Abstract
The supramolecular self-assembly formed between cyclodextrins (CDs) and polymers has inspired interesting development of many novel supramolecular hydrogels as injectable delivery systems for sustained drug or gene release due to their thixotropic nature, thermoreversible properties, and biocompatibility. A large number of supramolecular hydrogels have been formed between CDs and poly(ethylene oxide) or its block copolymers with a hydrophobic segment. The intermolecular interactions by the hydrophobic blocks further strengthen and stabilize the supramolecular network, opening up a new approach for designing long-term sustained delivery systems. Recent advances in this field have greatly improved the rheological and delivery properties of the supramolecular hydrogels, making them more suitable for biomedical applications. Novel supramolecular structures based on pseudoblock copolymers formed by host-guest inclusion complexation with new stimuli-responsive properties have also been developed, forming “smart” supramolecular hydrogels with more desired and promising properties for controlled release applications.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
7.1 Introduction
A supramolecular system consists of two or more molecular entities that are held together and organized by intermolecular non-covalent binding interactions [1]. There have been tremendous interest and studies on the supramolecular structures involving macrocyclic compounds which not only act as models for understanding natural supramolecular self-assembly and molecular recognition but also act as precursors for designing novel nanomaterials for applications in the electronics, biomedical, and pharmaceutical fields [2,3,4,5,6,7,8].
Cyclodextrins (CDs) are a series of natural cyclic oligosaccharides composed of 6, 7, or 8 D(+)-glucose units linked by α-1,4-linkages and named α-, β-, or γ-CD, respectively (Fig. 7.1a) [9, 10]. The CDs have a hydrophobic inner cavity with a depth of ca. 7.0 Å and an internal diameter of ca. 4.5, 7.0, or 8.5 Å for α-, β-, or γ-CD, respectively. Supramolecular inclusion complexes can be formed between CDs and various molecules that can fit into the cavities of CDs, and they have been used as models for extensive studies to understand the mechanisms of molecular recognition [11,12,13,14].
Hydrogel is a three-dimensional crosslinked macromolecular network formed from hydrophilic polymers. The three-dimensional network can retain large volumes of water, causing the swelling of the crosslinked structure in solution. The hydrophilicity of the polymer chains and the crosslinking density are the important factors that greatly influence the extent of swelling and the content of water retained. The crosslinking can be made by either covalent bonds or physical cohesion forces between the polymer chains, such as ionic bonds, hydrogen bonds, van der Waals forces, and hydrophobic interactions [15,16,17,18].
There has been great interest and investigations of polymeric hydrogels for biomedical applications due to their favorable biocompatibility, as well as high water content, which is attractive for delivery of delicate bioactive agents such as proteins [19,20,21,22]. Hydrogels provide a favorable environment for proteins or peptide drugs, and the release can be controlled by adjusting the crosslinking densities [23]. However, many hydrogels that require covalent crosslinking for gelation are limited to applications as implantables, and it is time-consuming to incorporate drugs by sorption, limiting the loading level as well. Moreover, the crosslinking process may conjugate the drugs to the hydrogels or impair the drugs’ chemical integrity. Therefore, it would be more attractive to develop a delivery system that is capable of simultaneous gelation and drug loading in aqueous environment without covalent crosslinking.
Recently, hydrogels based on polymer-cyclodextrin inclusion complexes have become a promising class of physical hydrogels suitable for controlled drug or gene delivery [10, 22, 24,25,26,27]. The first report on a CD inclusion polymer forming a hydrogel dated back to 1994, describes the discovery of a sol-gel transition during inclusion complexation between α-CD and high molecular weight PEO in aqueous solution [28]. The gelation was induced by the partial formation of inclusion complexes between α-CD and PEO, self-assembling into water-insoluble domains which acted as physical crosslinks. Since then, there have been overwhelming interest and extensive studies on the polymer-cyclodextrin-based supramolecular hydrogels.
This review will update the recent advances in supramolecular hydrogels self-assembled from polymer-cyclodextrin inclusion complexes developed for injectable controlled drug and gene delivery. The review also covers the design of new stimuli-responsive host-guest inclusion complexes based supramolecular hydrogels as “smart” functional materials for biomedical applications.
7.2 Injectable Drug Delivery Systems Based on α-CD-PEO Supramolecular Hydrogels
α-CD can form inclusion complexes with linear water-soluble polymers such as PEG that can penetrate the inner cavity of α-CD, forming a necklace-like supramolecular structure. The precipitation of the inclusion complexes of α-CD and PEO from aqueous solutions indicates the self-assembly of the formed complexes into larger supramolecular structures with altered hydrophobicity. The first example of the hydrogel formation between CDs and polymers was demonstrated through the supramolecular self-assembly of part of the chain of high molecular weight PEO, resulting in a sol-gel transition of the α-CD-PEO aqueous solutions (Fig. 7.2) [10, 28].
