. However, further increase in the temperature above LCST₂ induced the reformation of micelles (Fig. 6.78) and re-encapsulation of NR. Here, the thermo-induced formation and dissociation of micelles were reversible.

In 2010, Jian et al. [438] developed spiropyran-based novel thermo- and light-responsive BCP to fabricate micelles and reverse micelles in aqueous solution. The BCP namely poly(spiropyranmethacrylate)-b-poly((diethylene glycol) methyl ether methacrylate) (PSPMA-b-PDEGMMA) was synthesized by ATRP of spiropyran containing methylacrylate (SPMA) with di(ethylene glycol) methyl ether methacrylate (DEGMMA). At 15 °C and under visible light, the molecularly dissolved PSPMA-b-PDEGMMA in water was transforming into core–shell micelles (D = 80 nm) where photosensitive and hydrophobic PSPMA block was in the core and hydrophilic PDEGMMA formed the corona (Fig. 6.79).

Upon irradiation with UV light, spiropyran moiety changed from its nonpolar spiropyran to polar mecrocyanine form and resulting in the isothermal disruption of micelles (Fig. 6.79), and the process is fully reversible. Upon visible light exposure, mecrocyanine isomerized back into less polar spiropyran form and the micells are regenerated (Figure 6.79). However, further irradiation with UV light followed by heating resulted in the formation of reverse micelles having hydrodynamic diameter of 24 nm (Fig. 6.79). In this case, at higher temperature, thermosensitive PDEGMMA block forms the core and more polar mecrocyanine unit forms the corona (Fig. 6.79). This study represents a fascinating contribution to applying light and temperature independently in order to control the morphology of nanoaggregates in solution and can be used as “smart” polymer nanocarriers for controlled encapsulation, triggered release and re-encapsulation of model drug coumarin 102.

10.3 Redox- and pH-Responsive Polymer Nanostructures

Among the so-called chemically responsive drug delivery systems composed of polymeric materials, pH and redox are two popular stimuli employed to instigate sharp changes in the properties of polymer materials. These are the major chemical stimuli to trigger the drug release from cargos. Polymer nanocarrier that is designed to respond separately toward single pH or redox stimulus has been extensively investigated. However, polymer nanocarriers that can respond to both pH and redox stimuli are rare and still not investigated in detail [36].

A recent report described the formation of dual pH and redox sensitive micelles from a novel copolymer-based on PEG and reducible poly(β-amino ester)s (RPAE) containing disulfide bonds in the backbone and studied the intracellular release of doxorubicin (DOX) from these micelles (Fig. 6.80) [439]. According to them, these sub-100 nm micelles represented core–shell morphology with the RPAE constituting the core and the PEG as the shell and were stable under physiological conditions (pH > 7.0) (Fig. 6.80). At pH < 6.5, the protonation of tertiary amine of RPAE unit of the copolymer disrupts the hydrophilic-lyophilic balance in the micelles resulting in the dissociation of micelles (Fig. 6.80). In addition, dithiothreitol (DTT) triggered dissociation of RPAE-PEG micelles was also demonstrated due to the degradation of disulfide bonds present in the RPAE backbone (Fig. 6.80). They further showed that the encapsulated anticancer drug DOX can be released from RPAE-PEG micelles either in acidic pH (6.5) or upon treatment with concentrated DTT solution (Fig. 6.80). The most important advantage of this design is that the highest rate of DOX release from the copolymer (RPAE-PEG) micelles was observed in an environment at a low pH value and with a high concentration of reductive agent (Fig. 6.80).

