Keywords

4.1 Introduction

The emergence of diseases and disorders has made it more important than ever to treat the condition and restore the patient’s health. Conventional dosage forms have a number of drawbacks that prevent them from achieving steady-state drug concentration and drug targeting, such as multiple administrations of the therapeutic agent with a shorter half-life, lessened patient compliance, and increased toxicity. This restriction calls for the creation of functionalized and targeted medication delivery systems that improve the limitations of conventional preparation. Due to their sustained release property, site specificity, and high patient compliance, functionalized and targeted therapeutic delivery is used for the treatment of disease (Suthar et al. 2022; Patel et al. 2023).

Functionalized therapeutic nanomedicines are established for the diagnosis as well as treatment of different ailments. It offers a high level of drug delivery and transportation to the intended site for therapy and diagnosis. The physicochemical properties of the nano-formulation, such as size, shape, and the type of ligand attached for identifying and activating the receptor, extend the cellular and subcellular reach of the functionalized nano-formulation. As a result, developing nano-formulation requires very precise processes and control of the physicochemical properties. A variety of active drugs, such as imaging agents, proteins, peptides, and anticancer drugs may be given using several types of nano-formulation, including polymeric, lipid, and metals. Due to their structure’s flexibility and ease of modification, polymeric nanocarriers have drawn a lot of attention. They can also be transported to the desired location for action or response in response to environmental or physiological stimuli. Functionalization of polymeric nanocarriers can reduce sensitivity in biological environments when exposed to various stimuli like temperature, radiation, UV light, magnetic fields, oxidation, reduction, and enzymatic conditions, which may directly influence payload on NPs, biodistribution, biodegradability, stability, and biocompatibility of the therapeutic agent (Feng et al. 2014; Dong et al. 2014).

The therapeutic use, route of administration, and target site all influence the structure of the polymeric NPs. Polymeric NPs are typically administered intravenously, although they can also be administered orally, topically, or mucosally. In those circumstances, NPs must be provided by smart excipients and be able to target different body parts. Functionalized polymeric NPs have been developed to support in treating and diagnosing diseases such as cancer, viral infections, cardiovascular illness, lung disease, and urinary tract infections. Advanced polymeric NPs with variable size, shape, and charge are made possible by polymerization (O'Reilly et al. 2006). The vast surface area of polymeric NPs allows for the attachment of many ligands or functional groups. Polymeric NPs can quickly connect to capillaries and enter the target region. Because it has a longer clearance period than a typical dosage form, a smaller amount of the drug can still have good therapeutic effects while reducing toxicity.

Numerous researchers have reported that functionalized polymeric nanoparticles improve the efficacy of various medicinal treatments. Saroj and its affiliates developed functionalized, pH-sensitive polymeric NPs of etoposide to treat cancer. At blood pH, PNs showed a significantly higher release. It was significantly more hazardous to PC-3 and LNCaP, two types of prostate cancer cells, than pure etoposide (Saroj and Rajput 2018). Utilizing poly-lactic acid polymer and polyethylene glycol to adorn the surface, Patil and his collaborators created the functionalized polymeric NPs of paclitaxel. Biotin and folic acid functionalized the NPs, which were then verified by an NMR investigation. The ligand significantly increased NP accumulation at the mouse tumor site (Patil et al. 2009). For the purpose of addressing liver cancer cells, Zhu et al. developed the polydopamine functionalized NPs loaded with docetaxel using TPGS and polylactic acid polymer. The liver cancer cell line HepG2 was significantly taken up by the NPs. It also reduces the size of hepatoma tumors in nude mice much more than nonfunctionalized NPs (Zhu et al. 2016).

4.2 Composition

There are various types of polymer used for the development of functionalized NPs which are discussed below.