Both CDs and PEO are known to be biocompatible and bioabsorbable. As a result, a new class of injectable hydrogels based on the supramolecular hydrogels formed between CDs and PEO or its copolymers has been developed for controlled drug delivery [29]. These supramolecular hydrogels are thixotropic and thermoreversible. It was found that the viscosity of the hydrogels formed between α-CD and PEO decreased significantly when agitated (Fig. 7.3a) [10, 29] and was restored toward its original value within hours in most cases, when agitation was removed (Fig. 7.3b). These thixotropic and thermoreversible properties render the hydrogel formulations a unique injectable drug delivery system which can be injected even through a fine needle. For example, bioactive agents such as drugs, protein vaccines, or plasmid DNA can be firstly incorporated into the hydrogel in a syringe at room temperature without any contact with organic solvents. The drug-loaded hydrogel with thixotropic property can then be injected into the tissue under pressure, and serve as a depot for controlled release after restoration in situ (Fig. 7.4) [10]. These injectable hydrogels will be much more attractive when compared to implantable hydrogels.
It was investigated how the injection through needles affect the viscosity of the hydrogel [29]. The viscosity diminished greatly after injection, with a steeper decrease due to the higher shear rate caused by the finer needle. The maximum speeds at which the hydrogels can be injected through needles of different sizes were summarized in Table 7.1 [29]. It was more difficult to inject the hydrogels formed between α-CD and PEOs of higher molecular weights through the needles [29].
The drug delivery properties of the injectable supramolecular hydrogels have been investigated in vitro using a model system, whereby fluorescein isothiocyanate-labeled dextran (dextran-FITC) was loaded into the hydrogels and their in vitro release properties were evaluated [29]. The in vitro release profiles of dextran-FITC from the hydrogels formed with PEO of different molecular weights are shown in Fig. 7.5 [10, 29]. The significant reduce in release rate with increasing molecular weight of PEO up to 35,000 Da is presumably a result of chain entanglement and different complex stability. The hydrogels formed with 35,000 Da PEO (Gel-35 K-60) and 100,000 Da PEO (Gel-100 K-60) show relatively steady release rate over time, with Gel-100 K-60 showing the most sustained release kinetics. However, the study of release kinetics of Gel-100 K-60 was mainly for understanding the structure-property relationship, because it would be undesirable to use PEO of this large for in vivo applications as its clearance from the body would be difficult [29].
Hydrogels formed by PEO block copolymers have been proposed previously as matrix for sustained release [30, 31]. On the other hand, the gelation of the α-CD-PEO hydrogel relies on the formation of the inclusion complexes induced by the PEO-threaded CDs. The drug release properties can be fine-tuned by adjusting the composition, molecular weight, and chemical structure of the polymers or copolymers.
7.3 Supramolecular Physical Hydrogels Based on α-CD and Copolymers for Drug Delivery
7.3.1 Supramolecular Hydrogels Formed by α-CD and PEO-PPO-PEO Triblock Copolymer
Although the α-CD-PEO hydrogels showed promising properties for drug delivery, there are still two main challenges in applying them clinically. Firstly, the release kinetics is too fast as the dissociation of the hydrogels in aqueous solutions is rapid due to the hydrophilic property of PEO. This makes the α-CD-PEO hydrogels only suitable for short-span drug release for less than 1 week. Secondly, the high molecular weight of PEO of more than 10,000 Da will be undesirable for in vivo drug delivery as it is not biodegradable, and its renal clearance from the body will be difficult due to its large hydrodynamic size. To overcome these problems and develop supramolecular hydrogels with desirable properties suitable for long-term controlled drug release, a new design of supramolecular hydrogels based on α-CD and various triblock copolymers, which have a hydrophobic middle block flanked by PEO blocks at both ends, was proposed [23]. The hypothesis for this design is that the hydrogels can be further strengthened by the additional intermolecular hydrophobic interactions of the middle blocks and become more stable for long-term controlled drug release (Fig. 7.6) [10, 23].
This idea was first proved by a supramolecular hydrogel formed by α-CD and Pluronic PEO-PPO-PEO triblock copolymer [32]. In addition to the thixotropic and reversible properties, these hydrogels are thermosensitive. Different from the thermosensitive hydrogels formed by PEO-PPO-PEO triblock copolymer alone at high concentrations [33, 34], the addition of α-CD largely lowered the copolymer concentration required for gelation due to the partial formation of inclusion complexes between α-CD and the flanking PEO blocks [35].
The phase diagrams of the mixtures of aqueous solutions of PEO-PPO-PEO and α-CD illustrated the effect of α-CD in aiding the hydrogel formation. In Fig. 7.7, which shows the temperature-polymer concentration phase diagrams of the aqueous solutions of PEO-PPO-PEO (EO13PO30EO13) in the absence and presence of α-CD of different concentrations, it can be seen that the region in which the pure EO13PO30EO13 (α-CD: 0%) can form a hydrogel is very small and limited to very high copolymer concentrations. As the α-CD concentration increases, the gelation regions also increase, with the lowest gelation concentration becoming much lower. It is evident that the partial formation of inclusion complexes between α-CD and the EO blocks of the EO13PO30EO13 significantly changed the hydrophobicity of the copolymer, leading to a much lowered gelation concentration [35].
The controlled release properties of these supramolecular hydrogels have been studied in vitro by using FITC-labeled bovine serum albumin (BSA-FITC) as a model protein drug. Hydrogels formed by α-CD and PEO-PPO-PEO triblock copolymers of various molecular weights and chain compositions were found to have a wide range of release kinetics. Among the different hydrogel formulations, the ones with EO10PO44EO10 showed a sustained BSA release with a linear release kinetics for more than 1 week. However, the other hydrogel formulations, particularly those with EO113PO57EO113, EO13PO30EO13, EO11PO16EO11, EO76PO30EO76, were too unstable for long-term sustained release. The optimal composition of the copolymer in these supramolecular hydrogels for protein delivery is 25 or 30 wt% PEO. Therefore, it is very important to have a good balance between the PEO and PPO block lengths [10].
