Polymer-drug conjugates: revolutionizing nanotheranostic agents for diagnosis and therapy

Abstract

Nanotheranostics, an amalgamation of therapeutic and diagnostic capabilities at the nanoscale, is revolutionizing personalized medicine. Polymer-drug conjugates (PDCs) stand at the forefront of this arena, offering a multifaceted approach to treat complex diseases such as cancer. This review explores the recent advancements in PDCs, highlighting their design principles, working mechanisms, and the therapeutic applications. We discuss the incorporation of imaging agents into PDCs that allow for real-time monitoring of drug delivery and treatment efficacy. With the aim of improving patient care, the review examines how PDCs enable targeted drug delivery, minimize side effects, and provide valuable diagnostic data, hence enhancing the precision of medical interventions. We also address the challenges facing the clinical translation of PDCs, such as scalability, regulatory hurdles, and cost-effectiveness, providing a comprehensive outlook on the future of nanotheranostics in patient management.

Introduction

The burgeoning field of nanomedicine has introduced an array of innovative strategies for the diagnosis and treatment of diseases, marrying the precision of molecular targeting with the versatility of therapeutic delivery systems [1]. Polymer-drug conjugates (PDCs), a leading class within this domain, have garnered significant attention for their potential in enhancing clinical outcomes [2]. These conjugates amalgamate the therapeutic efficacy of drugs with the customizable properties of polymers, offering a new dimension in controlled and targeted drug delivery [3]. Since the conceptual framework proposed by Helmut Ringsdorf in 1975, PDCs have undergone substantial evolution, improving drug solubility, stability, and biodistribution while reducing the undesirable systemic side effects often associated with traditional therapies [4]. Importantly, the integration of therapeutic agents with polymeric carriers via covalent linkage allows for a controlled release mechanism, which can be tailored to the pathophysiological conditions of the disease site [5].

PDCs now stand at the cusp of theranostic applications—a combination of therapy and diagnostics—providing real-time monitoring of drug delivery and treatment response (Fig. 1) [6]. The dual functionality of PDCs aligns with the goals of personalized medicine, offering prospects for simultaneous imaging and treatment, ensuring that therapeutics are delivered effectively to the targeted site [7]. This introduction delineates the advancements in the chemistry and biology of PDCs, their nanotheranostic applications, and the prospects and challenges they propose in the translation from bench to bedside in modern medicine [8].

Fig. 1.

Illustration of polymer-drug conjugates as nanotheranostics, showcasing the combination of therapeutic agents with polymers for targeted drug delivery and integrated diagnostic imaging, offering enhanced precision in treatment and monitoring

PDC synthesis can be broadly classified into three approaches: direct conjugation of a drug to a preformed polymer drug modification followed by polymerization with comonomers, and utilizing drug molecules as monomers or polymerization initiators. The second method, involving drug derivatization prior to polymerization, offers superior control over drug loading and ensures compatibility with the polymerization process. This approach has been successfully employed with various polymerization techniques, including ring-opening polymerization for biodegradable PDCs and ring-opening metathesis polymerization and reversible addition-fragmentation transfer polymerization for non-biodegradable PDCs. Furthermore, this strategy enables the design of PDCs capable of triggered release from multi-drug conjugated systems.

Polymer conjugates incorporating both therapeutic drugs and imaging agents represent a powerful class of theranostic agents, enabling simultaneous treatment and diagnostic monitoring within a single platform. Diagnostic imaging provides crucial insights into the target site's status, drug behavior, and disease progression, allowing for real-time assessment of treatment efficacy. This integrated approach facilitates precise activation of therapeutic responses by monitoring drug biodistribution and localization. The inherent versatility and tunability of polymeric systems further simplify the development and optimization of these nanotheranostic platforms [5].

As PDC technology continues to advance, the development of nanotheranostic agents is poised to propel personalized treatment plans, dovetailing diagnosis with targeted therapy [9]. We explore the multifaceted nature of PDCs, their utility across a spectrum of diseases, and the potential they hold for revolutionizing therapeutic paradigms.

Polymers used in nanotheranostics

In the realm of nanotheranostics, polymers play a critical role due to their tunable properties and functionalities [10]. They serve as scaffolds for drug conjugation, agents for better solubilization, and platforms for targeted delivery of therapeutic and diagnostic components (Table 1) [11]. Following are some commonly used polymers in nanotheranostics:

Table 1.

PDC-based nanotheranostic materials in cancer targeting integrated diagnostic imaging