(a) Polyethylene Glycol Transferrin

Transferrin is a blood plasma glycoprotein containing iron bonds. Transferrin maintains the free iron level in biological fluids. Transferrin was established to preserve the character of PEGylation as well as allow NPs to reach the tumor site after recombinant human necrosis factor-alpha. This combination mainly exhibited preferential specificity for target tumor cells. Gan and his team formulated transferrin conjugate polylactic acid-TPGS pegylated NPs for brain delivery using Coumarin 6 as imaging or docetaxel as therapeutic agents. The conjugated NPs significantly crossed the blood-brain barrier and showed a significantly lower IC50 than unconjugated NPs (Gan and Feng 2010). Li et al. formulated the transferrin-coupled polyethylene glycol for gene delivery (PDNA). It exhibited prolonged drug release after an initial burst release (30%). It also showed significantly greater enhancement in binding to K562 cells than non-targeted NPs (Li et al. 2003). Wang et al. formulated the transferrin and folate conjugate Pluronic/poly (lactic acid) NPs loaded with paclitaxel. It showed an initial fast release, followed by a slow release over time. It was found to be toxic to cancer cells and penetrated cells better than non-targeted NPs (Wang et al. 2022).

b. Gelatin

Gelatin is a water-soluble polymer obtained from the chemical degradation of collagen. It is biocompatible and biodegradable. It did not cause any side effects after administration into the body. It provides the slow release of drugs (Manna et al. 2016). Chen et al. used photothermal therapy for breast cancer cells using folic acid-functionalized gelatin and gold nanoparticles. It showed high photothermal conversion power and killed the breast cancer cells under near-infrared laser radiation. Subcutaneous implantation of NPs showed excellent photothermal potential against breast cancer cells (Chen et al. 2020).

c. Alginate

It is an alginate-based natural, biocompatible, and biodegradable polymer used as a carrier of various drugs. It is a co-polymer of (1, 4) linked β-D mannuronate and α-l-glucuronate. It is water soluble in nature and mostly used for the preparation of nanoparticles, microparticles, hydrogels, etc. It is also used for the preparation of functionalized polymeric NPs (Bagre et al. 2013). Sahatsapan et al. formulated the Garcinia mangostana L extract loaded alginate NPs. The prepared NPs were further functionalized with catechol for intravesical chemotherapy. It exhibited high drug load, sustained release, and high stability. It accumulated in bladder tissue and MB49 cells at a higher rate than pure Garcinia mangostana L. extract (Sahatsapan et al. 2020). Fan et al. formulated doxorubicin-loaded sodium alginate NPs which are functionalized with adipic acid dihydrazide. It exhibited significantly higher release in the tumor environment at pH 5 than at pH 6.5. It also showed significantly high cellular uptake into Hela cells overexpressing CD44 and improved cell toxicity (Fan et al. 2016). Zhang and his colleagues formulated 5-fluorouracil-loaded sodium alginate NPs and functionalized them with graphene oxide for colon cancer. It showed the 5-fluorouracil properly released into the colon in a sustained manner. It was also observed that tumor growth significantly decreased with pure 5-fluorouracil. It also exhibited a controlled loading dose as well as improved bioavailability (Zhang et al. 2017a, b, c). Xie et al. developed graphene oxide functionalized sodium alginate NPs for the delivery of peptide protamine sulfate for doxorubicin delivery in another study. It showed that NPs were stable in various pH conditions as well as inhibited protein interaction. It also showed site-specific action against MCF-7 cells and higher cytotoxicity than plain doxorubicin (Xie et al. 2018).

d. Poly (Lactic-co-Glycolic) Acid

It is a synthetic biodegradable and biocompatible polymer that easily hydrolyzes into the body. It is water-insoluble and dissolved in various organic solvents like acetone, methanol, tetrahydrofuran, and ethyl acetate. PLGA is broadly applicable for the development of NPs, microspheres, and microcapsules (Table 4.1).

Table 4.1 Theranostic polymers and their applications
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4.3 Types of Theranostic Polymers

Theranostic polymeric nanomaterial has become very popular and has been used as a carrier for the diagnosis and treatment of cancer. Polymeric NPs have been developed to enhance the efficacy of drugs. The polymeric nanomaterial provides a long circulation time, leading to increased beneficial effects as well as reduced side effects (Jain and Zhong 2022; Greco and Vicent 2009). Functionalized polymeric NPs can load the drug for the target area and regulate the release of the drug at a personalized dose and time, which may enhance the therapeutic responses and minimize the side effects. The stimuli-responsive polymeric NPs are capable of controlling the release of therapeutic agents in disease areas (Ke et al. 2019) and can be used for the cure of various tumors (Fleige et al. 2012; Yu et al. 2014a, b). The responsive system can be classified into two types, i.e., internal as well as external stimuli. The pH, enzyme, redox potential, and hypoxia are the internal stimuli. However, light, magnetic field, temperature, ultrasound, and radiation are external stimuli (Karimi et al. 2016). On applying stimuli, the physiochemical characteristics of polymeric NPs change (permeability, hydrophilicity, or hydrophobicity), leading to imaging or therapeutic agent release to the target site.

