PEG Copolymers in Drug Delivery

Polyethylene glycol (PEG) has become an important polymer material in the pharmaceutical field due to its excellent biocompatibility, low toxicity, and tunable physicochemical properties. By copolymerizing with other molecules or polymers, PEG can enhance the solubility, stability, and bioavailability of drugs, particularly exhibiting significant advantages in improving the half-life and targeting of drugs. PEG copolymers effectively reduce immune responses to drugs in the body, enhance therapeutic efficacy, and minimize adverse reactions. Therefore, PEG copolymers not only show potential in traditional drug delivery but also play an increasingly important role in novel therapeutic areas such as nanoparticle drug carriers, vaccine delivery, and antibody-drug conjugates (ADCs). With further research into PEG copolymers, their application prospects in drug delivery systems will become even broader and more diversified.

What are Block Copolymers?

Block copolymers are a type of important multiphase system that has gained significant attention from physicists, chemists, and biologists in recent years due to their favorable properties. They are widely used in industries such as pharmaceuticals, construction, and chemicals. Block copolymers are formed by the head-to-tail connection of two or more macromolecules with different chemical structures and physical-chemical properties. Each segment of the polymer that constitutes a block copolymer is referred to as a "block." Due to the inherent differences in the hydrophilicity, solubility, and physicochemical properties of the polymer blocks, block copolymers can form various microstructures. Block copolymers are typically represented by A-B type two-block copolymers, A-B-C type or A-B-A type three-block copolymers, -(-A-B-)n- type multiblock copolymers, cyclic block copolymers, and star-branched copolymers, etc.

Fig. 1. PEG-PLGA copolymers (J Control Release. 2014, 183: 77-86).

Amphiphilic Block Copolymers for Drug Delivery

The choice of carriers is crucial in drug delivery systems, and block copolymer micelles, as high-quality polymer materials, have attracted widespread attention from both academia and industry due to their unique advantages. Based on extensive research and summarization of previous works, block copolymer micelles are selected as drug delivery carriers due to the following benefits:

• Simple preparation methods that do not cause environmental pollution;
• High structural stability of block copolymer micelles;
• Increased drug loading capacity, allowing for effective drug delivery;
• Block copolymer micelles typically have sizes ranging from 10 to 100 nm, ensuring long circulation in the bloodstream;
• Block copolymers can covalently bind drugs to the hydrophobic part of the copolymer or encapsulate drugs within the micelle via various interactions;
• High drug loading rates can be achieved without chemical modification.

In recent years, significant research has been conducted on block copolymers of polylactic acid (PLA), polycaprolactone (PCL), and their copolymers with PEG. These polymers exhibit some dissolution and degradation properties, with low crystallinity resulting in faster degradation, ultimately breaking down into water and CO₂. Furthermore, the intermediate lactic acid is a normal metabolite in the body. In PLA-PEG and PCL-PEG block copolymers, PLA and PCL are hydrophobic segments, while PEG is a hydrophilic segment. By adjusting the ratio of these two components and the relative molecular weight of the copolymer, the degradation properties can be controlled, thus regulating the release rate of drugs from microspheres.

PEG Copolymer

PEG is a polymer compound formed by the polycondensation of ethylene glycol monomers. It is widely used in the pharmaceutical, medical, and biopharmaceutical fields due to its excellent water solubility, low toxicity, and biocompatibility. PEG copolymers are polymers formed by the copolymerization of PEG with other monomers, usually consisting of two or more different chemical structural units, which diversify the physicochemical properties of PEG copolymers. By introducing different monomers, the hydrophilicity, hydrophobicity, molecular weight, and other key properties of PEG copolymers can be adjusted, providing customized solutions for drug delivery systems. The use of PEG copolymers, especially in drug delivery systems, can improve drug solubility, stability, and bioavailability while reducing drug toxicity. PEG copolymers are typically formed by the chemical bonding of PEG segments with other polymer segments. Common structures include:

• Block Copolymers: Composed of hydrophilic PEG and hydrophobic segments (such as polylactic acid, polycaprolactone), these are used to prepare self-assembling nanoparticle carriers.
• Graft Copolymers: PEG segments are grafted onto the main chain, forming a brush-like structure that enhances solubility and functionality.
• Crosslinked Copolymers: PEG is crosslinked with other molecules to form a network structure, widely used in hydrogel drug carriers.

