Polymer-drug Conjugates Research Articles

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

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.

Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound

Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.

Design, In Silico, and In vitro Evaluation of Polymer-Based Drug Conjugates Incorporated with Derivative of Cinnamic Acid, Zidovudine, and 4-Aminosalicylic Acid against Pseudo-HIV-1.

The incorporation of anti-HIV drugs into polymer to form polymer-drug conjugates has been reported to result in improved therapeutic activity. Zidovudine, an anti-HIV drug, was explored alone and in combination with known drug molecules using polyamidoaminebased carriers. Polymer-drug conjugates incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid were prepared and evaluated for their potential efficacy in vitro against pseudo- HIV-1. Aqueous Michael addition polymerization reaction was employed to prepare the conjugates. The conjugates were incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid. They were characterized by SEM/EDX, XRD, FTIR, NMR, LC-MS, particle size analysis, in vitro analysis, computational studies, and in silico toxicity predictions. The conjugates displayed spherically shaped morphology. The in vitro findings showed that polymer-drug conjugates, T15 and T16, with a single drug were effective against pseudo- HIV-1 at high concentrations of 111.11 and 333.33 μg/mL, respectively. The molecular docking studies confirmed the in vitro results. The Swiss ADME, ProTox-II, and GUSAR (General Unrestricted Structure-Activity Relationships) revealed that these compounds are promising antiviral compounds. The prepared polymer-drug conjugates with a single drug showed promising effects against the Pseudo-HIV-1, and the conjugates displayed features that make them potential anti- HIV therapeutics that require further studies.

Preparation of Tumor-Targeting pH-Sensitive Polymeric Nanoprodrugs through the Self-Assembly of Biotinylated Polymer–Drug Conjugates Utilizing a Simple Diels–Alder Chemical Strategy

Preparation of Tumor-Targeting pH-Sensitive Polymeric Nanoprodrugs through the Self-Assembly of Biotinylated Polymer–Drug Conjugates Utilizing a Simple Diels–Alder Chemical Strategy

Synthesis and Biological Evaluation of Gastroprotective Polymer Conjugates of Aceclofenac

: Nonsteroidal anti-inflammatory drugs account for a sizeable fraction of the drugs prescribed worldwide. If consumed for a long time, they can cause ulcers and lifethreatening side effects. Since the acidic group present in NSAIDs is mainly responsible for these side effects, the scientists try to synthesize polymer drug conjugates that avoid these side effects but still retain the potency of the parent drug. Macromolecular drug conjugates of aceclofenac were prepared by employing pectin, β cyclodextrin, deacetylated chitin (chitosan) and albumin (egg and bovine serum). The prepared conjugates were characterized and tested for their anti-inflammatory, antinociceptive and antiulcerogenic activity. Further experimentation was undertaken to analyze the behavior of compounds and their stability in hydrolytic conditions. Test compound A1, a pectin conjugate of aceclofenac, exhibited significant antinociceptive and anti-inflammatory activity with a significant decrease in ulcer index (4.45±0.24) as against aceclofenac (8.61±0.40) or vehicle (12.39±0.44) treated group. A novel and safer polymer drug conjugate of aceclofenac has been synthesized and evaluated.

Reactive Oxygen Species-Regulated Conjugates Based on Poly(jasmine) Lactone for Simultaneous Delivery of Doxorubicin and Docetaxel.

In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer-drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were conjugated onto novel poly(jasmine lactone) based copolymer via a thioketal (TK) linker. In addition, a photosensitizer (chlorin e6) was attached to the polymer, which served as a reactive oxygen species generator to cleave the TK linker. The conjugate is readily self-assembled into micelles less than 100 nm in size. Micelles demonstrate a notable increase in their ability to cause cell death when exposed to near-infrared (NIR) light on MDA-MB-231 breast cancer cells. The increase in cytotoxicity is higher than that observed with the combination of free DOX and DTX. The accumulation of DOX in the nucleus after release from the micelles (laser irradiation) was also confirmed by confocal microscopy. In the absence of light, micelles did not show any toxicity while the free drugs were found toxic irrespective of the light exposure. The obtained results suggest the targeted drug delivery potential of micelles regulated by the external stimuli, i.e., NIR light.

STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy.

The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. We developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of a novel dimeric amidobenzimidazole (diABZI) STING prodrug to hydrophilic poly(dimethylacrylamide-co-azido-ethylmethacrylate) polymer chains through a cathepsin B-responsive linker to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites, where it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in the tumor tissue. Consequently, SAPCon promoted an immunogenic tumor microenvironment characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+ T cells, resulting in inhibition of tumor growth, prolonged survival, and enhanced response to anti-PD-1 immune checkpoint blockade in orthotopic breast cancer models. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy.