PDC-based nanotheranostic materials	Investigated drug	Method of conjugation	Integrated imaging agent	Indication	Outcome	References
Doxorubicin-Loaded PDC with Fluorescent Imaging	Doxorubicin (DOX)	Polymer backbone via a pH-sensitive hydrazone bond	Fluorescent dye (e.g., Cy5.5)	Breast cancer	HPMA copolymers with low dispersity and a molecular weight near the limit of renal filtration can be used as highly efficient polymer carriers of tumor-targeted therapeutics or for theranostics with minimal side effects	[44]
Cisplatin-Encapsulated PDC with MRI Contrast Agent	Cisplatin	Cisplatin was encapsulated within a polymer micelle conjugated to a PEG shell	Gadolinium-based MRI contrast agent	Ovarian cancer	Upon complete release of cisplatin, all PtGdL is converted to GdL enabling subsequent MRI analyses of therapy efficacy	[45, 46]
Paclitaxel-Linked PDC with Near-Infrared Dye (IR-AFN@PTX-FA)	Paclitaxel	Paclitaxel was linked to the polymer backbone using a cleavable disulfide bond	Near-infrared (NIR) dye (e.g., IR780)	Lung cancer	IR-AFN@PTX-FA was found to selectively target tumors and showed very efficient NIR-II photothermal effects and pH/NIR-II triggered drug release effects, showing a remarkable, synergistic photothermal chemotherapy effect	[47]
Camptothecin-Conjugated PDC with Quantum Dots	Camptothecin	Camptothecin was conjugated via a biodegradable linker	Quantum dots	Prostate cancer	The drug-conjugated hybrid nanoparticles inhibit cell growth through the induction of apoptosis	[48]
Methotrexate-Loaded PDC with Photoacoustic Imaging Agent	Methotrexate	Methotrexate was conjugated using a biodegradable polymer linker	Photoacoustic dye (e.g., Indocyanine Green)	Rheumatoid arthritis and cancer	The drug release of methotrexate loaded chitosan nanoparticles could be triggered and controlled remotely by coating with TiO2-NPs	[49]
Gemcitabine-Conjugated PDC with Gold Nanoparticles	Gemcitabine	Gemcitabine was covalently bonded to a polymer backbone using a linker	Gold nanoparticles	Pancreatic cancer	Gold nanoparticles could be considered as a potential agent to sensitize pancreatic cancer cells to gemcitabine	[50]
Irinotecan-Encapsulated PDC with Fluorescent Quantum Dots	Irinotecan	Irinotecan was encapsulated within a polymeric micelle with a pH-sensitive core	Fluorescent quantum dots (e.g., CdSe/ZnS)	Colorectal cancer	Irinotecan-encapsulated polymeric micelle associated with a reduced burst effect, lack of toxicity and excellent antitumor efficacy	[51]
Doxorubicin-Conjugated PDC with Iron Oxide Nanoparticles	Doxorubicin (DOX)	Doxorubicin was conjugated to the polymer via an acid-labile hydrazone bond	Iron oxide nanoparticles	Liver cancer	The small sized magnetic nanoparticles with high drug loading capacity are suitable as theranostics for cancer treatment	[52]
Docetaxel-Loaded PDC with Near-Infrared (NIR) Fluorophores	Docetaxel	Docetaxel was linked to the polymer backbone using a biodegradable ester bond	Near-infrared (NIR) fluorophores (e.g., IR Dye 800CW)	Breast cancer	Simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence	[53]
5-Fluorouracil-Conjugated PDC with Upconversion Nanoparticles	5-Fluorouracil (5-FU)	5-FU was conjugated via a photo-cleavable linker	Upconversion nanoparticles	Skin cancer	Theranostics application through the use of luminescent properties of upconversion nanoparticles and the polymer architecture	[54]
Camptothecin-Conjugated PDC with Multifunctional Nanodiamonds	Camptothecin	Camptothecin was linked to a polymer backbone using a redox-sensitive disulfide bond	Multifunctional nanodiamonds	Brain cancer	Nanodiamonds with exceptional optical, thermal and mechanical properties emerged as a new therapeutic and diagnosis combinations	[55]
Methotrexate-Linked PDC with Positron Emission Tomography (PET) Tracers	Methotrexate	Methotrexate was conjugated to the polymer using a cleavable ester linkage	Positron Emission Tomography (PET) tracers (e.g., 18F-labeled agents)	Rheumatoid arthritis and cancer	PDCs are capable of molecular recognition and directing intracellular delivery of loaded drugs	[56]

Polyethylene glycol

Polyethylene glycol (PEG) is widely used due to its excellent biocompatibility and ability to evade the immune system, extending the circulation time of nanoparticles [12]. Kumar et al., developed a theranostic system for the concurrent targeted imaging and treatment of cancer, known as theranostic small-molecule drug conjugates. The system employed polyethylene glycol as the carrier and used Gallium 68 attached to a chelator for positron emission tomography imaging [13]. Yi et al., developed a novel triblock copolymer using a ring opening polymerization technique, resulting in a nanoparticle that could self-assemble [14]. The copolymer consisted of a hydrophilic methoxypoly(ethylene glycol) (mPEG) surface, a hydrophobic poly(carbobenzyloxy-L-lysine) core, and a cationic polypeptide corona made up of poly{N-[N-(2-aminosthyl)-2-aminosthyl] aspartamide} (PASP). The anti-mitotic drug monomethyl auristatin E was attached to the PASP segment through a linker that is sensitive to reductive conditions and capable of self-elimination [15]. For imaging purposes in living organisms, Cyanine 7.5 was integrated [16].

Poly(lactic-co-glycolic acid)

Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable polymer that is FDA approved for use in drug delivery systems [17]. It allows for the sustained release of therapeutic agents. Chatterjee and colleagues introduced a new method for creating nanoparticles by linking 1-pyrenebutyric acid (PBA) to a PLGA polymer framework using ethylenediamine as the connecting substance, resulting in stable fluorescent nanoparticles [18, 19]. The surface of these PLGA-PBA nanoparticles was further modified with the addition of methotrexate, a derivative of folic acid known to be effective against cancer cells, again utilizing ethylenediamine as the linker [20]. These nanoparticles were readily taken up by cancer cells, a process enhanced by methotrexate's similarity to folic acid, which likely facilitated the uptake through cellular folate receptors [21].

Poly(lactic acid)

Similar to PLGA, Poly(lactic acid) (PLA) is also biodegradable and used for its controlled release properties. Hu et al., fabricated multifunctional micelles by combining three distinct polymer-drug conjugates. They used a doxorubicin-conjugated polymer (mPEG-b-PLA-co-mercaptoethanole/DOX), a Rhodamine B-conjugated polymer (mPEG-b-PLA-co-ME/RhB), and a folic acid-conjugated polymer. Folic acid served as the targeting agent, and a pH-sensitive hydrazone bond was used as the linker [22, 23]. The created micelles varied in size from 150 to 300 nm. Through fluorescent imaging of the Rhodamine B component, it was observed that the micelles with folic acid were more stably retained in tumor tissues than those lacking folic acid targeting moieties [24].

Dendrimers

These are highly branched, spherical polymers with a well-defined, three-dimensional architecture, making them suitable for encapsulating diagnostic and therapeutic agents. Parashar et al. explored the use of poly(propylene imine) (PPI) dendrimers for the delivery of temozolomide (TMZ) and silver sulfide (Ag₂S) quantum dots (QDs) to target glioblastoma multiforme (GBM), an aggressive and treatment-resistant brain tumor. This approach aimed to enhance the therapeutic efficacy of TMZ while simultaneously enabling real-time imaging of the drug distribution and tumor response [25].

Chitosan

Chitosan is a biopolymer derived from chitin that has mucoadhesive properties, enhancing the delivery of drugs across mucosal surfaces [26]. Wu and colleagues developed a folate receptor-targeting theranostic nanoprobe, designated as PPa/FITC-SWCNT-FA, for the purpose of directing therapy to cancer cells and providing fluorescence imaging-guided photodynamic treatment. The base for these nanoprobes was formed using polyethylene-glycol-modified single-walled carbon nanotubes [27]. Two critical components were attached to this foundation: folic acid, which homes in on tumor cells, and pyropheophorbide, a photosensitizing pharmaceutical substance, both of which were covalently linked by bonding the carboxyl groups to the amino groups of chitosan [28]. Additionally, the fluorescent marker fluorescein isothiocyanate was covalently attached to the system. Their research demonstrated that the PPa/FITC-SWCNT-FA conjugate could precisely target cancer cells that exhibit an excess of folate receptors [29].

poly(N-isopropylacrylamide)

A temperature-responsive polymer that exhibits a sharp phase transition at its lower critical solution temperature, allowing for the controlled release of drugs in response to temperature changes in the body [30]. One notable example of the use of poly(N-isopropylacrylamide) (PNIPAM) in nanotheranostics is the work by Dr. Baipaywad and his team. In their research, they developed PNIPAM-based nanogels for the targeted delivery of doxorubicin and integrated imaging capabilities using gold nanoparticles for the treatment and monitoring of cancer [31].