PEG Copolymer Types

PEG copolymers can be classified based on structure, monomers, and function. In terms of structure, common types include linear copolymers, block copolymers, graft copolymers, and branched copolymers. Linear copolymers are formed by simple copolymerization of PEG with other monomers, resulting in a simpler structure; block copolymers alternate between hydrophilic and hydrophobic monomers, exhibiting distinct physicochemical properties, suitable for forming micelles or nanoparticles; graft copolymers graft other functional monomers onto the PEG backbone, enhancing their functionality; and branched copolymers use branched structures to increase spatial complexity, improving drug loading capacity and controlled release performance. Based on monomer type, common examples include PEG-fatty acid copolymers and PEG-polylactic acid copolymers. According to function, PEG copolymers can be categorized into drug-loaded, targeting, and self-assembling types, with each type adjusting the length and structure of the PEG chain to meet the specific requirements of different drug delivery systems.

PLA-PEG Copolymer

PLA-PEG copolymers are synthesized through the copolymerization of polylactic acid (PLA) and PEG. Polylactic acid is a biodegradable polymer with good biocompatibility, while polyethylene glycol offers good water solubility and biodegradability. PLA-PEG copolymers combine the degradability of PLA with the hydrophilicity of PEG, making them widely applicable in drug delivery, tissue engineering, and vaccine carriers. Their characteristics include good biodegradability, low toxicity, tunable solubility, and stable drug loading capacity. They are commonly used to prepare microspheres, nanoparticles, sustained-release drug carriers, and medical materials.

PLGA-PEG Copolymer

PLGA-PEG copolymers are synthesized by the copolymerization of polylactic acid-glycolic acid copolymers (PLGA) and PEG. PLGA has excellent biodegradability and biocompatibility, while PEG imparts good water solubility and lubricity to the copolymer. PLGA-PEG copolymers are widely used in drug delivery systems, tissue engineering, and biomedical fields. They can regulate the drug release rate, extend drug efficacy, and reduce side effects. These copolymers are commonly used to prepare degradable nanoparticles, microparticles, and targeted drug carriers, with significant applications in cancer therapy and vaccine development.

PEG-PCL Copolymer

PEG-PCL copolymers are synthesized by the copolymerization of PEG and polycaprolactone (PCL). Polycaprolactone has good biodegradability and flexibility, while PEG provides excellent hydrophilicity. PEG-PCL copolymers are widely used in drug delivery, tissue engineering, and biomedical fields due to their unique biodegradability, good hydrophilicity, and biocompatibility. These characteristics make them ideal for drug delivery systems and degradable scaffold materials, often used in the preparation of drug delivery systems, nanoparticles, microspheres, and tissue repair materials.

PGA-PEG Copolymer

PGA-PEG copolymers are synthesized by the copolymerization of polyglutamic acid (PGA) and PEG. Polyglutamic acid is a biodegradable polymer with good biocompatibility and biodegradability, while PEG provides excellent water solubility. PGA-PEG copolymers are widely used in drug delivery, gene delivery, and tissue engineering. Their characteristics include good water solubility, adjustable degradation rate, and strong drug loading capacity. They are commonly used to develop targeted drug delivery systems, gene carriers, and degradable biomedical materials.

PEG-DSPE Copolymer

Polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) block copolymers are amphiphilic and FDA-approved for medical use. They are widely used to prepare liposomes, polymeric nanoparticles, polymer-mixed nanoparticles, and solid lipid nanoparticles. Amphiphilic polymers consist of a hydrophobic core (DSPE) and a hydrophilic shell (PEG). The core-shell structure can encapsulate and carry poorly soluble drugs within the DSPE core, while the PEG shell reduces in vivo clearance and plasma protein adsorption of cholesterol-free liposomes. Therefore, using PEG-DSPE to form nanostructures can extend circulation time in the body and continuously release drugs within the optimal therapeutic concentration range.

PEG Copolymer in Drug Delivery Examples

PEG copolymers have a wide range of applications in drug delivery and play a significant role, particularly in enhancing drug stability, solubility, and targeted delivery. Through PEGylation, drugs can be effectively encapsulated in nanoparticles, liposomes, or hydrogels, thereby improving bioavailability and prolonging blood circulation time. For example, PEG-modified liposomes can enhance the stability of drugs in the bloodstream and utilize the enhanced permeability and retention (EPR) effect for tumor-targeted delivery. Additionally, PEGylation can reduce a drug's immunogenicity and clearance rate, extending its half-life and reducing toxic side effects. PEG copolymers demonstrate significant advantages in the fields of protein drugs, gene delivery, anticancer agents, and vaccines. By improving drug delivery, PEG copolymers not only enhance therapeutic outcomes but also provide new solutions for treating complex diseases.

