Poly(ethylene glycol) in Drug Delivery Pros and Cons as Well as Potential Alternatives

Purpose: PEG is the gold-standard stealth polymer for drug delivery, but its widespread use has revealed possible side effects and complications, including hypersensitivity, altered pharmacokinetics, toxic side products, stress-induced degradation, and non-biodegradability. This review critically discusses PEG’s advantages and drawbacks and evaluates potential alternative polymers for forming hydrophilic carrier shells.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that although PEG remains the best-investigated and most successful stealth polymer, its limitations—especially immunogenicity, non-biodegradability, and uncertain long-term fate—warrant systematic evaluation of alternative hydrophilic polymers that may offer comparable or improved performance.

Aims: Review the requirements for hydrophilic polymers in drug delivery. - Summarize the historical development and clinical success of PEGylated drugs, liposomes, micelles, and conjugates. - Discuss the advantages of PEG, including stealth behavior, prolonged circulation, reduced RES uptake, EPR effect, and biocompatibility. - Critically analyze PEG drawbacks: immunological responses, complement activation, hypersensitivity, accelerated blood clearance (ABC), pharmacokinetic irregularities, non-biodegradability, stress-induced degradation, and toxic side products. - Evaluate potential alternative polymers, including biodegradable poly(amino acid)s and non-biodegradable polymers such as poly(glycerol), poly(2-oxazoline)s, poly(acrylamide), poly(vinylpyrrolidone), and poly(N-(2-hydroxypropyl)methacrylamide). - Compare alternatives with PEG and identify gaps in biocompatibility, degradation, and excretion data.

Delivery system: Polymer: Poly(ethylene glycol) (PEG) and PEGylated carriers; alternatives including poly(amino acid)s (PGA, PHEA, PHEG), poly(glycerol) (PG), poly(2-oxazoline)s (PMoOx, PEtOx), poly(acrylamide) (PAAm), poly(vinylpyrrolidone) (PVP), and poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA). - Carrier types: Polymer–drug conjugates, liposomes, micelles, nanoparticles, microspheres, hydrogels, and block copolymer assemblies. - Payloads: Proteins, peptides, DNA, RNA, small molecules, anticancer drugs (e.g., doxorubicin, paclitaxel, camptothecin, platinum drugs), and contrast agents. - PEG roles: Stealth coating, steric stabilization, reduced opsonization, prolonged blood circulation, reduced renal filtration, and improved solubility/stability. - Alternative polymer roles: Hydrophilic shell, stealth coating, biodegradable backbone, or multifunctional carrier.

Approach: Review of preclinical and clinical literature, including historical studies from the 1950s–1970s and more recent work up to 2009–2010. Covers in vitro, in vivo, and clinical data. Animal models include mice, rats, rabbits, guinea pigs, monkeys, and dogs. Clinical examples include PEGylated protein drugs, Doxil/Caelyx, PEG-Intron, Pegasys, Neulasta, Somavert, Macugen, and Cimzia. No new primary experiments are reported.

Key methods: Pharmacokinetics: blood circulation half-life, AUC, organ distribution, renal clearance. - Immunological assays: complement activation (C3a, SC5b-9), anti-PEG antibody detection, hypersensitivity reactions, accelerated blood clearance. - Biocompatibility: cytotoxicity, hemocompatibility, erythrocyte aggregation, platelet activation. - Stability: mechanical stress, thermal degradation, photooxidation, peroxide formation. - Excretion and accumulation: urine, liver, spleen, kidney, and tissue deposition. - Clinical trial status and regulatory approval data.

Key results: PEGylated catalase: blood circulation time extended from 12 h to 48 h while maintaining enzyme activity. - Noncoated PLGA particles: 66% removed by liver within 5 min; less than 30% of 20 kDa PEG-coated nanospheres captured by liver at 2 h. - Conventional liposomes: completely cleared from blood after 5 h; 49% of PEGylated liposomes still circulating at same time. - Doxil/Caelyx: approved 1995; PEGylated liposomal doxorubicin. - Hypersensitivity: immediate HSR in 5–10% of patients treated with PEG-containing liposomal carriers; Doxil causes HSR in up to 25% of patients despite pretreatment. - Accelerated blood clearance (ABC): second dose of PEG liposomes decreased from (52.6 ± 3.7)% to (0.6 ± 0.1)% after 4 h in rats. - Anti-PEG antibodies: preexisting IgG and IgM anti-PEG antibodies identified in over 25% of healthy donors. - PEG excretion: in humans, 85% and 96% excreted in urine within 12 h after IV injection of 1 g of 1 kDa and 6 kDa PEG, respectively. - Toxic side products: 1,4-dioxane limited to 10 ppm, ethylene oxide to 1 ppm, formaldehyde to 30 ppm in pharmaceutical PEG. - Alternatives: PGA-paclitaxel reached phase III; PHPMA-doxorubicin (PK1) reached phase III; PHEA/PHEG liposomes showed reduced ABC but complement activation.

Interpretation: PEG remains the gold standard for polymeric drug delivery because of its hydrophilicity, stealth behavior, low toxicity, and extensive clinical validation. However, its non-biodegradability, immunogenicity, complement activation, ABC phenomenon, and degradation under stress are real concerns. None of the alternative polymers yet match PEG’s overall profile, but poly(amino acid)s are the most promising biodegradable alternatives, and poly(glycerol), poly(2-oxazoline)s, PVP, and PHPMA warrant further study. More systematic, contemporary investigations of biocompatibility, degradation, and excretion are needed before alternatives can replace PEG.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Many PEG toxicity and excretion studies date back to the 1950s–1970s and need updating with modern methods. - The fate of PEG and PEGylated delivery systems at the cellular level is not well understood. - No systematic long-term studies show whether PEG is completely excreted, where it accumulates, or its effects at accumulation sites. - Alternative polymers lack sufficient data on biocompatibility, degradation under stress, and excretion limits. - Clinical data for alternatives are limited; most are preclinical or early-phase. - No large-animal validation or comprehensive regulatory assessment is presented.