4.3.1 Internal Stimuli

(a) pH-Responsive Polymers

The pH-sensitive polymeric material is very interesting and commonly used to design responsive polymeric NPs. Due to the fast metabolism, the high amount of lactic acid secreted by cancer cells may give a toxic effect on the nearest tissue at pH 5.7–6.9. There are various pH stimuli-responsive polymeric NPs which have been reported by the researcher for the treatment of cancer cell (Kanamala et al. 2016). Chang et al. formulated poly[(d, l-lactide)-co-glycolide]-PEG-poly[(d, l-lactide) coglycolide] polymeric micelle and functionalized with N-bochistidine loaded with doxorubicin. The N-bochistidine increases the biodegradability and biocompatibility of the micelles. The release of DOX at pH 6.2 in the cancer environment than pH 7.4 in the normal tissue increases the therapeutic activity (Chang et al. 2010). Polymeric NPs can increase intracellular drug delivery and reduce the release of drug in the extracellular space. Hu et al. developed the pH-sensitive doxorubicin-loaded polymeric micelles. The micelles decrease the tumor cell due to the high accumulation of micelles (Hu et al. 2012). Yu et al. formulated the polymeric micelles of curcumin using pH-sensitive co-polymer methoxy poly (ethylene glycol)-poly(lactide)-poly (β-amino ester) polymeric formulation. The polymeric micelles exhibited high drug loading and remain stable at 37 °C. It showed significantly high cellular uptake in breast cancer cells when the pH fell from 7.4 to 5.5 and particle size decreases from 171 to 22 nm. It also showed a longer circulation time than simple micelles and deposited into tumors with high fluorescent intensity and 65.6% inhibition of tumor (Yu et al. 2014a, b). In another research, Zhao et al. formulated the mixed micelles using different polymers loaded with doxorubicin. The micelles showed significantly improved cytotoxicity of the tumor by binding of the ligand with the membrane and penetrated by endocytosis to the tumor and releasing the doxorubicin (Zhao et al. 2010). Xiong and associates formulated the pH-sensitive polymeric micelles loaded siRNA and doxorubicin using poly (ethylene oxide)-blockpoly (ε-caprolactone) biodegradable polymer. The doxorubicin was significantly released in an acid environment through hydrazone linkage. The siRNA inhibited Pgp expression and doxorubicin easily penetrated into MDA-MB-435 tumor models (Xiong and Lavasanifar 2011). Further, Ling et al. formulated polymeric NPs using pH-responsive ligands. The formulation showed higher therapeutic activity in heterogeneous drug resistance tumors (Ling et al. 2014).

(b) Redox-Responsive Polymers

The redox potential is a new technique to regulate drug release from polymeric NPs. The redox potential developed between healthy and tumor tissues as well as between intracellular and extracellular areas (Zhang et al. 2017). The glutathione tripeptide (γ-glutamyl-cysteinylglycine) (GSH) concentration is higher (4 times) in cancer cells than in normal cells (Thambi et al. 2016). However, the GSH level in intracellular (2–10 mM) is approximately 100–1000 times higher than in extracellular (2–10 μM) (Han et al. 2017). Wang et al. formulated the polyanhydride copolymer comprising disulfide bonds among the hydrophobic and hydrophilic sections. The copolymer self-assembled into a core-shell structure and GHS activated the micelles for disarrangement. The micelles showed significantly high embarrassment of tumor cells in mice due to the fast penetration of the therapeutic agent. The redox stimulating micelles showed improved therapeutics effect in solid tumors than non-redox micelles and prevented MDR resistance and enhanced overall anticancer activity (Wang et al. 2021). Liu and his group formulated the redox-responsive doxorubicin prodrug micelles using dextran-poly (ethylene imine) copolymers and bind through a disulfide link. The polymeric micelles exhibited 100–140 nm size and fast drug release under the influence of an intracellular redox environment. The micelles improved the deposition of doxorubicin in MCF-7/ADR cells. The MTT result showed prodrug micelles significant antitumor activity than pure doxorubicin. So redox-sensitive formulation could be a remarkable delivery to overcoming MDR (Liu et al. 2013).