Injectable Hydrogel of Chitosan-Octyl Itaconate Conjugate Modulates Inflammatory Response.

Itaconic acid and its derivative 4-octyl itaconate (OI) represent a novel anti-inflammatory medication that has demonstrated efficacy in multiple inflammation models because of its minimal side effects. Recently, natural polymers conjugated with small molecule drugs, known as polymer-drug conjugates (PDCs), have emerged as a promising approach to sustained drug release. In this work, we reported an approach to prepare a PDC containing an OI and make it into an injectable hydrogel. Chitosan (CS) was selected for PDC synthesis because of its abundant free amino groups that can be conjugated with molecules containing carboxyl groups by carbodiimide chemistry. We used an ethanol/water cosolvent system to synthesize a CS-OI conjugate via EDC/NHS catalysis. The CS-OI conjugate had improved water solubility and unique anti-inflammatory activity and did not show compromised antibacterial activity compared with unmodified CS. Beta-glycerophosphate (β-GP) cross-linked CS-OI hydrogel exhibited good injectability with sustainable OI release and effectively modulated inflammatory response in a rat model. Therefore, this study provides valuable insights into the design of PDC hydrogels with inflammatory modulatory properties.

Advanced Application of Polymer Nanocarriers in Delivery of Active Ingredients from Traditional Chinese Medicines.

Active ingredients from Traditional Chinese Medicines (TCMs) have been a cornerstone of healthcare for millennia, offering a rich source of bioactive compounds with therapeutic potential. However, the clinical application of TCMs is often limited by challenges such as poor solubility, low bioavailability, and variable pharmacokinetics. To address these issues, the development of advanced polymer nanocarriers has emerged as a promising strategy for the delivery of TCMs. This review focuses on the introduction of common active ingredients from TCMs and the recent advancements in the design and application of polymer nanocarriers for enhancing the efficacy and safety of TCMs. We begin by discussing the unique properties of TCMs and the inherent challenges associated with their delivery. We then delve into the types of polymeric nanocarriers, including polymer micelles, polymer vesicles, polymer hydrogels, and polymer drug conjugates, highlighting their application in the delivery of active ingredients from TCMs. The main body of the review presents a comprehensive analysis of the state-of-the-art nanocarrier systems and introduces the impact of these nanocarriers on the solubility, stability, and bioavailability of TCM components. On the basis of this, we provide an outlook on the future directions of polymer nanocarriers in TCM delivery. This review underscores the transformative potential of polymer nanocarriers in revolutionizing TCM delivery, offering a pathway to harness the full therapeutic potential of TCMs while ensuring safety and efficacy in a modern medical context.

Drug polymer conjugates: Average release time from thin films

The reaction–diffusion problem describing the release of drugs conjugated through labile bonds to polymeric thin films has a known analytical solution, when the reaction kinetics is of first order. Using this solution, an exact formula is derived for the average release time of the system. This simple expression provides the characteristic time of release tav as the sum of the corresponding average diffusion time plus the inverse reaction rate constant: tav=(1/12)⋅(L2/D)+(1/k), where L is the slab thickness, D the diffusion coefficient, and k the reaction rate constant. The former term dominates in a diffusion-controlled release, while the latter one in a reaction-controlled delivery. The crossover regime is exactly described by their sum. The obtained result for the average release time is verified by direct numerical integration through the drug release profiles of the analytical solution. The value of fractional drug release at the characteristic average time is between 60–64%. These results can be used for the design of polymer-drug conjugates with a desired delivery time scale, as well as for the experimental determination of the values of microscopic parameters D and k in a conjugated system of interest.

Maleic Anhydride-Derived Copolymers Conjugated with Beta-Lactam Antibiotics: Synthesis, Characterization, In Vitro Activity/Stability Tests with Antibacterial Studies

The synthesis and characterization of biocompatible three different maleic anhydride co-polymer conjugated with two different beta-lactam antibiotics at in vitro conditions were conducted. The polymer–drug conjugates were synthesized by coupling β-lactam antibiotics via amide bonds to the copolymer. In this work, six different drug-functionalized maleic anhydride copolymers (DFMACs) were synthesized by the chemical conjugation method. This method is based on the ring-opening reaction of the anhydride ring of the copolymer to form an amide bond linking the drug. The synthesized DFMACs were characterized by 1H NMR and FTIR/ATR spectroscopies and analyses were carried out by UV/VIS spectroscopy and Zeta-sizer instrument in detail with consecutive antibacterial tests. The existence of a newly formed amide covalent bond between the drug and the copolymer chains was confirmed by 1H NMR and FTIR/ATR studies. This is the first report on the application of the selected branched biodegradable polymeric matrices for the covalent conjugation of ampicillin and cefalexin. Optimum stability and activity conditions for the synthesized DFMACs were determined. Analyses were conducted under in vitro conditions including varying pH values and simulated body fluids as a function of time to obtain new drug delivery system candidates for the two different antibiotics.

