Reduction-Sensitive Dual Functional Nanomicelles for Improved Delivery of Paclitaxel

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• 作者：Xiaolan Zhang ; Ke Liu ; Yixian Huang ; Jieni Xu ; Jiang Li ; Xiaochao Ma ; Song Li
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：September 17, 2014
• 年：2014
• 卷：25
• 期：9
• 页码：1689-1696
• 全文大小：423K
• ISSN：1520-4812

文摘

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-FTS₂). PEG_5k-S-S-FTS₂ conjugate formed uniform micelles with very small size (鈭?0 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG_5k-FTS₂ 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-FTS₂ conjugate in tumor cells/tissues compared to PEG_5k-FTS₂ conjugate in vitro and in vivo. PEG_5k-S-S-FTS₂ exhibited a higher level of cytotoxicity toward tumor cells than PEG_5k-FTS₂ without a disulfide linkage. Furthermore, PTX-loaded PEG_5k-S-S-FTS₂ micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG_5k-FTS₂ micelles. More importantly, PTX-loaded PEG_5k-S-S-FTS₂ micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG_5k-FTS₂ micelles in an aggressive murine breast cancer model (4T1.2).