Han and his group formulated the polymeric NPs of doxorubicin using hyaluronic acid (HA)-polycaprolactone block polymer via disulfide linkage. The NPs significantly reduce the drug release under pH 7.4 and increased in existence of GSH bonds in the cytoplasm. It exhibited significantly higher therapeutic activity in cancer cells than non-crosslink polymer and free drugs (Han et al. 2015). Chiang et al. formulated the redox-sensitive micelles of camptothecin for the cure of selective cancer. The micelles released the camptothecin in tumor cells by activating reactive oxygen species and GSH. The reacting oxygen species stimulating diethyl sulfide of micelles causes swelling and GSH to promote the breaking of co-polymer and release of the drug into cancer cells (Chiang et al. 2015).

c. Enzymatic-Responsive Polymers

Enzyme-stimulating polymers were used as a drug carrier for the treatment of cancer (Mu et al. 2018). The enzymic is more efficient and faster than other stimuli. Various types of enzymes like proteases and phosphatases have been detected as biomarkers for the treatment and diagnosis of various diseases (He et al. 2016). The metalloproteinases (MMPs) enzyme is used to stimuli of enzyme-responsive systems in cancer theranostics. The MMPs are zinc-dependent endopeptidases accountable for the deprivation of extracellular matrix protein as well as regulated the bioactive substance on cells (Khokha et al. 2013). The expression of this enzyme is highly expressed in tumor cells than in normal cells and indorses tumor metastasis. As per the level of expression level variation, the MMPs are stimulators, and different nano-carrier systems are reported for diverse uses (Gallo et al. 2014; Callmann et al. 2015). Zhu et al. formulated the MMP2-sensitive polymeric micelles loaded with siRNA and hydrophobic drug using a PEG-ppPEI-PE copolymer. It exhibited good stability and easily penetrated cancer cells by enhancing the permeation effect and MMP2 activation (Zhu et al. 2014).

4.3.2 External Stimuli

(a) Light-Triggered Polymers

Light is the most generally employed stimulator for polymeric NPs to release the drug for treatment of any disease. The photothermal and photodynamic therapy (PTT and PDT) mostly used as light source for stimulation. The PTT is applied as a light-sensitive material that alters the light energy to heat and increases the temperature and activated NPs around tumor cell as well as cell death (Liu et al. 2019a, b). The PTT permits the precise dose of radiation to reduce the side effect of the normal cell around the cancer cell. PTT can also be used in combination with other therapy such as chemotherapy, surgery, and radiotherapy as a synergistic effect to increase the therapeutic effect (Liu et al. 2014; Yong et al. 2015). Bagheri and his research team developed light-sensitive pyrene-containing nanoparticles. The pyrene moieties stimulated the hydrophilic and hydrophobic transition of block polymer and fragment of the NPs, and then PTT stimulate the therapeutic compound for release into tumor cells (Bagheri et al. 2019). PDT is also an important light source for stimulating light-sensitive material. It is used at a definite wavelength, to produce the cytotoxic ROS and oxidize cellular macromolecules as well as stimulate tumor cell removal (Lucky et al. 2015). Light-stimulating polymeric NPs also use photo-induced drug release irradiated by external light. The mechanism involved a light-stimulating chemical effect, reducing hydrophobicity and photothermal effect (Son et al. 2019).

(b) Temperature-Responsive Polymers

Temperature is also usually applied as external inducer to stimulate the thermosensitive nanomaterial for releasing of the drug at desired site. The temperature-sensitive material can respond to changes in the temperature and destabilize the structure or change the aqueous solubility and release the drug to the target area (Karimi et al. 2016). The drug can be simply incorporated into the polymers at LCST and released at the desired site after applying external temperature. Choi and associates formulated the temperature-responsive polymeric NPs using pluronic/polyethyleneimine. The NPs showed swelling/deswelling behavior at 24–37 °C and PS size decreased from 330 to 100 nm, so free diffusion of encapsulated drug takes place due to high porosity (Choi et al. 2006). Goodall and his team formulated the thermosensitive polymeric NPs using N-isopropyl acrylamide (NIPAM) and decorated with scFv antibody targeting epidermal growth factor receptor (EGFR) expressed in the cancer cell. It significantly binds the MDA MB-468 cancer cells (Goodall et al. 2015). Similarly, Zeighamian et al. developed the curcumin loaded polymeric NPs using poly (N-isopropylacrylamide-co-methacrylic acid) (PNIPAAm–MAA) for MCF-7 breast cancer cells. NPs showed significantly high cytotoxicity against MCF-7 cells than pure curcumin (Zeighamian et al. 2015).