Poly(glutamic acid) and poly(aspartic acid)

These polypeptides can be used for drug conjugation and are sensitive to enzymatic action, allowing for degradation and drug release in specific tissue or cellular environments [32]. Dr. Kataoka's team designed polymeric micelles using poly(glutamic acid) (PGA) and poly(aspartic acid) (PAA) as the core-forming blocks. These micelles were then conjugated with doxorubicin, an anticancer drug, and functionalized with QDs for imaging purposes [33].

Poly(2-hydroxyethyl methacrylate)

Used in hydrogel matrices for controlled release, poly(2-hydroxyethyl methacrylate) (PHEMA) swells in water, permitting the incorporation and subsequent release of both hydrophilic and hydrophobic drugs [34]. Dr. Liangfang Zhang and his research team have made significant contributions to the development of PHEMA for nanotheranostics applications. One exemplary study led by Dr. Zhang explores the use of PHEMA-based nanoparticles for both therapeutic and diagnostic purposes [35]. The study demonstrated the versatility of PHEMA-based nanoparticles for theranostic applications. By combining drug delivery with diagnostic imaging, these nanoparticles offer a multifunctional platform for precision medicine, enabling simultaneous treatment and monitoring of therapeutic efficacy. Dr. Zhang's research exemplifies the potential of PHEMA-based nanotheranostics in advancing personalized medicine and improving patient outcomes [36].

Block copolymers

Such as PLGA-PEG, where one block provides biodegradability and the other block extends circulation time or enhances solubility. Dr. Robert Langer and Dr. Omid Farokhzad are prominent scientists who have contributed significantly to the field of nanotheranostics, particularly in the development of block copolymer-based systems such as PLGA-PEG nanoparticles [37]. The study demonstrated the potential of PLGA-PEG nanoparticles as versatile nanotheranostic platforms for cancer therapy [11]. By combining targeted drug delivery with imaging capabilities, these nanoparticles offer a multifunctional approach to personalized medicine, allowing for tailored treatment regimens and improved patient outcomes. Dr. Langer, Dr. Farokhzad, and their team's research exemplifies the transformative impact of block copolymer-based nanotheranostics in advancing cancer therapy [37].

N-(2-Hydroxypropyl) methacrylamide

N-(2-Hydroxypropyl) methacrylamide (HPMA) is a highly versatile polymer that has garnered significant attention in the field of nanotheranostics, particularly for the development of polymer-drug conjugates. HPMA-based PDCs offer a unique combination of properties, including biocompatibility, water solubility, and ease of modification, making them ideal candidates for targeted drug delivery and imaging applications. One of the key advantages of HPMA copolymers lies in their ability to encapsulate or conjugate various therapeutic agents, such as anticancer drugs, genes, or proteins. This conjugation can be achieved through different mechanisms, including covalent attachment, electrostatic interactions, or hydrophobic interactions. By linking these therapeutic payloads to the HPMA backbone, researchers can enhance drug solubility, prolong circulation time, and improve tumor targeting, ultimately leading to enhanced therapeutic efficacy and reduced systemic toxicity.

Furthermore, HPMA-based PDCs can be engineered to incorporate imaging agents, such as fluorescent dyes, quantum dots, or radionuclides. This dual functionality of HPMA-based PDCs allows for simultaneous therapy and diagnosis, enabling real-time monitoring of drug delivery, tumor response, and treatment efficacy. For instance, researchers have developed HPMA-based PDCs labeled with imaging agents that accumulate specifically in tumor tissues, providing valuable insights into tumor location, size, and progression [5].

Poly(glycolic acid)

Poly(glycolic acid) (PGA), a biodegradable and biocompatible polymer, has shown significant potential in the development of PDC-based nanotheranostic materials. Its unique properties, such as excellent biodegradability, tunable degradation kinetics, and ease of functionalization, make it a promising candidate for various biomedical applications. PGA-based PDCs have been extensively explored for drug delivery applications, particularly in cancer therapy. The ability to conjugate anticancer drugs to the PGA backbone allows for targeted delivery to tumor sites, improving drug efficacy and minimizing off-target effects. Moreover, the controlled degradation of PGA enables sustained drug release, reducing the frequency of administration and enhancing patient compliance [38].

Collagen

Collagen is a structural protein that forms a major component of the extracellular matrix in connective tissues, skin, and bones. Its high biocompatibility and biodegradability make it an attractive candidate for drug delivery. Collagen can be chemically modified and used to form drug conjugates. It has excellent tissue adhesion properties, making it particularly useful for localized drug delivery, such as wound healing and tissue regeneration. Collagen can be conjugated with chemotherapeutic agents to target cancerous tissues. Its slow degradation rate ensures that the drug is released over a prolonged period, providing sustained therapeutic effects [39].

Heparin

Heparin is a naturally occurring polysaccharide that is widely known for its anticoagulant properties. It has been used in various medical applications, including as a blood thinner. Heparin’s unique ability to bind to a wide range of proteins makes it a versatile carrier in polymer-drug conjugates. It can be chemically modified to conjugate with anti-cancer drugs or anti-inflammatory agents. Heparin also has the potential to target specific receptors, facilitating drug delivery to particular tissues or organs. Additionally, its inherent anticoagulant properties can help reduce blood clot formation during drug therapy. Anti-cancer therapy, with heparin-drug conjugates targeting tumor cells [40].

Albumin

Albumin is a highly abundant plasma protein with excellent biocompatibility and a long circulation half-life. It is frequently used in drug delivery systems due to its natural ability to bind and transport various molecules. Albumin has been extensively used in the development of drug conjugates due to its affinity for a variety of drugs and its ability to enhance the solubility of hydrophobic molecules. Drugs can be covalently linked to albumin, which not only stabilizes the drug but also enhances its bioavailability. Nanoparticles made from albumin-drug conjugates, such as the FDA-approved Abraxane (albumin-bound paclitaxel), have shown improved pharmacokinetic profiles and targeted drug delivery to tumors. Cancer therapy, particularly using albumin-bound nanoparticles (e.g., Abraxane) [41].

