期刊
JOURNAL OF CONTROLLED RELEASE
卷 194, 期 -, 页码 220-227出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2014.09.009
关键词
Polymer-drug conjugate; Drug delivery; Paclitaxel; Polypeptide; Controlled drug release
资金
- National Natural Science Foundation of China [51173184, 51373168, 51021003, 51233004, 51321062, 51390484]
- Ministry of Science and Technology of China (International Cooperation and Communication Program) [2011DFR51090]
- Program of Scientific Development of Jilin Province [20130206066GX, 20130727050YY]
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. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) 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 to verify the function of disulfide linkages. 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 promoted by the increased acidity (pH approximate to 5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced 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 demonstrated 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. (C) 2014 Elsevier B.V. All rights reserved.
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