Polymer-drug and polymer-protein conjugated nanocarriers: Design, drug delivery, imaging, therapy, and clinical applications.

Polymer-drug conjugates and polymer-protein conjugates have been pivotal in the realm of drug delivery systems for over half a century. These polymeric drugs are characterized by the conjugation of therapeutic molecules or functional moieties to polymers, enabling a range of benefits including extended circulation times, targeted delivery, controlled release, and decreased immunogenicity. This review delves into recent advancements and challenges in the clinical translations and preclinical studies of polymer-drug conjugates and polymer-protein conjugates. The design principles and functionalization strategies crucial for the development of these polymeric drugs were explored followed by the review of structural properties and characteristics of various polymer carriers. This review also identifies significant obstacles in the clinical translation of polymer-drug conjugates and provides insights into the directions for their future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity.

Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

Hydrophilic biomaterials: From crosslinked and self-assembled hydrogels to polymer-drug conjugates and drug-free macromolecular therapeutics

This “Magnum Opus” accentuates my lifelong belief that the future of science is in the interdisciplinary approach to hypotheses formulation and problem solving. Inspired by the invention of hydrogels and soft contact lenses by my mentors, my six decades of research have continuously proceeded from the synthesis of biocompatible hydrogels to the development of polymer-drug conjugates, then generation of drug-free macromolecular therapeutics (DFMT) and finally to multi-antigen T cell hybridizers (MATCH). This interdisciplinary journey was inspiring; the lifetime feeling that one is a beginner in some aspects of the research is a driving force that keeps the enthusiasm high. Also, I wanted to illustrate that systematic research in one wide area can be a life-time effort without the need to jump to areas that are temporarily en-vogue. In addition to generating general scientific knowledge, hydrogels from my laboratory have been transferred to the clinic, polymer-drug conjugates to clinical trials, and drug-free macromolecular systems have an excellent potential for personalizing patient therapies. There is a limit to life but no limit to imagination. I anticipate that systematic basic research will contribute to the expansion of our knowledge and create a foundation for the design of new paradigms based on the comprehension of mechanisms of physiological processes. The emerging novel platform technologies in biomaterial-based devices and implants as well as in personalized nanomedicines will ultimately impact clinical practice.

Structural optimization of diblock polymers that undergo thermo-responsive nanoparticle self-assembly for intravitreal drug delivery

Certain diseases of the eye require frequent intravitreal injections to sustain active drug concentrations due to the limited volume (≤50 µL) of solution that can be administered each injection. Drug delivery systems have been evaluated to reduce dosing frequency but achieving (i) high concentrations with low viscosity (<100 cP) and (ii) narrow range of particle size (∼20–70 nm) to prolong drug activity without affecting vision remain major challenges. To address these challenges, we synthesized a combinatorial library of thermo-responsive polymer-drug conjugates with diblock architecture and assessed how various parameters (monomer unit composition, block length, drug density and attachment site) affect properties impacting ocular injection suitability. Our screens identified a lead composition, p[(N-isopropylmethacyrlamide)–co-(N-benzylmethacrylamide)]-b-p(N-(2-hydroxypropyl)methacrylamide) with 20 mol% N-benzylmethacrylamide (p[(NIPMAM)–co-(BnMAM)]-b-p(HPMA)), that exists as unimers at room temperature that can be highly concentrated (200 mg/mL) and injected at low viscosity but self-assemble into 20–70 nm particles upon injection into vitreous humor at body temperature. Furthermore, covalent attachment of representative small molecule, peptide- and protein-based drugs had minimal to no impact on thermoresponsive and hydrodynamic behavior highlighting the versatility of the lead composition as a platform for delivering a broad range of different drug molecules.