Dextran

Dextran is a branched polysaccharide composed of glucose units. It is biodegradable and biocompatible, and its hydrophilic nature makes it an excellent candidate for drug delivery, particularly for hydrophobic drugs. Dextran’s hydroxyl groups can be modified to covalently link with drugs or therapeutic agents. It can be used to form nanoparticles or hydrogels for controlled drug release, making it suitable for both systemic and localized drug delivery. Dextran conjugates are also known for their ability to prolong circulation time, reduce immune clearance, and improve the pharmacokinetics of conjugated drugs. It has been used in cancer treatment, vaccine delivery, and drug delivery to the brain due to its capacity to cross the blood–brain barrier. Cancer therapy via dextran-drug conjugates has demonstrated improved drug accumulation in solid tumors, enhanced permeability, and reduced toxicity in comparison to free drugs [42].

Gelatin

Gelatin is a protein derived from collagen and is widely used in pharmaceuticals due to its biocompatibility, low immunogenicity, and ease of modification. It can form hydrogels, nanoparticles, and microspheres, providing diverse applications in drug delivery. Gelatin can be chemically modified to conjugate with various drugs, allowing for controlled and targeted drug release. It is often used in the form of nanoparticles, which can encapsulate and slowly release drugs at specific sites, such as tumors. Additionally, gelatin-based hydrogels are commonly used for the localized delivery of anti-cancer drugs, antibiotics, or growth factors in tissue engineering applications. Cancer therapy through gelatin-based nanoparticles [43].

Recent advancements in polymer-drug conjugates

Targeted delivery

Recent advancements in polymer-drug conjugates for targeted drug delivery have focused on enhancing the specificity and effectiveness of treatments while minimizing adverse effects on healthy tissues [57]. This has been achieved through the conjugation of various targeting molecules to the polymeric carriers that can selectively bind to markers expressed on diseased cells. One of the most significant developments involves using monoclonal antibodies or their fragments as targeting moieties [58]. These antibodies can recognize and bind to specific antigens present on the surface of cancer cells or other disease-related cells with high specificity. This allows the polymer-antibody drug conjugates to deliver the therapeutic agent directly to the affected cells, improving the drug's therapeutic index [59].

Dr. Choi and his team discussed short chains of amino acids, or peptides as another form of targeting ligands due to their smaller size and ease of modification. These can be chosen for their ability to bind to receptors that are overexpressed on the surface of certain types of diseased cells, such as cancer or inflamed tissue, enhancing the PDC's ability to localize and deliver drugs to the target site [60]. These low molecular weight compounds can be designed to target a wide range of biological markers. For example, folic acid has been used as a targeting agent because many cancer cells overexpress the folate receptor. Small molecules can penetrate tissues efficiently and bring the polymer-drug conjugates to the intended site of action [61].

Dr. Meng and his team reviewed a polymer-drug conjugate system using poly(ethylene glycol)-poly(aspartate) (PEG-PAsp) for the targeted delivery of doxorubicin to cancer cells. PEG-PAsp conjugates were attached covalently with doxorubicin attached at the poly(aspartate) segment via a pH-sensitive hydrazone linkage [62]. Additionally, folate molecules were attached to the PEG segment to target cancer cells overexpressing folate receptors. The study demonstrated that the PEG-PAsp-doxorubicin conjugates effectively targeted cancer cells and released doxorubicin in a controlled manner, resulting in enhanced therapeutic efficacy and reduced systemic toxicity (Fig. 2).

Fig. 2.

Illustration of tumor targeting using polymer-drug conjugates, depicting the dual function of delivering an anticancer drug while incorporating an imaging agent for precise tumor localization, treatment monitoring, and reduced off-target effects

Stimuli-responsive systems

The field of polymer-drug conjugates is advancing rapidly, with one of the most cutting-edge developments being the creation of stimuli-responsive systems [63]. These systems are engineered to react to specific physiological or external triggers, thereby releasing the drug payload in a controlled manner precisely where it is needed. Many diseases, including cancer, involve areas with abnormal pH levels. PDCs designed to be stable at the body’s normal pH but to disassemble and release their drug load at the lower pH found in tumor tissues or inflamed areas have been developed [64]. This targeted deployment minimizes systemic exposure and side effects while maximizing therapeutic impact.

Some PDCs can react to temperature changes. These systems exploit the slight increase in temperature in certain pathological conditions, such as inflamed tissues or tumor environments [65]. Polymers like poly exhibit a sharp change in solubility above a certain temperature, enabling the PDC to release the drug specifically when it reaches the heated diseased tissue. Enzyme-responsive systems take advantage of the fact that certain diseases are associated with overexpression of specific enzymes [66]. PDCs can be designed with linkers that are cleavable by these enzymes, resulting in the selective release of the drug in the presence of the target enzyme. This approach ensures that the drug is released only in the vicinity of diseased tissues where these enzymes are active, sparing healthy cells from exposure [67].

An excellent example of PDCs for stimuli-responsive drug delivery systems is the research conducted by Dr. Jianjun Cheng and his team. They developed a pH-sensitive polymer-drug conjugate for targeted cancer therapy. They designed and synthesized PEG-PAE block copolymers, where doxorubicin was conjugated to the poly(beta-amino ester) (PAE) segment through a pH-sensitive hydrazone bond. This pH-responsive behavior ensures that doxorubicin is selectively released in the vicinity of the tumor, minimizing systemic toxicity and enhancing therapeutic efficacy [68].

Improved linker chemistry

Improved linker chemistry is crucial in the design of polymer-drug conjugates as it determines the stability and drug release kinetics of the conjugate [69]. Linkers act as a bridge between the drug and the polymer backbone, and advancements in this area have led to the creation of linkers that are stable in circulation but can be cleaved under specific conditions present in the diseased tissues. Cleavable linkers are designed to be stable in the bloodstream to prevent premature drug release. Once they reach the target site, such as a tumor, they can be cleaved through various mechanisms. For instance, linkers can be pH-sensitive, cleaving in the acidic environment of tumors or inflamed tissue. Alternatively, they can be enzyme-sensitive, breaking down in the presence of certain enzymes overexpressed in disease states [70, 71].

Self-Immolative linker undergoes a cascade of chemical reactions triggered by a stimulus (like an enzyme or pH change), resulting in the complete breakdown of the linker and release of the drug [72]. This design allows for a more precise and complete release of the therapeutic agent. Hydrolysable linkers undergo hydrolysis in the body, a process that can be tuned to happen more quickly or more slowly depending on the chemical composition of the linker. By choosing the right hydrolyzable bond (e.g., ester, amide), researchers can control the drug release rate appropriate for the therapy. Some linkers are designed to serve multiple purposes, such as including a diagnostic moiety for imaging or providing a specific binding site for targeting. These linkers add functionality and enable the synthesis of theranostic agents [73].