7.3.2 Supramolecular Hydrogels Formed by α-CD and PEO-PHB-PEO Triblock Copolymer
Another triblock copolymer which has a hydrophobic middle block of poly((R)-3-hydroxybutyrate) (PHB) flanked by two PEO blocks has been synthesized and investigated [36]. PHB is a natural, optically active, and biodegradable biopolyester exhibiting high crystallinity and hydrophobicity. It is an attractive and promising polymer for biomedical applications. The PEO-PHB-PEO triblock copolymers with short PEO blocks (2000 Da) were found to form block-selected inclusion complexes with α-CD [37, 38], whereas the copolymers with longer PEO blocks (5000 Da) were able to form hydrogels (Table 7.2) [23]. The PHB block of PEO-PHB-PEO showed a very strong tendency toward self-assembly in aqueous solutions. Compared to other copolymers PEO-PPO-PEO or PEO-PLLA-PEO with similar compositions, PEO-PHB-PEO formed micelles in aqueous solution with a much lower critical micelle concentration [39].
Similar to the hydrogels formed between α-CD and PEO-PPO-PEO, α-CD also has an aiding effect for the gelation of PEO-PHB-PEO triblock copolymers at very low concentrations. For example, 13 wt% aqueous solutions of PEO-PHB-PEO could not form hydrogels in spite of the micelle formations. On the other hand, either 13 wt% of PEO-PHB-PEO copolymers formed hydrogels at room temperature in the solutions containing 9.7 wt% of α-CD (Fig. 7.8) [10, 23]. The inclusion complexes formed between α-CD and the PEO blocks of the copolymers were thought to aggregate into microcrystals, acting as physical crosslinks and inducing supramolecular hydrogel formation. Micellization of the PHB blocks by hydrophobic interactions is also crucial for facilitating the gel formation. Therefore, the gelation of the PEO-PPO-PEO triblock copolymers and α-CD in aqueous solutions is attributed to the cooperative effect of inclusion complexations between α-CD and PEO blocks and micellization of the PHB blocks of the triblock copolymers.
The structure of the supramolecular hydrogels formed by α-CD and PEO-PHB-PEO has been proposed based on X-ray diffraction studies (Fig. 7.8). In these complexes, the PEO chains penetrate α-CD rings from both ends, forming necklace-like inclusion complexes. Each of the PEO blocks in the supramolecular hydrogels has a molecular weight of ca. 5000 Da. However, only a length of PEO chains of about molecular weight 2000 Da or less from each end could be included by α-CD rings based on the studies of complex formation in these systems, which showed that only crystalline solid complexes formed at PEO lengths of 2000 Da or less [38, 39]. This hypothesis was also supported by the number of α-CD rings threaded onto a PEO chain which was then capped by bulky groups at both ends, as described in a previous study [9]. During the preparation of the α-CD-PEO polyrotaxanes, a maximum average number of 23 α-CD rings, corresponding to a PEO length of molecular weight 2000 Da, were trapped over each PEO chain, even if longer PEO segments were used. In the cases of PEO-PHB-PEO block copolymers whose PEO block length is 5000 Da, the PEO segments covered by α-CD rings should be less than 2000 Da from each end as the cooperative gelation process may hinder further threading of α-CD over the PEO chains. The cooperative action of partial inclusion complexation between α-CD and the flanking PEO blocks and the hydrophobic interactions between the middle PHB blocks lead to a self-assembly system, forming a strong network and a novel supramolecular hydrogel.
The in vitro release kinetics studies of the α-CD-PEO-PHB-PEO hydrogels have been carried out using dextran-FITC as a model drug [23]. Table 7.3 presents the list of α-CD-PEO-PHB-PEO hydrogel formulations with various compositions that were used for the in vitro controlled release studies. Gel-1 with PEO (35,000 Da) was used as a control for comparison. The in vitro release profiles of the dextran-FITC encapsulated in these hydrogel formulations are shown in Fig. 7.9 [10, 23]. Both aqueous solutions of pure PEO-PHB-PEO at 13 wt% could not sustain the dextran-FITC release as they dispersed in large amount of water or phosphate-buffered saline (PBS) in seconds. Compared to α-CD-PEO hydrogel which dissociated and dissolved in PBS within 5 days even though the molecular weight of PEO was very high (35,000 Da) [29], the α-CD-PEO-PHB-PEO (5000-3140-5000) hydrogels with reasonably high α-CD concentration (9.7 wt%) sustained the dextran-FTIC for more than 1 month, exhibiting excellent controlled release properties. For the other hydrogels with lower α-CD concentrations, the dextran-FITC release was much faster, implying that the inclusion complexation between α-CD and the PEO segments is essential for formation of a strong and stable supramolecular hydrogel. Interestingly, the α-CD-PEO-PHB-PEO (5000-1750-5000) hydrogel with a shorter PHB segment only sustained the dextran-FITC release for 6 days, regardless of the high α-CD concentration (9.7 wt%) used. It shows that the PHB block length also plays an important role in forming a stable supramolecular hydrogel. The hypothesis therefore further supported that the cooperative effect of partial inclusion complexation between α-CD and the flanking PEO blocks and the hydrophobic interactions between the middle PHB blocks lead to strong supramolecular hydrogels suitable for long-term sustained release, which many simple triblock copolymer hydrogels could not achieve. These findings show that the fine-tuning of the properties of the supramolecular hydrogels can be done not only by changing the PHB block length but also by varying the copolymers. This may open up a wide range of applications in the biomedical field. Different from the supramolecular hydrogels formed by α-CD and PEO homopolymers [28, 29], α-CD-PEO-PHB-PEO hydrogels formed a stronger supramolecular network due to the abovementioned cooperative effect. In addition to the lower molecular weights of copolymers required for sustained release, the PEO-PHB-PEO triblock copolymers are also biodegradable, making the hydrogel formulations more desirable as a bioabsorbable system after drug delivery and hydrogel dissociation into individual components [23].
