期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 608, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ijpharm.2021.121075
关键词
Polymers; PEG; Pharmacokinetics; Polymer pharmacokinetics; Reversible Addition-Fragmentation chain-Transfer (RAFT)
资金
- NHMRC CDF
- SIEF (Science and Industry Endowment Fund)
- CSIRO Research Office
This study investigated the potential of RAFT polymers as an alternative to PEG for prolonging the plasma exposure of therapeutic proteins. Among the tested polymers, p(HPMA-co-NIPAM) showed the most promise in prolonging plasma exposure of trastuzumab-Fab' and full length mAb, with lower immunogenicity compared to PEG. These findings suggest that p(HPMA-co-NIPAM) could be a promising copolymer for conjugation with therapeutic proteins.
PEGylation is the standard approach for prolonging the plasma exposure of protein therapeutics but has limitations. We explored whether polymers prepared by Reversible Addition-Fragmentation chain-Transfer (RAFT) may provide better alternatives to polyethylene glycol (PEG). Four RAFT polymers were synthesised with varying compositions, molar mass (M-n), and structures, including a homopolymer of N-(2-hydroxypropyl)meth-acrylamide, (pHPMA) and statistical copolymers of HPMA with poly(ethylene glycol methyl ether acrylate) p (HPMA-co-PEGA); HPMA and N-acryloylmorpholine, p(HPMA-co-NAM); and HPMA and N-isopropylacrylamide, p(HPMA-co-NIPAM). The intravenous pharmacokinetics of the polymers were then evaluated in rats. The in vitro activity and in vivo pharmacokinetics of p(HPMA-co-NIPAM)-conjugated trastuzumab Fab' and full length mAb were then evaluated. p(HPMA-co-NIPAM) prolonged plasma exposure more avidly compared to the other p (HPMA) polymers or PEG, irrespective of molecular weight. When conjugated to trastuzumab-Fab', p(HPMA-co-NIPAM) prolonged plasma exposure of the Fab' similar to PEG-Fab'. The generation of anti-PEG IgM in rats 7 days after intravenous and subcutaneous dosing of p(HPMA-co-NIPAM) conjugated trastuzumab mAb was also examined and was shown to exhibit lower immunogenicity than the PEGylated construct. These data suggest that p(HPMA-co-NIPAM) has potential as a promising copolymer for use as an alternative conjugation strategy to PEG, to prolong the plasma exposure of therapeutic proteins.
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