Dr. Davis and his team designed a polymer-drug conjugate using a biocompatible block copolymer, PEG-PGA, with the anticancer drug camptothecin conjugated via a disulfide linker [74]. The disulfide bond was chosen for its ability to be cleaved in the reductive environment of the tumor cells, which typically exhibit higher levels of glutathione compared to normal cells. Dr. Davis's research highlights the potential of polymer-drug conjugates with advanced linker chemistry in cancer therapy. By incorporating disulfide linkers that respond to the unique biochemical environment of tumor cells, the study exemplifies how improved linker chemistry can enhance the specificity and effectiveness of polymer-drug conjugates, offering a promising approach for targeted cancer treatment.

Self-assembly nanocarriers

Self-assembly nanocarriers have emerged as a powerful tool in the delivery of hydrophobic drugs because of their ability to encapsulate and protect these drugs within their structure. Amphiphilic copolymers are at the heart of this technology [75]. These molecules consist of two segments one hydrophilic and the other hydrophobic which spontaneously arrange themselves into nanoscale structures when dispersed in an aqueous environment. The process of self-assembly is driven by the tendency of the hydrophobic (water-repelling) segments of the copolymer to avoid water, leading them to come together to minimize their exposure to the aqueous environment [76]. This self-association results in the formation of various nanostructures such as micelles, with the hydrophobic segments forming the core and the hydrophilic segments forming a corona around the core [77].

In the case of micelles, the hydrophobic core serves as a reservoir for hydrophobic drugs, effectively increasing their solubility and stability in biological fluids [78]. The hydrophilic corona provides a stealth characteristic to the micelles, allowing them to evade rapid clearance by the immune system and enabling extended circulation in the bloodstream. Further tailoring of these structures is possible by modifying the chemical composition of the copolymer which can adjust the size, shape, and surface properties of the nanocarrier [79].

Dr. Jianjun Cheng and his team designed and synthesized a block copolymer, PEG-PAsp, where the anticancer drug doxorubicin was conjugated to the poly(aspartate) segment [68]. The PEG-PAsp block copolymer self-assembles into micelles due to the amphiphilic nature of the polymer. In aqueous solutions, the hydrophobic PAsp segment, conjugated with doxorubicin, forms the core of the micelles, while the hydrophilic PEG segment forms the outer shell. This self-assembly process enhances the solubility and stability of hydrophobic drugs like doxorubicin and allows for efficient drug loading and delivery.

Multifunctional PDCs

Advances have led to PDCs that combine therapeutic drugs with diagnostic imaging agents, allowing simultaneous treatment and monitoring of disease progression [5]. Dr. Rong and his team designed a multifunctional PDC that combines therapeutic and diagnostic capabilities [80]. They used a biocompatible PEG-PGA block copolymer as the backbone. Doxorubicin was covalently attached to the PGA segment via a pH-sensitive hydrazone linker. Additionally, a fluorescent dye, Cy5.5, was conjugated to the polymer to enable real-time imaging.

Expansion to non-oncologic diseases

While originally focused on cancer treatments, PDCs are now being explored for a diverse range of diseases, including infectious, cardiovascular, and autoimmune disorders [81]. Dr. Karthikeyan and his team developed a PDC aimed at treating inflammatory bowel disease (IBD). They utilized PEG-PLGA as the polymer backbone. Prednisolone was covalently attached to the PLGA segment via a hydrazone linker, ensuring drug release in response to the acidic microenvironment of inflamed tissues [82]. Additionally, the RGD peptide, known for its ability to target integrins overexpressed in inflamed tissues, was conjugated to the PEG segment to enhance the specificity of the PDC. The successful targeted delivery and controlled release of prednisolone in inflamed tissues underscore the versatility and promise of PDCs in treating a wide range of diseases beyond oncology [83].

Polymer-directed enzyme prodrug therapy

Polymer-directed enzyme Prodrug Therapy (PDEPT) represents an innovative strategy for targeted cancer treatment, merging the advantages of polymer-based drug delivery with prodrug activation [84]. By combining these two concepts, PDEPT aims to enhance the precision and effectiveness of cancer therapies while reducing harmful side effects associated with conventional treatments. The approach involves biocompatible polymers that deliver enzymes to tumors, activating prodrugs to release cytotoxic agents at the tumor site [85]. PDEPT involves three essential components:

Polymer conjugate

The polymer used in PDEPT, such as HPMA, is biocompatible and often tailored for tumor targeting. The polymer is covalently linked to an enzyme, ensuring stability and control in circulation and facilitating its delivery to tumor sites [86].

Prodrug

The prodrug is a chemically modified, inactive precursor of a cytotoxic drug. It remains non-toxic in its systemic form until activated by the enzyme delivered by the polymer. The design of the prodrug ensures that it is only triggered by a specific enzyme, minimizing off-target effects [87].

Enzyme

A critical factor in PDEPT is the enzyme linked to the polymer, chosen for its ability to activate the prodrug specifically. The enzyme's activity must be highly selective, ensuring it only activates the prodrug once it reaches the tumor microenvironment, thereby preventing damage to healthy tissues [88].

The targeted nature of PDEPT arises from its ability to preferentially accumulate in tumor tissues through the enhanced permeability and retention (EPR) effect. This process exploits the leaky vasculature typical of tumor environments, allowing the polymer-enzyme conjugate to concentrate at the tumor site. Once the polymer conjugate has accumulated, the prodrug is administered [89]. Upon reaching the tumor, the enzyme from the polymer conjugate encounters the prodrug, initiating its conversion into the active cytotoxic drug. This enzymatic activation is crucial for ensuring the cytotoxic effects are localized to the tumor area, limiting damage to surrounding healthy tissues. This results in highly targeted therapy with minimal systemic toxicity [90].

Targeted delivery of the enzyme directly to the tumor site, PDEPT ensures that the prodrug is activated only where needed, minimizing harmful exposure of healthy tissues to toxic drugs [91]. The localized nature of the activation process leads to a higher concentration of the active drug within the tumor, potentially increasing the treatment's effectiveness [92]. One of the most significant benefits of PDEPT is the reduction in systemic toxicity. Since the cytotoxic drug is activated primarily within the tumor, healthy tissues are spared, reducing the severe side effects commonly associated with traditional chemotherapy.