Recently, it was found that poly[(R,S)-3-hydroxybutyrate]-poly(ethylene oxide)-poly[(R,S)-3-hydroxybutyrate] (aPHB-PEO-aPHB) triblock copolymers with low molecular weight (< 5000 Da) were able to form unexpectedly strong hydrogels with α-CD, showing high stiffness in terms of storage modulus (G’) values in the order of 104–105 Pa [40]. The aPHB-PEO-aPHB triblock copolymers were synthesized and characterized to ensure the formation of well-defined polymer architectures so that α-CD rings can preferentially thread over the middle PEO block, forming block-selected polypseudorotaxanes [41, 42]. When the α-CD coverage over the PEO chains is sufficiently low, hydrogels were formed by the polypseudorotaxanes instead of precipitates. This could be easily explained by the increased hydrophilicity due to greater PEO exposure on the polypseudorotaxanes. However, the high strengths of the hydrogels formed were uncharacteristic for those whose guest polymers have low molecular weights of around 5000 Da. It was concluded that the hydrophobic association of the telechelic aPHB blocks attributed to the enhancement of the rheological properties of the hydrogel [40].
7.3.3 Supramolecular Hydrogels Formed by α-CD and PEO-PCL Diblock Copolymer
Supramolecular hydrogels based on other biopolyester block copolymers have also been developed for drug delivery [43,44,45]. An amphiphilic biodegradable diblock copolymer of PEO and poly(ε-caprolactone) (PCL) was studied to form supramolecular hydrogels with α-CD [43]. Similar to the α-CD-PEO-PPO-PEO and α-CD-PEO-PHB-PEO hydrogels, the driving force for the gelation was a combination of the inclusion complexations between α-CD and the PEO blocks of PEO-PCL copolymers and the hydrophobic interactions between the PCL blocks. Rheological studies reveal that the α-CD-PEO-PCL hydrogels are thixotropic and reversible.
The in vitro controlled release properties of the α-CD-PEO-PCL hydrogels have also been studied using dextran-FITC as a model macromolecular drug. It was found that there was still about 20% of the entrapped dextran-FITC retained in the hydrogels for up to 1 month. The results showed that the α-CD-PEO-PCL supramolecular hydrogels sustained the release for much longer time when compared to α-CD-PEO supramolecular hydrogels, even if the molecular weight of the PEO block was much lower. It was concluded that the strong hydrophobic interactions between the uncovered PCL blocks resulted in lower molecular weight of PEO needed for long-term sustained release. The amount of α-CD also has an effect on the drug release properties of the supramolecular hydrogels. Reducing the α-CD content accelerated the drug release rate. As PCL is biodegradable and FDA-approved for use in drug delivery systems, the α-CD-PEO-PCL supramolecular hydrogels are promising as minimally invasive therapeutic drug delivery systems with fine-tuned properties.
7.3.4 Stimuli-Responsive Supramolecular Hydrogels
Besides the thixotropic and reversible nature of α-CD-PEG polypseudorotaxane hydrogels that make them stimuli-responsive, there are other interesting stimuli-responsive properties that can be incorporated into supramolecular hydrogels. One example is a thermoresponsive reversible “smart” supramolecular hydrogel developed recently [46]. A star-shaped poly(N-isopropylacrylamide) (PNIPAAm) with a β-CD core has been synthesized and studied previously [47,48,49,50]. In this design, a novel star-star supramolecular architecture was self-assembled through inclusion complexation between this star-shaped PNIPAAm and a star-shaped adamantyl-terminated 8-arm PEG. This star-star supramolecular architecture further self-aggregated into a 3D network, inducing the formation of a thermoresponsive “smart” hydrogel (Fig. 7.10). The β-CD core and adamantyl (Ad) moiety formed strong and specific host-guest inclusion complexes which acted as physical crosslinks in this supramolecular network. PNIPAAm is a well-known thermoresponsive polymer which exhibits reversible phase transition in aqueous solution with a lower critical solution temperature (LCST) at 32 °C [51]. At room temperature, the aqueous solution of the star-star pseudoblock copolymer formed by host-guest inclusion complexation was clear and free flowing. Upon heating to 37 °C, this host-guest solution turned into a white stable hydrogel.
