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 (R...

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Bibliographic Details
Published in:Biomacromolecules 2008-11, Vol.9 (11), p.3106-3113
Main Authors: Jia, Zhongfan, Wong, Lingjiun, Davis, Thomas P, Bulmus, Volga
Format: Article
Language:English
Subjects:
Applied sciences
Biological and medical sciences
Cross-Linking Reagents
Disulfides - chemistry
Doxorubicin - administration & dosage
Drug Delivery Systems
Exact sciences and technology
General pharmacology
Hydrogen-Ion Concentration
Medical sciences
Methacrylates - chemistry
Micelles
Organic polymers
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Physicochemistry of polymers
Polymers - chemical synthesis
Polymers with particular properties
Preparation, kinetics, thermodynamics, mechanism and catalysts
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Summary: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.
ISSN:1525-7797
1526-4602
DOI:10.1021/bm800657e