PDEPT is still in the developmental stages, but early research has demonstrated promising results. Enzymes like carboxypeptidase G2 and nitroreductase have been investigated for their potential in PDEPT, showing success in activating prodrugs specifically at tumor sites [93]. These preliminary studies have laid the foundation for more advanced research into enzyme-prodrug combinations that could lead to optimized therapies in the future.

However one major issue with PDEPT is immunogenicity, where the polymer-enzyme conjugate may trigger an immune response, reducing its effectiveness and potentially causing adverse effects [94]. Additionally, the efficiency of delivering the polymer conjugate to the tumor remains a crucial area for improvement. Optimizing the tumor penetration and cellular uptake of these conjugates is crucial for maximizing the efficacy of the therapy.

Method of synthesis of polymer-drug conjugates

Polymer-drug conjugates are synthesized by chemical reactions to connect a drug molecule to the polymer carrier. The choice of synthesis method depends on several factors, including the nature of the polymer and drug, the desired drug loading and release profile, and the intended application. Several established methods exist to do this, each having its own benefits and limitations depending on the specific polymer and drug.

Coupling through functional groups

This common approach utilizes reactive functional groups on both the polymer and the drug. For instance, carboxyl groups on the polymer can react with hydroxyl or amino groups on the drug, forming ester or amide linkages, respectively. Similarly, thiol groups on the polymer can react with maleimide or halo acetyl groups on the drug, creating thioether linkages. This method offers versatility and control over the conjugation process [95, 96].

Click chemistry

An efficient, selective method that relies on bioorthogonal reactions (occurs under physiological conditions without disturbing native biomolecules). A classic example is the copper-catalyzed azide-alkyne cycloaddition, where the triazole is a stable linkage, and an azide-on polymer would react with an alkyne on a drug. Click chemistry offers high yields and excellent control over the conjugation site [5].

Ring-opening polymerization

This technique is particularly useful for synthesizing PDCs with biodegradable polymers like polylactide or polycaprolactone. The drug molecule was introduced into the polymerization system, leading to an analogous PDC with a clearly defined structure. This enables exact regulation of the drug loading and release behavior.

Polymerization of drug monomers

The drug molecule is altered to incorporate polymerizable groups (for example, acrylates or methacrylates). These drug monomers can then be copolymerized with other monomers to form a PDC, where the drug is directly integrated into the polymer chain. This method offers high drug loading capacity but requires careful design of the drug monomer to maintain its therapeutic activity.

Encapsulation techniques

While not true conjugation, encapsulation techniques entrain the drug in a biodegradable polymeric matrix, such as nanoparticles or micelles. An advantage of this strategy is that it may favor hydrophobic compounds or compounds susceptible to chemical modification. The encapsulation could protect the drug from degradation and allow controlled release at the site of action [38].

Drug release mechanisms of PDCs at taregeted site

The mechanisms of action of polymer-drug conjugates encompass several sophisticated and strategic functionalities tailored to achieve specific therapeutic goals. Passive Targeting utilizing the Enhanced Permeability and Retention effect, PDC nanoparticles accumulate passively in tumor tissues due to their leaky vasculature and poor lymphatic drainage. In contrast active targeting involves the use of specific ligands or antibodies attached to the PDCs that recognize and bind to unique receptors or antigens expressed on the surface of target cells, ensuring the delivery of the drug directly to the diseased cells or tissues [97].

The drug is typically linked to the polymer via a linker that is stable in the circulation but designed to release the drug at the targeted site in response to a specific stimulus such as a change in pH, enzymatic activity, or reductive environments within diseased tissues. In response to external stimuli such as temperature change, magnetic fields, or light, PDCs can change their structure to release the drug. This approach is beneficial for achieving on-demand drug release. PDCs can be internalized by target cells through endocytosis. The polymer and drug are then released within the endosomal or lysosomal compartments, where the drug can exert its effect [98].

The drug itself can be modified and integrated into the polymer structure as a prodrug, which is inactive until it is converted to its active form by intracellular processes after cellular uptake. Certain PDCs are designed to elicit or suppress specific immune responses, contributing to the eradication of diseased cells, such as the activation of the immune system to target cancer cells. PDCs can exhibit multivalency where multiple identical drug molecules are presented in a spatial arrangement that can interact with multiple target receptors simultaneously, enhancing therapeutic efficacy [99].

Polymer-drug conjugates with imaging agents

The incorporation of imaging agents into polymer-drug conjugates is a significant advancement in the field of nanotheranostics, allowing for the real-time monitoring of drug delivery and treatment efficacy [11]. This is particularly relevant in the treatment of diseases like cancer, where it’s crucial to track the precise location and concentration of the therapeutic agent within the body [100] (Fig. 3). Ali Tarighatnia and his team reviewed the recent advances in the design and development of nanosystems and their potential use for image-guided cancer treatment. Specifically, they highlighted approaches involving the encapsulation of tyrosine kinase inhibitors for the exploration, diagnosis, and monitoring of various types of cancers under the guidance of several imaging modalities [101].

Fig. 3.

Illustration of different imaging agents incorporated into polymer-drug conjugates, highlighting the use of carbon dots, quantum dots, fluorescent dyes, MRI contrast agents, and radioactive isotopes for enhanced diagnostic imaging and real-time monitoring of drug delivery

Radioisotopes

These are used in positron emission tomography and single-photon emission computed tomography. They enable the tracking of PDC distribution and accumulation in real-time. Dr. Sanjiv Sam Gambhir and his team designed a PDC incorporating a therapeutic agent and a radioisotope for combined cancer therapy and imaging [102]. The chosen polymer was PEG-PGA, a biocompatible and biodegradable block copolymer. Doxorubicin was conjugated to the PGA segment through a pH-sensitive hydrazone bond, allowing targeted drug release in the acidic tumor microenvironment. Additionally, the polymer was labeled with the radioisotope 64Cu to enable PET imaging [103].

Magnetic resonance imaging contrasts

Paramagnetic ions like gadolinium or iron oxide nanoparticles can be conjugated to PDCs to provide contrast in MRI scans, thereby monitoring the location and persistence of the drug delivery system. Dr. Kazunori Kataoka and his team developed a multifunctional polymer-drug conjugate of PEG-PGA-doxorubicin-SPION conjugate. PEG-PGA-doxorubicin-SPION conjugates effectively targeted and released doxorubicin in the tumor site, resulting in significant tumor growth inhibition with minimal systemic toxicity. The MRI contrast capability provided by SPIONs allowed for non-invasive monitoring of the treatment, offering insights into the biodistribution and therapeutic efficacy of the PDCs [30, 104, 105]. Seraj Mohaghegh and his team designed magnetic nanoparticles loaded with erlotinib and conjugated them with anti-mucin16 aptamer to introduce new image-guided nanoparticles for targeted drug delivery as well as non-invasive MRI contrast agents. Their study suggested that erlotinib loaded magnetic nanoparticles can be efficiently used as an image-guided co-drug delivery system for the treatment ovarian cancer [106].

