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.
Centre for Advanced Macromolecular Design, School of Chemical Sciences and Engineering, The University of New South Wales, Sydney 2052, NSW, Australia.
Zhongfan
Z
Jia
Lingjiun
L
Wong
Thomas P
TP
Davis
Volga
V
Bulmus
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