(c) Magnetic-Responsive

Magnetic-responsive formulation contains the magnetite or maghemite core, so it is called the superparamagnetic iron oxide NPs. By applying of the magnetic filled NPs increases the accumulation of drug at the site of action. The magnetic-responsive system has the property of diagnosis in a single formulation and therapy so-called theranostic (Yildiz and Yildiz 2015). The magnetic polymeric NPs must be stable and biocompatible as well as functionalized in various uses. Basuki and associates formulated the α-D-mannose-functionalized diblock PEG-glycopolymer and coated with magnetic NPs for the lung cancer. It exhibited significantly increased cellular uptake into lung cancer cell (Basuki et al. 2014). In another study, Jaidev et al. formulated the fluorescent IONPs and gemcitabine encapsulated NPs using PLGA polymer and decorated them with HEGF antibodies for pancreatic cancer. It significantly enhanced tumor retention and inhibited the growth of tumors (Jaidev et al. 2015).

4.4 Theranostic Applications of Functionalized Polymeric Nanoparticles

Polymers are large molecules made up of several repeating subunits. These macromolecules polymers have been successfully used for carrier of a variety of therapeutic agents to the body. Due to their electro-optical and photoluminescence characteristic, these types are quite interesting (Pecher and Mecking 2010) for drug delivery. Biodegradable NPs offer an advantage over non-biodegradable NPs such as surface-to-mass ratio, quantum characteristics, biodegradability, decreased toxicity, and capacity to adsorb and transport other molecules into body (Wu et al. 2020) (Table 4.2).

Table 4.2 List of polymeric delivery systems under clinical trials (Chang et al. 2021)
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4.4.1 Application in Bioimaging

In comparison to inorganic nanomaterials, polymeric NPs have advantages like biocompatibility, stability, biodegradability, and inexpensive (Abelha et al. 2020). Smart polymers, or stimulus-responsive polymers, are extremely effective that adapt to their surroundings. In addition to light intensity and wavelength, responsive polymers can also be sensitive to electrical and magnetic fields, humidity, chemical compounds, temperature, and pH levels. These materials may react in a variety of ways, such as changing their transparency or color, turning into water conductive materials, or changing their shape. Usually, only very slight environmental modifications are required to cause a polymer’s properties to alter (Chatterjee and Hui 2019). Bioimaging is a non-invasive technique for tracking biological behavior over time that doesn’t interfere with normal life processes like movement and respiration while also making it easy to capture the 3D structure of the specimen. It helps multicellular organisms’ tissues and studies of subcellular structure to be connected (Xu 2018).

4.4.2 Optical Imaging

Most commonly used imaging technique is optical imaging for diagnosis of disease (Liu et al. 2019a, b). Due to the exceptionally low tissue absorption, the optical imaging systems use near-infrared (NIR), i.e., 700–1000 nm (Carr et al. 2018). Fluorescent NIR probes like cyanine compounds are low molecular weight organic molecules with exceptional optical properties which are used (Nagamani et al. 2019) for imaging. Cyanine were added to various polymer compositions in an effort to increase bioavailability and durability in order to alleviate these restrictions like NIR fluorescent probes insertion in lipooligosaccharides (Wang et al. 2019), water-soluble carboxylated N-acylated poly (amino ester)-based polymers (Mahmoud et al. 2019), and polymer micelles have all been reported (Shao et al. 2019). Yang and his research group developed a self-assembled polymer nanocarrier for imaging and anticancer therapy (Yang et al. 2020). Their nanocarrier is comprised of PEG that has hydrophobic poly (ortho ester) and hydrophilic poly (glycidyl methacrylate) modified with ethylenediamine (PEG-g-p(GEDA-co-DMDEA)).

4.4.3 Ultrasound Imaging

In ultrasound imaging technique, the sound waves transferred to the body at a frequency of 2 MHz or higher for diagnosis. It is a cheap, non-invasive, efficient, and real-time imaging technique (Liu et al. 2019a, b). This strategy is widely used in the cancer treatment and received the greatest attention. Yang et al. described multifunctional PLGA nanobubbles as theranostic agents and doxorubicin for breast cancer (Yang et al. 2015). MCF-7 cancer cells that had been treated with doxorubicin and P-gp siRNA as a platform for performing cellular ultrasound imaging. In another study, nanobubble-paclitaxel loaded liposomes prepared for ultrasound-sensitive drug and ultrasound imaging were recorded (Prabhakar and Banerjee 2019).

4.4.4 Magnetic Resonance Imaging

MRI contrast agents (CAs) can modify the relaxation periods of protons in various organs on contact with external magnetic field (Luk and Zhang 2014). The low molecular weight complexes are unable to produce accurate MRI images of the tumor. It has shown significant promise to solve these drawbacks to encapsulate contrast agent with polymeric NPs especially smart polymers that respond to tumor-specific stimuli (Vijayan and Muthu 2017; Hu 2020). There are different types of formulations reported for MRI imaging like nanogels, polymersomes, and micelles. Aouidat and his team explained the gold core-shell NPs (Gd(@AuNPs) are a major component of the new Gd (III)-biopolymer-Au (III) complex. They demonstrated the advantages of Gd@AuNPs for treating the hepatocytes in the liver. It provides a potent cellular uptake of Gd@NPs and conserving a T1 contrast inside cells that allows consistent in vivo detection using T1-weighted MR imaging.

4.4.5 Photoacoustic Imaging

This is a visualization method and also known as photoacoustic imaging, and was just recently discovered. This technique generates localized heat and thermoelastic stress waves when tissues absorb a brief light pulse effect (Valluru and Willmann 2016). Lyu and associates developed an intraparticle molecular orbital engineering technique to increase the effectiveness of polymeric NPs for phototherapy and photoacoustic illumination for cancer therapy. They showed that it can be used with theranostic nanoagents to produce superior photoacoustic imaging (Lyu et al. 2016).

4.4.6 X-Ray Computed Tomography

The visualization method known as photoacoustic imaging was just recently discovered. This technique generates localized heat and thermoelastic stress waves when tissues absorb a brief light pulse effect. The delivery system made of polymers is the best choice for addressing biocompatibility and biodegradability issues (Zhou et al. 2016; Zhang et al. 2017a, b, c). Lyu et al. (2016) developed an intraparticle molecular orbital engineering technique to increase the effectiveness of polymeric NPs for cancer therapy. They showed that it can be used with theranostic nanoagents to produce superior photoacoustic imaging.

4.4.7 Radionuclide Imaging

Numerous investigations have concentrated on the development of polymeric nano-vehicles with the radionuclide imaging (Di Mauro et al. 2015). Sun and his research team described a polymeric carrier using a hydrophobic poly (FTS) block, a hydrophilic poly (oligo (ethylene glycol) (POEG) block, and a central block of poly (4-vinylbenzyl azide). They developed a farnesylthiosalicylate-based, triblock copolymer. Radio-labeled PTX/POVF nano-micelles were rapidly absorbed and slowly excreted from tumor tissues in the mice using PET imaging (Sun et al. 2018). In another study, Le Goas et al. (2019) formulated the hybrid poly (methacrylic acid)-grafted gold NPs to enhance systemic absorption in tumor-bearing mice. This research examined a nanomedicine technique for lowering the dose of radioiodine to accomplish RT imaging.