Fluorophores

Optical imaging employs fluorescent dyes that are included in PDCs, such as Cy7.5 or rhodamine, which allow for less invasive, real-time visualization of drug distribution. Dr. Xiaoyuan Chen and his team developed a PDC with integrated optical imaging capabilities using PEG-PGA with Paclitaxel and a fluorescent dye, Cy5 to enable optical imaging. The optical imaging capabilities provided by Cy5 allowed for real-time monitoring of the treatment, offering valuable information on the biodistribution and therapeutic response of the PDCs [8, 107].

Ultrasound contrasts

Microbubbles or nanobubbles can be integrated into PDCs to enhance ultrasound imaging, giving insight into the biodistribution of the nanocarriers. Dr. Wang and his team developed a PDC with integrated ultrasound imaging capabilities. They utilized PEG-PGA with Docetaxel along with microbubbles to provide ultrasound contrast enhancement [108]. Ali Tarighatnia and his team updated the classification of the most attractive ultrasound contrast agents (USCAs), especially with regards to their advantages and disadvantages for application in US imaging. They discussed the clinical translations of US diagnostic strategies to explore nanoparticle-based USCAs against various diseases [109].

Clinical applications of polymer-drug conjugates

PDCs have emerged as a powerful tool in modern cancer treatment due to their ability to enhance the therapeutic efficacy of chemotherapeutic agents while reducing systemic toxicity. One of the most significant clinical applications of PDCs is their use in targeted drug delivery, especially in solid tumors such as breast, lung, and ovarian cancers. By conjugating drugs to polymers like PEG or polyglutamic acid, the pharmacokinetics of these agents are improved, enabling longer circulation times and controlled release of the active drug at the tumor site. For instance, PEGylated doxorubicin has been used successfully in treating breast cancer, allowing for higher drug concentrations in the tumor and lower systemic toxicity compared to free doxorubicin [110, 111]. Nastaran Hashemzadeh and his team provided a comprehensive insights into the immunotherapy and articulate the recent advances like PDCs in terms of the therapeutic strategies used to control this disease, including immune checkpoint inhibitors, vaccines, chimeric antigen receptor T cells therapy, and nanomedicines [112].

Another important clinical application of PDCs is in overcoming multidrug resistance, which is a common issue in cancer therapy. Polymer conjugation can prevent the premature efflux of drugs from cancer cells by stabilizing the drug molecule and enhancing its intracellular uptake. In trials, paclitaxel-PEG conjugates demonstrated improved therapeutic outcomes in patients with ovarian and lung cancers, specifically in those who had developed resistance to standard chemotherapy treatments [111].

In addition to cancer therapy, PDCs are being explored for the treatment of inflammatory diseases, such as rheumatoid arthritis. By linking anti-inflammatory drugs to biocompatible polymers, researchers aim to deliver higher drug doses directly to inflamed tissues, minimizing the adverse effects seen with systemic drug administration [110]. This approach has shown promise in preclinical models, suggesting potential future applications in a range of chronic inflammatory conditions.

Furthermore, biodegradable polymers are gaining attention for their clinical potential. These materials, such as PLGA, offer a safer alternative for long-term use, as they break down into non-toxic byproducts. This characteristic makes them particularly suitable for controlled drug release systems in cancer treatment, where prolonged drug exposure can improve outcomes without the need for repeated dosing [111]. The clinical integration of PDCs continues to expand, offering new possibilities for safer and more effective therapies across a wide range of diseases.

Limitations and challenges in clinical translation of PDCs

PDCs present several limitations hinder their widespread clinical adoption. One significant challenge is drug release control. The conjugation of drugs to polymers can alter the drug's pharmacokinetics, and achieving precise and predictable release rates at the target site is often difficult. In some cases, the drug may be released too slowly or prematurely, reducing therapeutic efficacy. For example, in pH-sensitive or enzyme-responsive systems, variations in the tumor microenvironment can cause suboptimal release [110].

Immunogenicity and biocompatibility is another limitation. Some polymers, particularly synthetic ones, may trigger immune responses or exhibit poor compatibility with biological systems. Even polymers like PEG, which is widely used for its biocompatibility, have been associated with the development of antibodies after repeated administration, reducing its effectiveness in future treatments. This immune reaction can lead to faster clearance from the body and diminished therapeutic outcomes [111]. Additionally, the long-term accumulation of non-biodegradable polymers in tissues poses a risk of chronic toxicity, especially for patients requiring long-term therapy.

Manufacturing and scalability also present significant challenges. The synthesis of PDCs is complex and requires stringent control over molecular weight, drug loading, and polymer-drug linkage chemistry. Variability in these parameters can lead to inconsistent therapeutic outcomes. Moreover, large-scale production of PDCs that maintain the same quality and efficacy as those produced in laboratory settings is technically challenging and expensive​. Targeting specificity PDCs are also a big concern. Although PDCs are designed to exploit the EPR effect in tumors, this passive targeting mechanism is not universally effective across all tumor types. Tumor heterogeneity, poor vascularization, and the dynamic nature of the tumor microenvironment can hinder the accumulation of PDCs at the desired site, leading to suboptimal drug delivery. Active targeting strategies, such as ligand-receptor interactions, have been explored, but ensuring high specificity without off-target effects remains difficult. Regulatory challenges related to the approval of PDCs further complicate their clinical use. Because PDCs are complex constructs involving both drugs and polymers, they often face stringent regulatory hurdles that require extensive evaluation of both components' safety and efficacy. This can prolong the development timeline and increase costs, making it harder for companies to bring these therapies to market.

The clinical translation of polymer-drug conjugates from laboratory research to widespread medical use is complicated by several challenges. Developing a robust and scalable manufacturing process for PDCs is challenging due to the complexity of their synthesis. Each PDC is comprised of a polymer backbone, drug molecule, linker, and often a targeting moiety, each requiring precise synthesis and assembly. Scaling up production while ensuring batch-to-batch consistency, maintaining quality, and meeting Good Manufacturing Practice standards is non-trivial [113].