In situ administration of STING-activating hyaluronic acid conjugate primes anti-glioblastoma immune response

Glioblastoma (GBM) is an aggressive brain tumor, with a highly immunosuppressive tumor immune microenvironment (TIME). In this work, we investigated the use of the STimulator of INterferon Genes (STING) pathway as an effective means to remodel the GBM TIME through the recruitment of both innate and adaptive immune cell populations. Using hyaluronic acid (HA), we developed a novel polymer-drug conjugate of a non-nucleotide STING agonist (MSA2), called HA-MSA2 for the in situ treatment of GBM. In JAWSII cells, HA-MSA2 exerted a greater increase of STING signaling and upregulation of STING-related downstream cyto-/chemokines in immune cells than the free drug. HA-MSA2 also elicited cancer cell-intrinsic immunostimulatory gene expression and promoted immunogenic cell death of GBM cells. In the SB28 GBM model, local delivery of HA-MSA2 induced a delay in tumor growth and a significant extension of survival. The analysis of the TIME showed a profound shift in the GBM immune landscape after HA-MSA2 treatment, with higher infiltration by innate and adaptive immune cells including dendritic, natural killer (NK) and CD8 T cell populations. The therapeutic potential of this novel polymer conjugate warrants further investigation, particularly with other chemo-immunotherapeutics or cancer vaccines as a promising combinatorial therapeutic approach.

Zwitterionic polymer-dexamethasone conjugates penetrate and protect cartilage from inflammation

Improving the pharmacokinetics of intra-articularly injected therapeutics is a major challenge in treating joint disease. Small molecules and biologics are often cleared from the joint within hours, which greatly reduces their therapeutic efficacy. Furthermore, they are often injected at high doses, which can lead to local cytotoxicity and systemic side effects. In this study, we present modular polymer-drug conjugates of zwitterionic poly(carboxybetaine acrylamide) (pCBAA) and the anti-inflammatory glucocorticoid dexamethasone (DEX) to create cartilage-targeted carriers with slow-release kinetics. pCBAA polymers showed excellent cartilage penetration (full thickness in 1 h) and retention (>50 % after 2 weeks of washing). DEX was loaded onto the pCBAA polymer by employing two different DEX-bearing comonomers to produce pCBAA-co-DEX conjugates with different release kinetics. The slow-releasing conjugate showed zero-order release kinetics in PBS over 70 days. The conjugates elicited no oxidative stress on chondrocytes compared to dose-matched free DEX and protected bovine cartilage explants from the inflammatory response after treatment with IL-1β. By combining cartilage targeting and sustained drug release properties, the pCBAA-co-DEX conjugates solve many issues of today's intra-articular therapeutics, which could ultimately enable better long-term clinical outcomes with fewer side effects.

Revolutionizing Medicine: Advances in Polymeric Drug Delivery Systems

Polymeric drug delivery systems have emerged as a transformative force in modern medicine, reshaping the landscape of drug delivery and patient care. This review article comprehensively explores the advancements and innovations that have propelled polymeric drug delivery systems to the forefront of medical research and practice. Beginning with a historical perspective, we trace the evolution of drug delivery systems, highlighting the pivotal role played by polymers in this journey. We delve into the diverse array of polymeric drug delivery systems, ranging from nanoparticles and hydrogels to implantable devices and polymer-drug conjugates, elucidating their unique characteristics and applications. A critical focus of this review lies in the criteria governing polymer selection, including biocompatibility, biodegradability, and drug-loading capabilities. We illuminate the remarkable impact of polymeric drug delivery systems across various medical domains, including oncology, central nervous system disorders, cardiovascular diseases, infectious diseases, and chronic conditions. Furthermore, we explore recent breakthroughs, such as smart polymers for responsive drug release and nanotechnology-driven precision medicine, which are revolutionizing patient care. Clinical success stories and FDA-approved polymeric drug delivery systems underscore the tangible benefits these innovations bring to patients. Despite these remarkable achievements, challenges and future directions are also examined, addressing regulatory considerations, scalability issues, and the integration of emerging technologies. We conclude by emphasizing the transformative potential of polymeric drug delivery systems and call for sustained research and development efforts to harness their full capabilities. This review illuminates the dynamic and promising future of polymeric drug delivery systems in revolutionizing medicine and advancing the frontiers of patient-centric care.

Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.

Polyethylene Glycol-Based Polymer-Drug Conjugates: Novel Design and Synthesis Strategies for Enhanced Therapeutic Efficacy and Targeted Drug Delivery.

Due to their potential to enhance therapeutic results and enable targeted drug administration, polymer-drug conjugates that use polyethylene glycol (PEG) as both the polymer and the linker for drug conjugation have attracted much research. This study seeks to investigate recent developments in the design and synthesis of PEG-based polymer-drug conjugates, emphasizing fresh ideas that fill in existing knowledge gaps and satisfy the increasing need for more potent drug delivery methods. Through an extensive review of the existing literature, this study identifies key challenges and proposes innovative strategies for future investigations. The paper presents a comprehensive framework for designing and synthesizing PEG-based polymer-drug conjugates, including rational molecular design, linker selection, conjugation methods, and characterization techniques. To further emphasize the importance and adaptability of PEG-based polymer-drug conjugates, prospective applications are highlighted, including cancer treatment, infectious disorders, and chronic ailments.