Anticancer Drug Delivery

PEG copolymers have widespread applications in anticancer drug delivery, particularly in improving drug solubility, reducing side effects, and enabling targeted delivery. For example, paclitaxel-loaded micelles made with PEG-PLA copolymers significantly improve paclitaxel's solubility, solving its poor water solubility issue. Paclitaxel is a widely used anticancer drug, but its clinical application is limited due to its low solubility and high toxicity. By forming micelles with PEG copolymers, paclitaxel can be stably carried in vivo, ensuring effective drug release at the tumor site while minimizing toxicity to healthy tissues. Moreover, PEG-modified liposomes, such as Doxil®, increase the drug's circulation time and enable passive targeting using the EPR effect at tumor sites. PEG surface modification reduces the immunogenicity of liposomes, enhancing drug biodistribution and ensuring higher therapeutic efficacy.

Protein Drug Delivery

Protein drugs play a critical role in treating various diseases, but their stability is often compromised due to degradation and short plasma half-lives. PEG copolymers can effectively address this issue by forming PEG-protein complexes, improving the stability and plasma half-life of protein drugs. PEGylation not only reduces the immunogenicity of protein drugs but also prevents rapid clearance by the liver and kidneys. For example, insulin, a common protein drug, can achieve controlled release using PEG-acrylamide-crosslinked hydrogels as carriers. These hydrogels regulate insulin release rates, reducing dosing frequency, improving patient compliance, and enhancing therapeutic efficacy. Furthermore, PEGylation can improve the solubility of protein drugs, particularly those with poor water solubility, ensuring better bioavailability in the body.

Gene Drug Delivery

Gene drugs, such as DNA and siRNA, show great potential in treating genetic diseases and cancer, but their clinical application is often limited by instability, degradation, and low transfection efficiency. PEG copolymers can address these challenges, significantly improving gene drug delivery. Nanoparticles formed with PEG-PEI copolymers effectively encapsulate nucleic acids, protecting them from degradation by enzymes in the body while enabling targeted delivery through surface modifications. These nanoparticles increase the uptake of gene drugs by target cells and promote effective gene expression. Especially in cancer therapy, PEG-modified nanoparticles enable tumor-specific delivery, improving treatment selectivity and efficacy. Additionally, PEG-modified viral vectors are widely used in gene therapy. PEGylation can reduce the immunogenicity of viral vectors, extend their circulation time in the body, and enhance gene delivery efficiency. This technology plays a crucial role in improving the effectiveness and safety of gene therapies.

Vaccine Delivery

PEG copolymers also play a critical role in vaccine development and delivery. The effectiveness of vaccines largely depends on the stability of the antigen and the ability to stimulate an immune response. PEG copolymers enhance vaccine stability and immunogenicity by modifying vaccine carriers. For example, PEG-modified nanoparticles or liposomes can serve as vaccine carriers, helping antigens remain stable in the body for longer and improving immune system recognition by extending circulation time. These systems can also reduce side effects of immune responses, thereby enhancing vaccine safety. PEG-lipid conjugate-based vaccine delivery systems have shown promising immune responses and efficacy in clinical studies, particularly in the development of flu and COVID-19 vaccines, with significant potential applications.

Antibiotic Delivery

Antibiotics are commonly used to treat bacterial infections, but issues such as uneven distribution, low bioavailability, and resistance have limited their effectiveness. PEG copolymers can effectively improve antibiotic delivery. For example, PEG-modified nanoparticle carriers can enhance cell uptake and target antibiotics to infection sites, improving efficacy and reducing side effects. Additionally, PEGylation reduces the rapid clearance of drugs in the body, extending their half-life in the bloodstream and ensuring continuous action against infections. PEG copolymers also enhance the effectiveness of antibiotics in treating drug-resistant bacterial infections and minimize adverse effects.

Antiviral Drug Delivery

PEG copolymers have shown great potential in antiviral drug delivery as well. Antiviral drugs typically face challenges such as low solubility, poor stability, and significant side effects. PEG copolymers can overcome these challenges by enhancing drug solubility, improving bioavailability, and enabling targeted delivery. For example, PEG-modified nanoparticles can effectively encapsulate antiviral drugs and deliver them to infection sites, increasing local drug concentration while reducing systemic toxicity. In the treatment of viral infections such as HIV and hepatitis B, the use of PEG-drug carriers has been shown to significantly improve efficacy and reduce toxic side effects. Additionally, PEGylation reduces the clearancse rate of drugs in the body, ensuring the drug remains effective at therapeutic concentrations for extended periods.