Rheological tests have been carried out and proved that the host-guest mixture was in a sol state at lower temperatures [46]. Above the gelling temperature (36.9 °C), the PNIPAAm chains on the host polymer collapsed and aggregated, inducing physical crosslinking of the self-assembled star-star pseudoblock copolymer and forming a supramolecular hydrogel. It was observed that the physical hydrogel formed completely turned back into a clear and free-flowing solution upon cooling. The rheological measurements also revealed high reversibility and repeatability of the hydrogel when treated with repeated cycles of heating and cooling. The thermoreversible sol-gel transition rendered this supramolecular hydrogel unique and different from other reported systems based on β-CD/Ad [52,53,54,55,56,57]. More importantly, this supramolecular system has great potential for injectable drug delivery. Therapeutic drugs can be easily mixed with the star-star pseudoblock copolymer formed by host-guest inclusion complexation at room temperature. After injection into the body, this clear solution with very low viscosity then undergoes a temperature-induced gelation. The resulting stable supramolecular hydrogel will be able to release the entrapped drugs in a sustained manner.
7.4 Injectable Gene Delivery Systems Based on α-CD-PEO Supramolecular Hydrogels
In a recent study, α-CD-PEG supramolecular hydrogels with anchored DNA nanoparticles have been developed and demonstrated to show promising properties for injectable sustained gene delivery [58]. In this novel design, as illustrated in Fig. 7.11, biodegradable amphiphilic methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly[2-(dimethylamino)ethyl methacrylate] (MPEG-PCL-PDMAEMA) triblock copolymers were firstly synthesized and formed micelles in aqueous solutions, with the hydrophobic PCL segments as the core. pDNA was then condensed by the cationic PDMAEMA into polyplexes which were stabilized by MPEG. The MPEG chains on the corona also served as physical crosslinking moieties to anchor the polyplexes within the α-CD-PEG supramolecular hydrogels. Subsequently, sustained pDNA polyplexes release would be achieved as the hydrogel dissolved over time.
A series of ECD/pDNA polyplexes anchored supramolecular hydrogels have been prepared and listed in Table 7.4 [58]. Hydrogels with ECD/pDNA polyplexes anchored (Gel-1, Gel-2, and Gel-3) all have a shorter gelation time than the control (Gel-4) which consists of only α-CD and PEG. Rheological tests of the hydrogel formulations also revealed that all ECD/pDNA polyplexes anchored hydrogels (Gel-1, Gel-2, and Gel-3) showed significantly higher stiffness (in terms of G’) and strength (in terms of yield point) than the control (Gel-4). The self-assembly of the hydrogel was driven by the crystalline columnar α-CD which acted as physical crosslinks. The enhancement of hydrogel properties could be the result of the “multi-arm” crosslinking effect by the ECD/pDNA polyplexes whose MPEG chains (5000 Da) are highly accessible to α-CD rings and jointly form polypseudorotaxane domains with the α-CD-PEG complexes in the supramolecular hydrogel. Moreover, the hydrophobic PCL core of the polyplexes may also improve the strength and stability of the supramolecular hydrogels. For an injectable delivery system, timely recovery is crucial after huge deformation during injection under great pressure. It was found that Gel-4 took around 25 min to recover, whereas Gel-2 demonstrated almost instantaneous recovery immediately after removal of the high stress. Therefore, the strong and stable ECD/pDNA polyplexes anchored hydrogels with excellent recovery characteristics are promising candidates as injectable delivery systems.
The in vitro DNA release behavior of the pDNA-encapsulated supramolecular hydrogels was investigated by a hydrogel dissolution study (Fig. 7.12) [58]. All gel formulations did not show significant burst release and were fully eroded upon complete DNA release, exhibiting a controlled release profile. The results suggest that the DNA release was mainly controlled by the gradual erosion of the supramolecular hydrogels in aqueous solutions as α-CD rings dethreaded from PEG and MPEG chains [23, 29]. However, the ECD/pDNA polyplexes anchored hydrogels (Gel-1, Gel-2, and Gel-3) could sustain the DNA release up to 5–6 days, longer than that of α-CD-PEG control (Gel-4) which could only sustain the release up to 3 days. The longer sustained release achieved could also be a result of higher stability against hydrogel dissolution due to the “multi-arm” crosslinking effect by the ECD/pDNA polyplexes. In addition to the higher DNA loading efficiency and more sustained release as compared to other PEG hydrogel systems [59,60,61], the pDNA released was proven to be in the form of stable polyplexes and, more importantly, showing good bioactivity at different time points in the in vitro gene transfection efficiency study. All these findings suggest that these injectable and bioactive pDNA polyplexes anchored supramolecular hydrogels with improved rheological properties have immense potentials as sustained gene delivery systems.
7.5 Conclusions and Prospects
Recent advances in the studies of inclusion complexes between cyclodextrins and various polymer chains have led to interesting developments of supramolecular hydrogels with many different compositions and structures for biomedical applications. Injectable drug or gene delivery systems can be developed based on the supramolecular hydrogels self-assembled through inclusion complexation between CDs and various biodegradable block copolymers to achieve sustained and controlled release of drugs or genes. The development of supramolecular networks has opened up new possibilities for designing novel delivery systems. For proper and smarter designs, the supramolecular systems can be controlled by using different copolymers with different compositions. In addition, stimuli-responsive properties can be incorporated into supramolecular structures based on pseudoblock copolymer formed by host-guest inclusion complexation, forming “smart” hydrogel with more desired and promising properties for biomedical applications.
