Randomized PEG-based ABA polyether block copolymers as a non-antigenic drug delivery system
Julian Schmidt (1), Anna Stoffregen (1), Holger Frey (1)
1) Department of Chemistry, Johannes Gutenberg University, 55128 Mainz, Germany
julian.schmidt@uni-mainz.de; hfrey@uni-mainz.de
Abstract:
Poly(ethylene glycol) (PEG) is an essential building block in modern nanomedical applications. Poloxamers are one of the most frequently used PEG-based pharmaceuticals.1 However, a significant prevalence of anti-PEG antibodies (APAs) up to 83 % has been documented.2 Accelerated blood clearance (ABC effect) and complement activated-related pseudoallergy (CARPA) poses a serious risk for patients treated with PEG-based nanoformulations.3 As a novel approach, we have developed the randomized PEG (rPEG) technology, which preserves the well-established PEG structure and chemistry while significantly reducing antibody recognition.4
This study focused on a fully polyether-based ABA triblock copolymer system utilizing rPEG as a non-antigenic, hydrophilic A-block and hydrophobic glycidyl ethers as B-block. The ABA triblock copolymers were synthesized using living anionic ring-opening polymerization (AROP) with sequential monomer addition. The resulting rPEG-b-P(AnisylGE)-b-rPEG copolymers were employed to solubilize curcumin via the thin-film method. In conclusion, the rPEG-b-P(AnisylGE)-b-rPEG copolymers successfully demonstrate the potential of a fully polyether-based drug delivery system with significantly reduced anti-PEG antibody recognition, though improvements in micelle stability are necessary.
References:
(1) Miao, G.; He, Y.; Lai, K.; Zhao, Y.; He, P.; Tan, G.; Wang, X. Accelerated blood clearance of PEGylated nanoparticles induced by PEG-based pharmaceutical excipients. J. Controlled Release 2023, 363, 12–26. DOI: 10.1016/j.jconrel.2023.09.003.
(2) Deuker, M. F. S.; Mailänder, V.; Morsbach, S.; Landfester, K. Anti-PEG antibodies enriched in the protein corona of PEGylated nanocarriers impact the cell uptake. Nanoscale Horiz. 2023, 8 (10), 1377–1385. DOI: 10.1039/D3NH00198A.
(3) Chen, B.-M.; Cheng, T.-L.; Roffler, S. R. Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies. ACS Nano 2021, 15 (9), 14022–14048. DOI: 10.1021/acsnano.1c05922
(4) Dreier P.; Matthes R.; Fuß F.; Schmidt J.; Schulz D.; Linden G., Barent R.; Schüttner S.; Neun B. W.; Cedrone E.; Dobrovolskaia M.A.; Bros M; Frey H. Isomerization of Poly(ethylene glycol): A Strategy for the Evasion of Anti-PEG Antibody Recognition. JACS 2025 XXXX, XXX, XXX-XXX, DOI: 10.1021/jacs.5c02716.