Another exciting example of dual pH- and redox-responsive polymer architecture is a core crosslinked micelle which was reported by Wang and his coworkers [440]. They designed the polymer on the concept of “AND” logic gate for intracellular drug delivery, since drug can only be released when both pH and redox stimuli are present. In this pioneering work, a drug molecule, adriamycin (ADR) was first attached to a hydrazine functionalized poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA) BCP via the formation of hydrazone. The ADR-conjugated PEO-b-P(MAA-Hyd) can be self-assembled to form stable micelle which was further crosslinked in the presence of dithiodiethanoic acid. No remarkable ADR release was found under reducing conditions at neutral pH, due to the intact hydrazone linkage, even though the micelles were uncrosslinked due to the reduction of disulfides (Fig. 6.81). ADR was also not released upon treatment of the crosslinked micelles in an acidic pH. However, ADR was cleaved from the polymer backbone in acidic condition but it was trapped within the crosslinked micelles, and therefore, no effective release was observed (Fig. 6.81). The effective release of ADR could only be observed by simultaneous treatment at low pH and reducing reagents (Fig. 6.81). This smart device is therefore equipped with two triggers, pH, and redox with the “AND” logic gate for the releasing action, which is favorable for more complicated physiological conditions because the “ON” state is only realized under the simultaneous presence of the both the stimuli.

11 Multiple Stimuli-Responsive Polymer Nanostructures

Multiple stimuli-responsive polymer nanomaterials are responsive to more than two stimuli, are materially interesting, and are comparatively less investigated. However, recent research activities toward triple responsive polymer systems have gained propulsion. It is worth mentioning that effect of more than two stimuli on polymer system is highly advantageous because it will not only increase the degree of precision but also enlarge the switching window to play with its properties more sophisticatedly because of the higher level of complexity of the polymer.

11.1 Temperature-, pH- and Light-Responsive Polymer Nanostructures

Temperature-, pH-, and light-responsive polymer systems can only be obtained by the combination of building blocks that contain all pH-, thermo-, and photoresponsive moieties. In this direction, Zhou, Tang, and his coworkers reported the synthesis of temperature-, pH-, and light-responsive water soluble N,N-dimethylaminoethyl methacrylate (DMAEMA) homopolymers containing an azobenzene moiety as the terminal group by ATRP (Fig. 6.82) [54]. Indeed, the as-synthesized homopolymer exhibited a LCST-type transition that can be altered reversibly in response to pH and photoisomerization of the terminal azobenzene moiety. In an acidic pH (pH = 4), the DMAEMA units are fully protonated, resulting in increase in polarity and hence no LCST was observed. However, upon increase in pH, the LCST cloud point was lowered to 68 °C at pH = 7–30 °C at pH = 11 because of the continuous deprotonation of dimethyl amino groups. Additionally, upon UV light irradiation, the trans-to-cis photoisomerization of the azobenzene moiety increases the hydrophilicity of the polymer which leads to increase in cloud point. This kind of polymer systems is highly interesting for a variety of potential applications such as controlled drug delivery, intelligent materials because of their multistimuli-responsive property.

Another thermo-, pH-, and light-responsive polymer system was reported by Shinbo, Sumaru, and coworkers where they synthesized PNIPAAm functionalized with spirobenzopyran (SP) [441]. They investigated that the phase transition properties of aqueous solution of this copolymer exhibited a logic gate response with respect to light irradiation and in increase in temperature. It is worth mentioning that the PNIPAAm part in the polymer is responsible thermoresponsive behavior while light and pH-responsiveness is provided by the spirobenzopyran (SP) unit (Fig. 6.83). Similarly, Achilleos and Vamvakaki described synthesis of statistical copolymers comprising of a DMAEMA unit and a polymer block containing spiropyran unit [442]. In this case, not only the dimethylamino functionality acted as a pH-responsive unit, but also the spiropyran unit was able to respond to changes in pH along with the photoisomerization between the spiropyran and merocyanine isomers. Here, both the functional groups (DMAEMA and spiropyran) have dual-responsive property. DMAEMA moiety is sensitive toward both pH and temperature while spiropyran unit is sensitive toward pH and light.