References
Lehn JM (1995) Supramolecular chemistry: concepts and perspectives. VCH Verlagsgesellschaft mbH. https://doi.org/10.1002/3527607439
Nepogodiev SA, Stoddart JF (1998) Cyclodextrin-based catenanes and rotaxanes. Chem Rev 98(5):1959–1976. https://doi.org/10.1021/cr970049w
Raymo FM, Stoddart JF (1999) Interlocked macromolecules. Chem Rev 99(7):1643–1664. https://doi.org/10.1021/cr970081q
Ashton PR, Ballardini R, Balzani V, Bělohradský M, Gandolfi MT, Philp D, Prodi L, Raymo FM, Reddington MV, Spencer N, Stoddart JF, Venturi M, Williams DJ (1996) Self-assembly, spectroscopic, and electrochemical properties of [n]rotaxanes1. J Am Chem Soc 118(21):4931–4951. https://doi.org/10.1021/ja954334d
Chichak KS, Cantrill SJ, Pease AR, Chiu S-H, Cave GWV, Atwood JL, Stoddart JF (2004) Molecular borromean rings. Science 304(5675):1308–1312
Schmieder R, Hübner G, Seel C, Vögtle F (1999) The first cyclodiasteromeric [3]rotaxane. Angew Chem Int Ed 38(23):3528–3530. https://doi.org/10.1002/(SICI)1521-3773(19991203)38:23<3528::AID-ANIE3528>3.0.CO;2-N
Vögtle F, Dünnwald T, Schmidt T (1996) Catenanes and rotaxanes of the amide type. Acc Chem Res 29(9):451–460. https://doi.org/10.1021/ar950200t
Gibson HW, Bheda MC, Engen PT (1994) Rotaxanes, catenanes, polyrotaxanes, polycatenanes and related materials. Prog Polym Sci 19(5):843–945. https://doi.org/10.1016/0079-6700(94)90034-5
Harada A, Li J, Kamachi M (1992) The molecular necklace: a rotaxane containing many threaded [alpha]-cyclodextrins. Nature 356(6367):325–327
Li J, Loh XJ (2008) Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv Drug Deliv Rev 60(9):1000–1017. https://doi.org/10.1016/j.addr.2008.02.011
Bender ML, Komiyama M (1978) Cyclodextrin chemistry. Reactivity and structure: concepts in organic chemistry, vol 6. Springer-Verlag, Berlin/Heidelberg. https://doi.org/10.1007/978-3-642-66842-5
Szejtli J (1998) Introduction and general overview of cyclodextrin chemistry. Chem Rev 98(5):1743–1754. https://doi.org/10.1021/cr970022c
Wenz G, Han B-H, Müller A (2006) Cyclodextrin rotaxanes and polyrotaxanes. Chem Rev 106(3):782–817. https://doi.org/10.1021/cr970027+
Chen Y, Liu Y (2010) Cyclodextrin-based bioactive supramolecular assemblies. Chem Soc Rev 39(2):495–505. https://doi.org/10.1039/B816354P
Peppas NA (1987) Hydrogels in medicine and pharmacy, vol 1. CRC Press Inc., Boca Raton
Park K, Shalaby WSW, Park H (1993) Biodegradable hydrogels for drug delivery. Technomic Publishing Company Inc., Lancaster
Kishida A, Ikada Y (2002) In: Dumitriu S (ed) Polymeric biomaterials. New York, Marcel Dekker
Li J (2004) In: Teoh SH (ed) Biomaterials engineering and processing series, vol 1. World Scientific Publishing, Hackensack
Hoffman AS (2002) Hydrogels for biomedical applications. Adv Drug Deliv Rev 54(1):3–12. https://doi.org/10.1016/S0169-409X(01)00239-3
Kim SW, Bae YH, Okano T (1992) Hydrogels: swelling, drug loading, and release. Pharm Res 9(3):283–290. https://doi.org/10.1023/a:1015887213431
Park H, Park K (1996) Biocompatibility issues of implantable drug delivery systems. Pharm Res 13(12):1770–1776. https://doi.org/10.1023/a:1016012520276
Li J (2009) Cyclodextrin inclusion polymers forming hydrogels. In: Wenz G (ed) Inclusion polymers, Advances in polymer science, vol 222. Springer, Berlin Heidelberg, pp 175–203. https://doi.org/10.1007/12_2008_9
Li J, Li X, Ni X, Wang X, Li H, Leong KW (2006) Self-assembled supramolecular hydrogels formed by biodegradable PEO–PHB–PEO triblock copolymers and α-cyclodextrin for controlled drug delivery. Biomaterials 27(22):4132–4140. https://doi.org/10.1016/j.biomaterials.2006.03.025
Li J (2010) Self-assembled supramolecular hydrogels based on polymer–cyclodextrin inclusion complexes for drug delivery. NPG Asia Mater 2:112–118
Liu KL, Zhang Z, Li J (2011) Supramolecular hydrogels based on cyclodextrin-polymer polypseudorotaxanes: materials design and hydrogel properties. Soft Matter 7(24):11290–11297
Li JJ, Zhao F, Li J (2011) Polyrotaxanes for applications in life science and biotechnology. Appl Microbiol Biotechnol 90(2):427–443. https://doi.org/10.1007/s00253-010-3037-x
Li J, Zhao F, Li J (2011) Supramolecular polymers based on cyclodextrins for drug and gene delivery. In: Nyanhongo GS, Steiner W, Gübitz G (eds) Biofunctionalization of polymers and their applications, Advances in biochemical engineering/biotechnology, vol 125. Springer, Berlin/Heidelberg, pp 207–249. https://doi.org/10.1007/10_2010_91
