One-pot conversion of RAFT-generated multifunctional block copolymers of HPMA to doxorubicin conjugated acid- and reductant-sensitive crosslinked micelles.
N-(2-Hydroxypropyl)methacrylamide (HPMA) containing polymers that are widely used as anticancer drug carriers. We have synthesized new amphiphilic block copolymers of HPMA with a functional monomer 2-(2-pyridyldisulfide)ethylmethacrylate (PDSM) via reversible addition-fragmentation chain transfer (RAFT) polymerization. In a one-pot reaction, the versatility of PDS groups on poly(PDSM)- b-poly(HPMA) was used to conjugate an anticancer drug, doxorubicin (DOX), and also simultaneously crosslink the micellar assemblies via acid-cleavable hydrazone bonds and reducible disulfide bonds. DOX-conjugated crosslinked micelles with an average diameter of approximately 60 nm were observed to be formed in aqueous medium. Disintegration of the micelles into unimers in the presence of a disulfide reducing agent confirmed the crosslinking via disulfide bonds. While the release of DOX from the crosslinked micelles at pH 5.0 was faster compared to the release at pH 7.4, a high proportion of released DOX was found to retain the original active structure. Overall results demonstrate the simplicity and the versatility of the poly(PDSM)- b-poly(HPMA) system, which are potentially important in the design of new generation of polymer therapeutics.
Jia
Zhongfan
Z
Centre for Advanced Macromolecular Design, School of Chemical Sciences and Engineering, The University of New South Wales, Sydney 2052, NSW, Australia.
Wong
Lingjiun
L
Davis
Thomas P
TP
Bulmus
Volga
V
D003432:Cross-Linking Reagents; D004220:Disulfides / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D006863:Hydrogen-Ion Concentration; D008689:Methacrylates / Q000737:chemistry*; D008823:Micelles; D011108:Polymers / Q000138:chemical synthesis*
D003432:Cross-Linking Reagents; D004220:Disulfides; D008689:Methacrylates; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate