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Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel

Author:xcs Date:2014-11-18 21:06:33
 The synthesis of polymer-drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. We develop a novel anti-cancer PDC for on-demand delivery of paclitaxel (PTX) engineered with redox and pH dual-sensitive behaviors. A simple polymer, 3,3’-dithiodipropionic acid functionalized poly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG-b-P(LL-DTPA) to obtain the disulfide-containing polymer-PTX conjugate (P(L-SS-PTX)). Another structural similar polymer-PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared as a control. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be increased at pH 5. In vitro study demonstrated that the P(L-SS-PTX) exhibited significantly better cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice showed the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery.

Journal: Journal of Controlled Release

Author: Shixian Lv, Zhaohui Tang, Dawei Zhang, Wantong Song, Mingqiang Li, Jian Lina, Huaiyu Liu , Xuesi Chen

DOI: http://dx.doi.org/10.1016/j.jconrel.2014.09.009