The multifaceted nature of PDCs means they are often classified as both a drug and a device by regulatory agencies, which can lead to complex and lengthy approval processes. The heterogeneity within PDC preparations may pose additional regulatory challenges, as regulators require thorough characterization and proof of consistent quality and efficacy. The production of PDCs involves multiple steps, specialized equipment, and often costly materials and reagents. Demonstrating cost-effectiveness compared to existing treatments is vital to the adoption of PDCs in clinical settings. The high cost can limit accessibility and adoption by healthcare systems, especially in low-resource settings.

PDCs need to demonstrate a clear benefit over existing therapies in terms of efficacy and safety in clinical trials. It can be difficult to predict how well pre-clinical results will translate to humans due to differences in disease pathology and pharmacokinetics. Variability among patient responses due to genetic, environmental, and lifestyle factors can affect the efficacy of PDCs, making it challenging to design one-size-fits-all therapeutics and complicating clinical trial design and interpretation of results. PDCs’ potential to be customized for individuals raises ethical and privacy concerns regarding genetic testing and data handling, requiring careful consideration and legislation [114].

Future of PDC based nanotheranostics

Polymer-drug conjugates have emerged as a promising avenue for targeted drug delivery and imaging, paving the way for next-generation nanotheranostic agents. The future of PDC-based nanotheranostics is bright, driven by ongoing research and technological advancements aimed at overcoming current limitations and unlocking their full potential. Extensive research on PDCs and their uses has highlighted several important areas that will drive the growth of this exciting field. These key areas represent the forefront of PDC research and development.

Enhanced targeting and delivery precision

The future of PDC-based nanotheranostics lies in their potential to converge targeted drug delivery with real-time monitoring, leading to personalized treatment regimens. PDCs can be tailored to individual patient profiles, potentially improving outcomes for treatments of cancer and other diseases [115]. Research into more sophisticated targeting moieties, such as aptamers or highly specific antibodies, may provide new ways to further enhance the specificity and efficacy of PDC-based therapies. The design of PDCs that can release their payload in response to multiple environmental triggers like pH, redox potential, and enzymes, could provide more precise control over drug release kinetics and location. PDCs that combine both therapeutic and diagnostic functions (theranostics) will continue to evolve [116]. These could incorporate different types of therapeutic agents, such as chemotherapy, immunotherapy, and gene therapy, alongside diagnostic imaging agents. The development of new biocompatible and biodegradable polymers with drug conjugation in mind may lead to PDCs with improved safety profiles and greater efficiency [117].

Advanced imaging modalities and multimodal imaging

The use of next-generation imaging agents in PDCs will likely improve the ability to monitor treatment in real time, help in early diagnosis, and provide detailed feedback on the efficacy of the therapeutic agents [118]. Further integration of nanotechnology can lead to smarter drug delivery systems with higher payload capacities, improved penetration to difficult-to-reach tissues, and on-demand drug release. There will be an emphasis on developing PDC nanocarriers that have improved stability, longevity, and biocompatibility. This includes designing PDCs that can evade the immune system for longer circulation times and enhanced delivery efficiency [119].

Overcoming challenges and translational hurdles

Addressing potential immune responses and long-term toxicity associated with PDCs is crucial for clinical translation. Strategies include developing biocompatible and biodegradable polymers, optimizing surface modifications, and conducting thorough preclinical safety evaluations. Developing cost-effective and scalable manufacturing processes that meet stringent regulatory requirements is essential for translating PDC-based nanotheranostics from the laboratory to the clinic.

Conclusion

The exploration of polymer-drug conjugates as nanotheranostic agents illuminates a promising path toward the advancement of personalized medicine. The integration of diagnostic and therapeutic functionalities within a single platform presents a paradigm shift in how we approach the treatment of complex diseases, particularly cancer. PDCs offer significant advantages in terms of targeted delivery, controlled release, and reduced systemic toxicity, ultimately leading to improved patient outcomes. The research highlighted within this review underscores the multifaceted nature of PDCs and the innovative strategies employed to optimize their design and deployment in clinical settings. While challenges remain, particularly in the areas of clinical translation, scalability, and cost-effectiveness, the potential to fine-tune these nanosystems tailors therapy at a precision level previously unattainable. The future of polymer-drug conjugates in treatment lies in their ability to provide precise, targeted drug delivery with reduced side effects, particularly in cancer therapy. Advances in biocompatible polymers and responsive release mechanisms will enhance their efficacy and personalization in treating complex diseases. The continued evolution of PDCs, supported by a deeper understanding of disease biology and advances in polymer science, is set to herald a new era of nanotheranostics that will significantly impact the landscape of medical treatment and diagnostics.

Abbreviations

Ag₂S

Silver sulfide

Cy5.5

Cyanine 5.5

DOX

Doxorubicin

EPR

Enhanced permeability and retention

FDA

Food and drug administration

GBM

Glioblastoma multiforme

HPMA

N-(2-Hydroxypropyl) methacrylamide

IR-AFN@PTX-FA

Paclitaxel-Linked PDC with Near-Infrared Dye

mPEG

Methoxypoly(ethylene glycol)

MRI

Magnetic Resonance Imaging

NIR

Near-infrared

PAA

Poly(aspartic acid)

PAE

Poly(beta-amino ester)

PASP

Poly{N-[N-(2-aminosthyl)-2-aminosthyl] aspartamide}

PBA

1-Pyrenebutyric acid

PDCs

Polymer-drug conjugates

PDEPT

Polymer-directed enzyme Prodrug Therapy

PEG

Polyethylene glycol

PEG-PAsp

Poly(ethylene glycol)-poly(aspartate)

PET

Positron Emission Tomography

PGA

Poly(glutamic acid)

PGA

Poly(glycolic acid)

PHEMA

Poly(2-hydroxyethyl methacrylate)

PLA

Poly(lactic acid)

PLGA

Poly(lactic-co-glycolic acid)

PNIPAM

Poly(N-isopropylacrylamide)

PPa/FITC-SWCNT-FA

Pheophorbide A/Fluorescein Isothiocyanate-Single-Walled Carbon Nanotube-Folic Acid

PtGdL

Platinum-Gadolinium prodrug

QDs

Quantum dots

RhB

Rhodamine B

SPION

Superparamagnetic Iron Oxide Nanoparticles

TMZ

Temozolomide

USCAs

Ultrasound contrast agents

Author contributions

Conceptualization, AKP (Ashish Kumar Parashar); formal analysis, GKS and PKJ; resources, VA and VS; writing original draft preparation, AKP; review and editing, BDK and VA; supervision, VA. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Code availability

Not applicable.

Declarations

Competing interests

The authors declare no competing interests.