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首页> 外文期刊>ACS applied materials & interfaces >Building Stable MMP2-Responsive Multifunctional Polymeric Micelles by an All-in-One Polymer-Lipid Conjugate for Tumor-Targeted Intracellular Drug Delivery
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Building Stable MMP2-Responsive Multifunctional Polymeric Micelles by an All-in-One Polymer-Lipid Conjugate for Tumor-Targeted Intracellular Drug Delivery

机译：通过一体化聚合物 - 脂质缀合物构建稳定的MMP2响应多官能聚合物胶束，用于肿瘤靶向细胞内药物递送

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摘要

In this study, we described an all-in-one polymerlipid conjugate (PEG2k-ppTAT-PEG1k-PE) that could self-assemble to matrix metalloproteinase 2 (MMP2)-sensitive multifunctional micelles. The assembled micelles had several key features, including a protective long chain poly(ethylene glycol) (PEG2k) (the outer shell), an MMP2-sensitive peptide linker (pp) (the tumor-targeting middle layer), a trans-activating transcriptional activator (TAT) peptide (the cell-penetrating middle layer), and a stable PEG1k-PE micelle for drug loading (the inner core). In the absence of MMP2, the PEG2k-ppTAT-PEG1k-PE micelles were intact and showed low bioactivity due to the surface-anchored PEG2k, whereas in the presence of MMP2, the pp was cleaved, resulting in the PEG2k deshielding and exposure of the previously hidden TAT for enhanced intracellular drug delivery. Even if completely cleaved by MMP2, the remaining PEG1k-PE micelles were stable and the micelles particle size and drug release were not significantly influenced. The paclitaxel (PTX)-loaded PEG2k-ppTAT-PEG1k-PE micelles showed significant MMP2-dependent cellular uptake, tumor penetration, and anticancer activity in various cancer cells and three-dimensional multicellular spheroids. Because of the enhanced intracellular drug accumulation, these multifunctional micelles were able to sensitize the drug-resistant cancer cells and their spheroids to PTX treatments. Furthermore, in vivo tumor uptake and retention data indicated that the PEG2k-ppTAT-PEG1k-PE micelles could dramatically increase the residence time of their payloads in the tumor.
机译：在本研究中，我们描述了一种可以自组装成基质金属蛋白酶2（MMP2） - 密封性多官能胶束的一体化聚合物酰磷脂（PEG2K-PPTAT-PEG1K-PE）。组装胶束具有几个关键特征，包括保护性的长链聚（乙二醇）（PEG2K）（外壳），MMP2敏感肽接头（PP）（肿瘤靶向中间层），是反式激活转录活化剂（TAT）肽（细胞穿透中间层）和用于药物负载的稳定PEG1K-PE胶束（内核）。在没有MMP2的情况下，PEG2K-PPTAT-PEG1K-PE胶束完整并由于表面锚固的PEG2K而显示出低的生物活性，而在MMP2的存在下，PP被切割，导致PEG2K脱离和暴露以前隐藏着增强的细胞内药物递送。即使通过MMP2完全切割，剩余的PEG1K-PE胶束也稳定，胶束粒度和药物释放没有显着影响。紫杉醇（PTX） - 加载的PEG2K-PPTAT-PEG1K-PE胶束显示出显着的MMP2依赖性蜂窝摄取，肿瘤渗透和抗癌活性在各种癌细胞和三维多细胞球状体中。由于增强的细胞内药物积累，这些多功能胶束能够使耐药性癌细胞及其球状体敏化至PTX治疗。此外，在体内肿瘤摄取和保留数据中表明PEG2K-PPTAT-PEG1K-PE胶束可以显着增加其有效载荷在肿瘤中的停留时间。

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