4.4.8 Radioactive Polymeric Nanoparticles for Imaging and Therapy

In addition to providing functional and molecular imaging, radioactive nanoparticles (RNPs) are also helpful for diagnosing since theranostic applications. The radioactive polymeric NPs can be developed by using one of two approaches for achieving the imaging goals. This approach is adaptable and can be used in functionalization chemistry to add different radioelements into ligands on the surface of NPs. RNPs based on polymeric NPs have many benefits over a large number of NPs that have undergone preclinical and clinical testing. In contrast to conventional radionuclide therapy, RNPs have a higher payload capacity for radionuclides that can be employed for non-invasive imaging and/or therapy. Concentration of radioactive material used for nuclear imaging or radiotherapy depends upon types of radioactive material (El-Say and El-Sawy 2017). By boosting the accumulation of the diseased tissue target areas through passive or active targeting, the RNPs have the potential to significantly enhance therapies and diagnostics. It was observed that DTPA-derivatized liposomes and radiolabeled micelles have been frequently utilized to study the biodistribution studies (Psimadas et al. 2012). In addition, they did not exhibit high intestinal excretion 12 h after injection but showed high accumulation of NPs in the liver and spleen due to high radioactivity levels in healthy Lewis rats (Psimadas et al. 2012; Lim et al. 2016). In a different study, the 111In-labeled polymeric NPs with a radiosensitizer based on ruthenium were found to be targeted therapeutic effects in tumor that overexpress EGFR (Ng et al. 2014; Gill et al. 2018). Nano radiopharmaceuticals based on 99mTc and rhenium-186 have become crucial tools for the diagnosis and treatment of several illnesses or dysfunctions of organs and systems (Hua et al. 2015; Costa et al. 2019). A nicotinic acid (HYNIC)-type ligand system was utilized to label with 99mTc during the radiolabeling process, which was carried out via a direct labeling strategy (Kovacs et al. 2014). Direct irradiation of NPs, direct labeling, utilizing radioactive species as raw materials, and indirect labeling using radioactive species as raw materials are the ways to produce polymeric radioactive NPs (Lamb and Holland 2018). The fundamental issue with direct irradiation of NPs, especially polymeric NPs, is the heating and damage to the nanostructure that the high c-radiation background and irradiation process induce (Haume et al. 2016; Lamb and Holland 2018).

4.4.9 Application in Infectious Diseases

Pathogens like viruses, bacteria, fungus, and parasites can cause infectious diseases. These microbes quickly reproduce and alter homeostasis. A rise in the totality and morbidity index is highly correlated with the occurrence of various diseases (Jain et al. 2015a, b; Chauhan et al. 2022; Juneja et al. 2022; Bagre et al. 2022). By utilizing radio-labeled chitosan-leukocytes, Fairclough and associates developed the radio-labeled chitosan-leukocytes for enhancement of diagnosis of inflammatory process (Fairclough et al. 2016). The 89Zr and 64Cu were used for radiolabeling NPs. The findings indicated that compared to 64Cu-chitosan NPs, the 89Zr-chitosan NPs displayed a reduced efflux (Fairclough et al. 2016) of therapeutic agents. Santos et al. formulated the betamethasone and dexamethasone PLA (poly-lactic acid) NPs labeled with 99mTc and reported an in vivo model of Staphylococcus aureus infection and inflammation. The 99mTc-PLA NPs-betamethasone showed accumulation at the S. aureus inflammation site, demonstrating the potential application of this technology for the detection of infection and inflammation foci in vivo (Santos et al. 2017). Pterostilbene and crude grape pomace extract loaded in PLGA-NPs were tested by Simonetti and colleagues against a Candida albicans biofilm using six coumarin fluorescence probes. These PLGA-NPs showed a substantial suppression of C. albicans biofilm (Simonetti et al. 2019). Helal-Neto et al. developed 99mTc labeled ethambutol NPs using PCL (poly-caprolactone) polymer. The outcomes demonstrated that these NPs have a theranostic impact on the Mycobacterium bovis strain both in vitro and in vivo (Helal-Neto et al. 2019).

4.5 Conclusion

Over last few decades, significant advancements in application of nanomedicine have been witnessed to diagnose and treat different diseases and ailments including cancer by exploiting phenomena of targeting delivery based on enhanced permeability and retention (EPR) effect, pH-responsive delivery, or ligand-based targeting. Nanoparticles made of polymers and metals have been explored by scientists for therapeutic, imaging, and theranostic application. Although metal-based nanoparticles have shown various applications in the field of biomedical sciences including therapeutics and diagnostics as well as in the fields like electronics due to their unique physicochemical properties, yet use of metal-based nanoparticles is limited by colloidal instability, related toxicity issues, and non-specific interactions with biological systems. In contrast, polymeric nanoparticles offer advantages of versatility, biocompatibility and biodegradability, colloidal stability, and site specificity which could be further improved by surface functionalization. Furthermore nano-hybrids or nano-conjugates of polymer and metallic nanoparticles may be designed as a multifunctional nanomedicine to circumvent challenges of each other and to potentiate the drug delivery efficiency as well as for simultaneous delivery of imaging and/or therapeutic agents in nanotheranostics.