Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)–Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy

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• 作者：Feng-Zhen Wang ; Lei Xing ; Zheng-hai Tang ; Jin-Jian Lu ; Peng-Fei Cui ; Jian-Bing Qiao ; Lei Jiang ; Hu-Lin Jiang ; Li Zong
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：April 4, 2016
• 年：2016
• 卷：13
• 期：4
• 页码：1298-1307
• 全文大小：595K
• ISSN：1543-8392

文摘

Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)–glycyrrhetinic acid (PEI–GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI–GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI–GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI–GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI–GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI–GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.