Improved Micellar Formulation for Enhanced Delivery for Paclitaxel

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• 作者：Jieni Xu ; Xiaolan Zhang ; Yichao Chen ; Yixian Huang ; Pengcheng Wang ; Yuan Wei ; Xiaochao Ma ; Song Li
• 刊名：Molecular Pharmaceutics
• 出版年：2017
• 出版时间：January 3, 2017
• 年：2017
• 卷：14
• 期：1
• 页码：31-41
• 全文大小：657K
• ISSN：1543-8392

文摘

We have previously improved the bioactivity of PEG<sub>5ksub>-FTS<sub>2sub> system by incorporating disulfide bond (PEG<sub>5ksub>-S-S-FTS<sub>2sub>) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG<sub>5ksub>-FTS<sub>2sub> system (PEG<sub>5ksub>-Fmoc-FTS<sub>2sub>) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG<sub>5ksub>-FTS<sub>2sub> to form a simple PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> micellar system. PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC). Compared with PEG<sub>5ksub>-Fmoc-FTS<sub>2sub>, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> in treated tumor cells compared to PEG<sub>5ksub>-Fmoc-FTS<sub>2sub>, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG<sub>5ksub>-Fmoc-FTS<sub>2sub>. PTX release kinetics of PTX/PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> was much slower than that of Taxol and PTX/PEG<sub>5ksub>-Fmoc-FTS<sub>2sub> in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> system maintained PTX in circulation for a longer time and delivered more PTX to tumor sites with less accumulation in major organs. Finally, PTX-loaded PEG<sub>5ksub>-Fmoc-S-S-FTS<sub>2sub> micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG<sub>5ksub>-Fmoc-FTS<sub>2sub> micelles.