Another triple-stimuli (thermo/pH/light)-responsive copolymer system was reported by Wang and coworkers [443]. In this report, poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) P(NIPAAm-co-NHMAAm) was first synthesized by free radical polymerization method. Afterwards, photosensitive 2-diazo-1,2-napthoquinone (DNQ) was partially grafted onto P(NIPAAm-co-NHMAAm) backbone through esterification to obtain triple-stimuli (thermo/pH/light)-responsive copolymer P(NIPAAm-co-NHMAAm-co-DNQMA) (Fig. 6.84). The NIPAM and NHMA moieties of the copolymer P(NIPAAm-co-NHMAAm-co-DNQMA) are considered to be thermo- and pH-responsive, respectively, while DNQ was designated as photoresponsive unit (Fig. 6.84). Upon UV light irradiation, hydrophobic DNQ moiety of the copolymer can undergo “Wolff” rearrangement irreversibly and converted into hydrophilic 3-indenecarboxylic acid derivative (Fig. 6.84). Photoirradiation increases the polarity and resulting in the change of hydrophilic-hydrophobic balance of the entire polymer. Indeed, they showed that the phase transition profile of P(NIPAAm-co-NHMAAm-co-DNQMA) copolymer can be tailored easily by pH variation as well as by UV light irradiation.

An interesting example of triple-stimuli (thermo/pH/light)-sensitive polymeric micelles for controlled release application was reported in 2013 by Dong and his coworkers [444]. To achieve the triple-stimuli sensitivity, they first synthesized hydrophilic pH/thermo-sensitive poly(N,N-dimethylaminoethyl methacrylate) (PDEAEMA). Afterwards, 14 mol% of dimethylamioethyl functionality of PDMAEMA block was quaternized by light-responsive 1-(bromomethyl)pyrene to introduce hydrophobicity into polymer system (Fig. 6.85). The BCP self-assembled into core–shell micelles in aqueous medium where the hydrophobic pyrene moieties constitute the core and the dimethylaminoethyl (DMAE) moieties forming the shell (Fig. 6.85). Above the LCST, PDMAEMA block becomes hydrophobic which resulted in shrinking of the micellar size (Fig. 6.85). However, upon UV light irradiation below LCST, photosolvolysis of pyrenylmethyl groups from the quaternized amine increases the hydrophilicity of the whole block polymer resulting in the complete disruption of micelles (Fig. 6.85). In addition, the micelles are collapsed to a complex micelle at high pH and swollen/dissociated at low pH (Fig. 6.85). It should be mentioned that the pH and the temperature-responsive behavior of this polymer were totally reversible while light-responsive behavior is fully irreversible because after light irradiation, the disrupted micelles never regain its initial form. These multistimuli-responsive polymer micelles have great potentiality to act as a sensitive nanocarrier for controlled release under the stimuli of UV light, temperature, and pH, especially under UV light and low pH where all the loaded guest molecules such as NR could be released completely.

11.2 Light-, Redox-, and Temperature-Responsive Polymer Nanostructures

Light-, redox-, and temperature-responsive polymer systems are also very interesting because of their unprecedented precision and versatility. However, this type of triple (light/redox/temperature)-responsive polymer systems are rare and less investigated. Theato et al. reported the synthesis of triple (light/redox/temperature)-responsive PNIPAM-based copolymers containing azobenzene and TEMPO moieties by post-polymerization modification strategy utilizing well-defined poly(pentafluorophenyl acrylate) (PPFPA) (Fig. 6.86) [445]. Here, TEMPO moiety is redox-responsive and can be reduced as well as re-oxidized in a reversible fashion by using ascorbic acid as a reducing agent and red prussiate as an oxidizing agent, respectively. The reduction of the TEMPO moiety to the corresponding hydroxylamine enhanced the hydrophilicity of the entire copolymer and resulting in the increase of LCST-type cloud point. However, oxidation of the hydroxylamine moiety back to the TEMPO radical was achieved directly by addition of red prussiate which led to a significant decrease of the cloud point. It is worth mentioning that the LCST-type cloud point of the copolymer can be fine-tuned simply by changing the degree of reduction of the TEMPO moieties. Additionally, upon UV light irradiation, the trans-to-cis photoisomerization of the azobenzene moiety increases the polarity of the entire polymer which also leads to increase in LCST-type transition.