Li J, Harada A, Kamachi M (1994) Sol-gel transition during inclusion complex formation between [α]-cyclodextrin and high molecular weight poly(ethylene glycol)s in aqueous solution. Polym J 26(9):1019–1026. https://doi.org/10.1295/polymj.26.1019
Li J, Ni X, Leong KW (2003) Injectable drug-delivery systems based on supramolecular hydrogels formed by poly(ethylene oxide)s and α-cyclodextrin. J Biomed Mater Res A 65A(2):196–202. https://doi.org/10.1002/jbm.a.10444
Jeong B, Bae YH, Lee DS, Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery systems. Nature 388(6645):860–862
Jeong B, Bae YH, Kim SW (2000) Drug release from biodegradable injectable thermosensitive hydrogel of PEG–PLGA–PEG triblock copolymers. J Control Release 63(1–2):155–163. https://doi.org/10.1016/S0168-3659(99)00194-7
Li J, Li X, Zhou Z, Ni X, Leong KW (2001) Formation of supramolecular hydrogels induced by inclusion complexation between pluronics and α-cyclodextrin. Macromolecules 34(21):7236–7237. https://doi.org/10.1021/ma010742s
Bromberg LE, Ron ES (1998) Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery. Adv Drug Deliv Rev 31(3):197–221. https://doi.org/10.1016/S0169-409X(97)00121-X
Loh XJ, Goh SH, Li J (2007) New biodegradable thermogelling copolymers having very low gelation concentrations. Biomacromolecules 8(2):585–593. https://doi.org/10.1021/bm0607933
Ni X, Cheng A, Li J (2009) Supramolecular hydrogels based on self-assembly between PEO-PPO-PEO triblock copolymers and α-cyclodextrin. J Biomed Mater Res A 88A(4):1031–1036. https://doi.org/10.1002/jbm.a.31906
Li J, Li X, Ni X, Leong KW (2003) Synthesis and characterization of new biodegradable amphiphilic poly(ethylene oxide)-b-poly[(R)-3-hydroxy butyrate]-b-poly(ethylene oxide) triblock copolymers. Macromolecules 36(8):2661–2667. https://doi.org/10.1021/ma025725x
Li X, Li J, Leong KW (2003) Preparation and characterization of inclusion complexes of biodegradable amphiphilic poly(ethylene oxide)−poly[(R)-3-hydroxybutyrate]−poly(ethylene oxide) triblock copolymers with cyclodextrins. Macromolecules 36(4):1209–1214. https://doi.org/10.1021/ma0213347
Li X, Li J, Leong KW (2004) Role of intermolecular interaction between hydrophobic blocks in block-selected inclusion complexation of amphiphilic poly(ethylene oxide)-poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide) triblock copolymers with cyclodextrins. Polymer 45(20):6845–6851. https://doi.org/10.1016/j.polymer.2004.07.038
Li J, Ni X, Li X, Tan NK, Lim CT, Ramakrishna S, Leong KW (2005) Micellization phenomena of biodegradable amphiphilic triblock copolymers consisting of poly(β-hydroxyalkanoic acid) and poly(ethylene oxide). Langmuir 21(19):8681–8685. https://doi.org/10.1021/la0515266
Liu KL, J-l Z, Li J (2010) Elucidating rheological property enhancements in supramolecular hydrogels of short poly[(R,S)-3-hydroxybutyrate]-based amphiphilic triblock copolymer and [small alpha]-cyclodextrin for injectable hydrogel applications. Soft Matter 6(10):2300–2311. https://doi.org/10.1039/B923472A
Liu KL, Goh SH, Li J (2008) Controlled synthesis and characterizations of amphiphilic poly[(R,S)-3-hydroxybutyrate]-poly(ethylene glycol)-poly[(R,S)-3-hydroxybutyrate] triblock copolymers. Polymer 49(3):732–741. https://doi.org/10.1016/j.polymer.2007.12.017
Liu KL, Goh SH, Li J (2008) Threading α-cyclodextrin through poly[(R,S)-3-hydroxybutyrate] in poly[(R,S)-3-hydroxybutyrate]−poly(ethylene glycol)−poly[(R,S)-3-hydroxybutyrate] triblock copolymers: formation of block-selected polypseudorotaxanes. Macromolecules 41(16):6027–6034. https://doi.org/10.1021/ma800366v
Loh XJ, Sng KBC, Li J (2008) Synthesis and water-swelling of thermo-responsive poly(ester urethane)s containing poly(epsilon-caprolactone), poly(ethylene glycol) and poly(propylene glycol). Biomaterials 29(22):3185–3194. https://doi.org/10.1016/j.biomaterials.2008.04.015
Wu D-Q, Wang T, Lu B, Xu X-D, Cheng S-X, Jiang X-J, Zhang X-Z, Zhuo R-X (2008) Fabrication of supramolecular hydrogels for drug delivery and stem cell encapsulation. Langmuir 24(18):10306–10312. https://doi.org/10.1021/la8006876
Wang T, Jiang X-J, Lin T, Ren S, Li X-Y, Zhang X-Z, Q-z T (2009) The inhibition of postinfarct ventricle remodeling without polycythaemia following local sustained intramyocardial delivery of erythropoietin within a supramolecular hydrogel. Biomaterials 30(25):4161–4167. https://doi.org/10.1016/j.biomaterials.2009.04.033
