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

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.