Dai Xin, Fan Wei, Wang Yingzhe, Huang Lijie, Jiang Ying, Shi Lei, Mckinley DeAngelo, Tan Wen, Tan Chalet
Cancer Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Mercer University College of Pharmacy , Atlanta, Georgia 30341, United States.
Pre-incubator for Innovative Drugs and Medicine, School of Bioscience and Bioengineering Center, South China University of Technology , 382 Waihuan Road, Guangzhou, Guangdong 510006, China.
Mol Pharm. 2016 Feb 1;13(2):520-33. doi: 10.1021/acs.molpharmaceut.5b00756. Epub 2015 Dec 23.
In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-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 PEG5K-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 PEG5K-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 PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.
在本研究中，我们以1:4:20的摩尔比合成了一种由聚乙二醇5000（PEG5K）、维生素E（VE）和二乙烯三胺（DET）组成的新型阳离子共聚物。当所得的PEG5K-VE4-DET20共聚物与中性PEG5K-VE4共聚物按1:8的重量比混合时，形成了纳米聚集体，这些纳米聚集体被研究作为紫杉醇和let-7b模拟物联合递送的纳米载体。我们发现PEG5K-VE4-DET20纳米聚集体可以长时间包封紫杉醇，并在组织蛋白酶B存在的情况下突发释放药物，证明了共聚物的生物可降解性。在N/P比为12:1时，PEG5K-VE4-DET20纳米聚集体与let-7b模拟物形成稳定的多聚体，这些多聚体被肿瘤细胞有效摄取并经历内体逃逸。在携带突变KRAS的非小细胞肺癌A549细胞中，负载紫杉醇和let-7b模拟物的纳米聚集体（N-PTX/let-7b）显著增强了紫杉醇的细胞毒性，诱导细胞凋亡，并降低了肿瘤细胞的侵袭性。在携带皮下A549异种移植瘤的小鼠中，静脉注射N-PTX/let-7b比紫杉醇更有效地抑制肿瘤生长。我们的研究证明了PEG5K-VE4-DET20纳米聚集体用于同时递送疏水性药物和miRNA模拟物的前景。