Zhang Z-X, Liu KL, Li J (2013) A thermoresponsive hydrogel formed from a star–star supramolecular architecture. Angew Chem Int Ed 52(24):6180–6184. https://doi.org/10.1002/anie.201301956
Zhang Z-X, Liu X, Xu FJ, Loh XJ, Kang E-T, Neoh K-G, Li J (2008) Pseudo-block copolymer based on star-shaped poly(N-isopropylacrylamide) with a β-cyclodextrin core and guest-bearing PEG: controlling thermoresponsivity through supramolecular self-assembly. Macromolecules 41(16):5967–5970. https://doi.org/10.1021/ma8009646
Zhang Z-X, Liu KL, Li J (2011) Self-assembly and micellization of a dual thermoresponsive supramolecular pseudo-block copolymer. Macromolecules 44(5):1182–1193. https://doi.org/10.1021/ma102196q
Song X, Wen Y, J-l Z, Zhao F, Zhang Z-X, Li J (2016) Thermoresponsive delivery of paclitaxel by β-cyclodextrin-based poly(N-isopropylacrylamide) star polymer via inclusion complexation. Biomacromolecules 17:3957–3963. https://doi.org/10.1021/acs.biomac.6b01344
Song X, J-l Z, Wen Y, Zhao F, Zhang Z-X, Li J (2017) Thermoresponsive supramolecular micellar drug delivery system based on star-linear pseudo-block polymer consisting of β-cyclodextrin-poly(N-isopropylacrylamide) and adamantyl-poly(ethylene glycol). J Colloid Interface Sci 490:372–379. https://doi.org/10.1016/j.jcis.2016.11.056
Schild HG (1992) Poly(N-isopropylacrylamide): experiment, theory and application. Prog Polym Sci 17(2):163–249. https://doi.org/10.1016/0079-6700(92)90023-R
Sandier A, Brown W, Mays H, Amiel C (2000) Interaction between an adamantane end-capped poly(ethylene oxide) and a β-cyclodextrin polymer. Langmuir 16(4):1634–1642. https://doi.org/10.1021/la990873a
Auzély-Velty R, Rinaudo M (2002) New supramolecular assemblies of a cyclodextrin-grafted chitosan through specific complexation. Macromolecules 35(21):7955–7962. https://doi.org/10.1021/ma020664o
Kretschmann O, Choi SW, Miyauchi M, Tomatsu I, Harada A, Ritter H (2006) Switchable hydrogels obtained by supramolecular cross-linking of adamantyl-containing LCST copolymers with cyclodextrin dimers. Angew Chem Int Ed 45(26):4361–4365. https://doi.org/10.1002/anie.200504539
Charlot A, Auzély-Velty R, Rinaudo M (2003) Specific interactions in model charged polysaccharide systems†. J Phys Chem B 107(32):8248–8254. https://doi.org/10.1021/jp022580n
Charlot A, Auzély-Velty R (2007) Synthesis of novel supramolecular assemblies based on hyaluronic acid derivatives bearing bivalent β-Cyclodextrin and adamantane moieties. Macromolecules 40(4):1147–1158. https://doi.org/10.1021/ma062322e
Koopmans C, Ritter H (2008) Formation of physical hydrogels via host−guest interactions of β-cyclodextrin polymers and copolymers bearing adamantyl groups. Macromolecules 41(20):7418–7422. https://doi.org/10.1021/ma801202f
Li Z, Yin H, Zhang Z, Liu KL, Li J (2012) Supramolecular anchoring of DNA polyplexes in cyclodextrin-based polypseudorotaxane hydrogels for sustained gene delivery. Biomacromolecules 13(10):3162–3172. https://doi.org/10.1021/bm300936x
Agarwal A, Unfer RC, Mallapragada SK (2008) Dual-role self-assembling nanoplexes for efficient gene transfection and sustained gene delivery. Biomaterials 29(5):607–617. https://doi.org/10.1016/j.biomaterials.2007.10.010
Deng J, Luo Y, Zhang L-M (2011) PEGylated polyamidoamine dendron-assisted encapsulation of plasmid DNA into in situ forming supramolecular hydrogel. Soft Matter 7(13):5944–5947. https://doi.org/10.1039/C1SM05259D
Ma D, Zhang H-B, Chen D-H, Zhang L-M (2011) Novel supramolecular gelation route to in situ entrapment and sustained delivery of plasmid DNA. J Colloid Interface Sci 364(2):566–573. https://doi.org/10.1016/j.jcis.2011.08.051
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer-Verlag GmbH Germany, part of Springer Nature
About this chapter
Cite this chapter
Song, X., Li, J. (2018). Recent Advances in Polymer-Cyclodextrin Inclusion Complex-Based Supramolecular Hydrogel for Biomedical Applications. In: Li, J., Osada, Y., Cooper-White, J. (eds) Functional Hydrogels as Biomaterials. Springer Series in Biomaterials Science and Engineering, vol 12. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-57511-6_7
Download citation
DOI: https://doi.org/10.1007/978-3-662-57511-6_7
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-57509-3
Online ISBN: 978-3-662-57511-6
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)