One interesting example of multistimuli (light/redox/temperature)-sensitive amphiphilic BCP micelles was reported by Thayumanavan and his coworkers [446]. The synthesized BCP consists of an acid-sensitive tetrahydropyran-protected poly(hydroxylethyl methacrylate) (PHEMA) as the hydrophobic part and a temperature-sensitive PNIPAAm as the hydrophilic part with an intervening disulfide bond which is designated as redox-sensitive unit (Fig. 6.87). The BCP exhibited LCST-type cloud point which can be tuned under wide range of temperature upon pH variation and redox reagent treatment. They have also investigated the micelle formation, and its disruption in response to different stimuli (Fig. 6.87). Upon mild acidic condition (pH = 4), deprotection of PHEMA takes place and consequently, the PHEMA block becomes hydrophilic which causes the disruption of BCP micelle due to the dramatic change in the hydrophilic/lipophilic balance (Fig. 6.87). On the other hand, above the LCST point, the hydrophilic thermoresponsive PNIPAAm block was converted to hydrophobic block, rendering the polymer insoluble in water which does not maintain its micellar structure any longer (Fig. 6.87). Finally, the addition of DTT triggers the reductive cleavage of disulfide linkage resulting in the separation of BCP into two distinct blocks, the hydrophobic PHEMA block precipitates while the hydrophilic PNIPAAm stays in solution and hence no assembly. They investigated the release kinetics of encapsulated guest molecule and showed that the application of just single stimulus leads to a very slow or incomplete release kinetic, but the combination of two stimuli accelerates the release of the encapsulated guest molecules, making drug delivery much more efficient.

11.3 Temperature-, Enzyme-, and pH-Responsive Polymer Nanostructures

Thayumanavan and his coworkers also reported a series of amphiphilic oligomers that exhibits sensitivity toward temperature, enzymatic reaction, and pH [447]. The amphiphiles composed of a penta(ethylene glycol) and alkyl moiety attached to the meta-positions of a benzoyl building block, which were then attached to oligoamine scaffolds to yield monomeric to hexameric oligomers. Temperature sensitivity of oligomers was assessed by turbidity measurements using the high-tension voltage response of the photomultiplier on a CD spectrometer keeping the concentration of oligo ethyleneglycol (OEG) unit constant. The LCSTs of these oligomers showed increasingly sharp transitions with increasing numbers of OEG functional groups, indicating enhanced cooperativity in dehydration of the OEG moieties when they are covalently attached. Additionally, the oligomers are also esterase enzyme sensitive because the alkyl moiety is terminated with an ester. After the treatment of the oligomer with esterase, the final product was a pH-sensitive carboxylic acid which can upshot the hydrophilic-lyophilic balance as well as LCST cloud point of the oligomer.

12 Responsive Polymer Materials in Advanced Energy Applications

Stimuli-responsive polymer-engineered nanomaterials are not much explored as advanced energy materials. However, among the different categories of stimuli-responsive polymers, redox-responsive polymers are important materials in fabricating devices toward various advanced energy applications. Redox-responsive polymers are electroactive macromolecules containing functional groups that can be reversibly oxidized and reduced. Redox reactions can take place in a polymer side-chain, as in the case of a polymer carrying ferrocene functional group or in the polymer main chain, as in the case of conjugated electrically conducting polymers, such as polyaniline [448]. Due to the reversibility and easy external control of any redox process, these polymers are interesting materials for different applications including design of a number of electrochemical devices such as batteries, supercapacitors, electrochromic devices, thermoelectric cells, optoelectronic devices, biofuel cells.

