Reduction-Sensitive Dual Functional Nanomicelles for Improved Delivery of Paclitaxel

[Image: see text] We have developed a dual-functional nanocarrier composed of a hydrophilic polyethylene glycol (PEG) and a hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist), which is effective in delivery of hydrophobic anticancer drug, paclitaxel (PTX). To facilitate the retention of the therapeutic activity of the carrier, FTS was coupled to PEG via a reduction-sensitive disulfide linkage (PEG(5k)-S-S-FTS(2)). PEG(5k)-S-S-FTS(2) conjugate formed uniform micelles with very small size (∼30 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG(5k)-FTS(2) micellar system resulted in a 4-fold decrease in the critical micelle concentration (CMC). In addition, the PTX loading capacity and colloidal stability of PTX-loaded micelles were improved. HPLC-MS showed that parent FTS could be more effectively released from PEG(5k)-S-S-FTS(2) conjugate in tumor cells/tissues compared to PEG(5k)-FTS(2) conjugate in vitro and in vivo. PEG(5k)-S-S-FTS(2) exhibited a higher level of cytotoxicity toward tumor cells than PEG(5k)-FTS(2) without a disulfide linkage. Furthermore, PTX-loaded PEG(5k)-S-S-FTS(2) micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG(5k)-FTS(2) micelles. More importantly, PTX-loaded PEG(5k)-S-S-FTS(2) micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG(5k)-FTS(2) micelles in an aggressive murine breast cancer model (4T1.2).