Effective Reductionof Anti-PEG Antibody Recognitionvia PEG Copolymers with Ethyl Glycidyl Ether and Isopropyl GlycidylEther

Anti-PEG antibodies (APAs) lead to accelerated blood clearance of PEGylated drugs and nanocarriers. Randomized PEG (rPEG) reduces APA recognition by randomly incorporating glycidyl methyl ether in PEG. Extending this concept, statistical copolymerization of ethylene oxide with ethyl glycidyl ether (EGE) or isopropyl glycidyl ether (iPGE) was investigated. Copolymers of EO with 13–28 mol % EGE or 6–20 mol % iPGE showed low dispersity (Đ ≤ 1.09). Via online-NMR monitoring, reactivity ratios in DMSO were rEO = 1.39 and rEGE = 0.72 for P(EO-co-EGE) and rEO = 1.35 and riPGE = 0.74 for P(EO-co-iPGE). All copolymers were soluble in PBS buffer at physiological temperatures and noncytotoxic, except for 20% iPGE content, shown by cell viability and immunostimulatory effects on murine splenocytes. All copolymers exhibit significantly reduced APA recognition (ELISA) with stronger effects for the sterically demanding iPGE. The findings highlight mP(EO-co-EGE) and mP(EO-co-iPGE) as promising PEG alternatives for nanomedicine and bioconjugation.