As mentioned above, redox polymers are important materials for the biofuel cell, which is a simple electrochemical device that converts chemical into electrical energy using enzymes as catalysts where glucose is used as fuel. In order to convert energy efficiently, in a biofuel cell, the effective immobilization of enzymes is required. This can be done by immobilization of enzyme in redox-active polymer hydrogel network associated with electrodes [449]. For example, redox polymers were used for the electrical contacting of oxidases and dehydrogenases with electrodes acting as anodes of biofuel cells, and for the electrical wiring of bilirubin oxidase, cytochrome oxidase, and laccase with electrodes, that yield the cathode units of the biofuel cells [450]. Osmium-based redox polymers have shown to be the most promising candidates to act as mediators in cathodes of membrane-less biofuel cell [451]. In a study, oxygen-reducing enzyme electrodes were first prepared from laccase of Trametes versicolor and a series of osmium-based redox polymer as mediators covering a range of redox potentials from 0.11 to 0.85 V, which was used as an electrode for a biofuel cell.

A microstructured redox hydrogel was reported by photochemical approach and enzymes are immobilized inside the gel and evaluated with respect to its potential in biosensor and biofuel cell applications. For this, poly(dimethylacrylamide) polymers with both electroactive ferrocene groups and photoreactive benzophenone groups are synthesized and deposited as thin films on electrode surfaces [452]. Upon UV light irradiation, glucose oxidase containing polymer layer cross links and becomes firmly adhered to the glassy carbon electrodes. They obtained the glucose-oxidizing electrodes with very high catalytic current responses.

Among the other electrochemical energy storage systems, supercapacitors are a particular type of systems where the energy is stored through Faradic mechanism, a redox reaction, taking place at the electrode and the electric charge is stored electrostatically. Supercapacitors are able to charge/discharge at high rates containing high power density compared with batteries. There several reports of Pseudocapacitor electrodes that are made up of polymer composites with metal oxides [453] or carbons [454], polymer-coated carbons [455] or conducting polymers such as polyaniline [456], polypyrrole [457], polythiophene [458], and their derivatives. Conducting polymers are suitable electrode materials as they are able to storage charges in their doped state. For this reason, several different strategies of fabricating composite electrode materials, nanostructured conducting polymers such as nanorods, nanofibers, nanowires, and nanotubes [459] or using carbons as negative electrodes have been investigated. Polyaniline was used as supercapacitor electrode material due to its high electroactivity, stability, and specific capacitance [460]. Composite electrodes of graphene and polyaniline also studied to get good cycle stability and high specific capacitance [461].

Cong et al. [462] presented the fabrication of a flexible graphene–polyaniline composite paper by in situ electropolymerization of polyaniline nanorods on the graphene paper with a specific capacitance of 763 F g⁻¹ at a discharge current of 1 A g⁻¹ and a good cycling stability with 82% of capacity retention after 1000 cycles. In recent years, nanostructured polypyrrole materials have been developed as more powerful supercapacitors [463]. For example, Huang et al. reported the synthesis of length controllable and well-oriented polypyrrole nanowire arrays with a capacitance of 566 F g⁻¹ and retention of 70% after hundreds of charge/discharge cycles [464]. In another report, polypyrrole was used together with carbon materials to design a positive electrode material [465].

Recently, dye sensitized solar cells (DSSC) are very promising and can be readily achieved with certain level of efficiencies [466]. It is also considered as the next-generation photovoltaic devices. In this type of DSSC, the key component is a triiodide/iodide redox couple usually dissolved in an organic liquid electrolyte. This DSSC technology faces high-temperature stability issues to pass standardized packaging durability tests of solar cells. One of the solutions is its solidification [467] using a number of redox-responsive polymers [467]. Among all the different strategies, one of the important strategies includes the incorporation of iodide redox couple in poly(vinyl imidazolium) iodide polymeric ionic liquids. In another interesting strategy, PEDOT was successfully proposed due to its redox properties as a solid substitute of the iodine liquid electrolytes [468]. As per their report, the best performances of these solid solar cells are still low (aprox. 7%) but the advantages are considerable because they can be processed easily.

