Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer

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• 作者：Xin Dai ; Wei Fan ; Yingzhe Wang ; Lijie Huang ; Ying Jiang ; Lei Shi ; DeAngelo Mckinley ; Wen Tan ; Chalet Tan
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：February 1, 2016
• 年：2016
• 卷：13
• 期：2
• 页码：520-533
• 全文大小：1007K
• ISSN：1543-8392

文摘

In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG_5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG_5K-VE₄-DET₂₀ copolymer formed nanoassemblies when mixed with the neutral PEG_5K-VE₄ copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG_5K-VE₄-DET₂₀ nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG_5K-VE₄-DET₂₀ nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG_5K-VE₄-DET₂₀ nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.