Improved Micellar Formulation for Enhanced Delivery for Paclitaxel.
Improved Micellar Formulation for Enhanced Delivery for Paclitaxel.
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DOI：
10.1021/acs.molpharmaceut.6b00581
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发表时间：
2017-01
影响因子：
4.9
通讯作者：
Jieni Xu;Xiaolan Zhang;Yichao Chen;Yixian Huang;Pengcheng Wang;Yuan Wei;Xiaochao Ma;Song Li
中科院分区：
文献类型：
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作者：
Jieni Xu;Xiaolan Zhang;Yichao Chen;Yixian Huang;Pengcheng Wang;Yuan Wei;Xiaochao Ma;Song Li
我们先前已经通过引入二硫键来提高PEG 5 k-FTS 2系统的生物活性随后，将芴基甲氧基羰基（Fmoc）部分引入到PEG 5 k-FTS 2系统中（PEG 5 k-Fmoc-FTS 2）以增强药物负载能力（DLC）和制剂稳定性。2在本研究中，我们将二硫键和Fmoc基团引入PEG 5 k-FTS 2，形成简单的PEG 5 k-Fmoc-S-S-FTS 2胶束体系。PEG 5 k-Fmoc-S-S-FTS 2缀合物形成丝状胶束，临界胶束浓度（CMC）降低约10倍。与PEG 5 k-Fmoc-FTS 2相比，我们的新体系表现出进一步增强的DLC和胶体稳定性。与PEG 5 k-Fmoc-FTS 2相比，在经处理的肿瘤细胞中从PEG 5 k-Fmoc-S-S-FTS 2释放更多的FTS，这与我们的新载体在这些癌细胞中的细胞毒性增加相关。将紫杉醇（PTX）负载到PEG 5 k-Fmoc-S-S-FTS 2胶束中后，其显示出比紫杉醇和PTX负载的PEG 5 k-Fmoc-FTS 2更强的抑制肿瘤细胞增殖的效率。在正常释放介质中，PTX/PEG 5 k-Fmoc-S-S-FTS 2的PTX释放动力学远慢于Taxol和PTX/PEG 5 k-Fmoc-FTS 2。相比之下，在含有谷胱甘肽（GSH）的介质中，PEG 5 k-Fmoc-S-S-FTS 2胶束中的PTX显示出更快和更完全的释放。药代动力学和组织分布研究表明，我们的PEG 5 k-Fmoc-S-S-FTS 2系统使PTX在循环中维持更长的时间，并将更多的PTX递送到肿瘤部位，在主要器官中的蓄积更少。最后，与在PEG 5 k-Fmoc-FTS 2胶束中配制的紫杉醇和PTX相比，负载PTX的PEG 5 k-Fmoc-S-S-FTS 2胶束导致上级体内治疗效果。
We have previously improved the bioactivity of PEG5k-FTS2 system by incorporating disulfide bond (PEG5k-S-S-FTS2) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG5k-FTS2 system (PEG5k-Fmoc-FTS2) 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 PEG5k-FTS2 to form a simple PEG5k-Fmoc-S-S-FTS2 micellar system. PEG5k-Fmoc-S-S-FTS2 conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC). Compared with PEG5k-Fmoc-FTS2, our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG5k-Fmoc-S-S-FTS2 in treated tumor cells compared to PEG5k-Fmoc-FTS2, which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG5k-Fmoc-S-S-FTS2 micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG5k-Fmoc-FTS2. PTX release kinetics of PTX/PEG5k-Fmoc-S-S-FTS2 was much slower than that of Taxol and PTX/PEG5k-Fmoc-FTS2 in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG5k-Fmoc-S-S-FTS2 micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG5k-Fmoc-S-S-FTS2 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 PEG5k-Fmoc-S-S-FTS2 micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG5k-Fmoc-FTS2 micelles.