In general metal alloys are generally used as thermoelectric materials that generate electricity directly from heat. However, recently it has been suggested that organic semiconductors could offer cost-effective alternatives, made from solution that could open up new possibilities, including harvesting energy over large areas. This requires thermoelectric materials that are readily synthesized, air stable, environmentally friendly, and solution processable to create patterns on large areas [469]. There are very few conducting polymers that have been explored as thermoelectric materials [470]. However, research in this area is still not progressed much and extensive efforts are required to understand and utilize polymers. Crispin and coworkers showed that the PEDOT can be used as thermoelectric materials with its low intrinsic thermal conductivity (λ = 0.37 W m⁻¹ K⁻¹) leaded to a record thermoelectric figure of merit (Seebeck coefficient) ZT = 0.25 at room temperature. This value was slightly lower than the values required for efficient devices [469]. According to their report, the thermoelectric properties of PEDOT were mostly associated to its thermal and electrical conductivity, it is worth to remark that those properties and its doping level are directly linked to its redox properties [469].

13 Conclusions and Outlook

In the present century, the major focus of materials research is to develop “smart” responsive materials, mostly based on polymers that can be triggered by the stimuli present in living cells without causing any toxicity or inauspicious effects. Here, we have emphasized some recent developments in polymer and material science that covered the stimuli-responsive polymer nanomaterials. Various design strategies for the development of various stimuli-responsive polymer nanomaterials were systemically described with an aim to their potential applications. However, many challenges still need to be addressed, especially as far as applications of those systems are concerned. Now it is time to extend their use to biocompatible and biodegradable nanostructured polymer materials since, as mentioned earlier, the key interest of this type of nanomaterials is to develop a “smart” method for controlled drug delivery applications.

A straightforward perspective to prepare biocompatible and biodegradable stimuli-responsive block copolymer (BCP) micelles/vesicles probably is to combine the hydrophilic biocompatible polymers (such as PEO or poly(2-oxazoline)) with different functionalized hydrophobic polypeptide such as poly(glutamic acid), poly(aspartic acid), poly(lysine) by applying the established methodologies as discussed above. As for example, for photocontrolled drug delivery, one needs to develop biocompatible BCP nanomaterials that have some essential characteristics such as low cytotoxicity, can contain larger amount of payloads, stable inside the blood stream for a long circulation time, can selectively accumulate in the diseased cells or tissues and then, can be disrupted by NIR light in a controlled manner.

However, much advance research remains to be done to achieve this level of functions and controls. It is also important to control the size and shape of the nanostructured-responsive polymeric materials when someone thinks about the making of real and efficient and triggered drug delivery systems. For stimuli-responsive polymers and BCPs, it may also be interesting to start exploring some possible applications in other areas such as cosmetics, agricultural industries, optical devices, responsive coatings. Finally, the design, synthesis, and development presented in this chapter will surely be helpful for introduction of new concepts in stimuli-responsive polymer materials which may be beneficial for many new applications in future.

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Acknowledgements

Y. B. and S. J. thank IACS for providing fellowship. M.D. thanks CSIR, New Delhi, for fellowship. We thank Mr. Anupam Saha, Mr. Tanmoy Maji, and Mr. Avijit Bose for helpful discussion and support during the preparation of the manuscript.

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Polymer Science Unit, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700032, India
Yajnaseni Biswas, Somdeb Jana, Madhab Dule & Tarun K. Mandal

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Yajnaseni Biswas
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Somdeb Jana
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Madhab Dule
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Tarun K. Mandal
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Correspondence to Tarun K. Mandal .

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School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
Zhiqun Lin
School of Chemistry & Materials Science, South-Central University for Nationalities, Wuhan, Hubei, China
Yingkui Yang
School of Chemistry & Materials Science, South-Central University for Nationalities, Wuhan, Hubei, China
Aiqing Zhang

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Biswas, Y., Jana, S., Dule, M., Mandal, T.K. (2017). Responsive Polymer Nanostructures. In: Lin, Z., Yang, Y., Zhang, A. (eds) Polymer-Engineered Nanostructures for Advanced Energy Applications. Engineering Materials and Processes. Springer, Cham. https://doi.org/10.1007/978-3-319-57003-7_6

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DOI: https://doi.org/10.1007/978-3-319-57003-7_6
Published: 18 June 2017
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-57002-0
Online ISBN: 978-3-319-57003-7
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)

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