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

• Published in: Journal of controlled release 2014-11, Vol.194, p.220-227
• Main Authors: Lv, Shixian, Tang, Zhaohui, Zhang, Dawei, Song, Wantong, Li, Mingqiang, Lin, Jian, Liu, Huaiyu, Chen, Xuesi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Controlled drug release; Delayed-Action Preparations; Disulfides - chemistry; Drug delivery; Drug Delivery Systems; Hemolysis - drug effects; Humans; Hydrogen-Ion Concentration; Lysine - analogs & derivatives; Lysine - chemistry; Melanoma, Experimental - drug therapy; Mice; Mice, Inbred C57BL; Micelles; Oxidation-Reduction; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Pentetic Acid - chemistry; Polyethylene Glycols - chemistry; Polymers; Polymer–drug conjugate; Polypeptide
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2014.09.009

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≈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. A well-defined polymer–drug conjugate with redox and pH-sensitive drug release feature was developed for efficient delivery of paclitaxel [Display omitted]