Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy
Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles To Induce Autophagy-Mediated Liver Cancer Combination Therapy
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聚(乙烯亚胺)-甘草次酸纳米颗粒共同递送阿霉素和shAkt1诱导自噬介导的肝癌联合治疗
DOI：
10.1021/acs.molpharmaceut.5b00879
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发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Zong, Li
中科院分区：
文献类型：
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作者：
Wang, Feng-Zhen;Xing, Lei;Zong, Li
联合治疗已被开发为肝细胞癌治疗的一种有前途的治疗方法。在这里，我们报告了一个低毒性和高性能的纳米粒子系统，是自组装从聚（乙烯亚胺）-大黄酸（PEI-GA）的两亲性共聚物作为一个通用的基因/药物双重递送纳米平台。PEI-GA通过将疏水GA部分经由酰化反应化学缀合至亲水PEI主链来合成。PEI-GA纳米载体可有效包裹阿霉素（DOX），载药量约为12%，并可进一步与DNA形成PEI-GA/DOX/DNA复合物，实现药物和基因的共递送。配合物的直径为102 +/- 19 nm，zeta电位为19.6 +/- 0.2 mV。此外，配合物具有肝癌靶向性，并能促进肝癌细胞HepG 2的内化。DOX化疗可诱导细胞凋亡，PI 3 K/Akt/mTOR信号通路对自噬的调节起有益作用。在此，揭示了利用PEI-GA/DOX/shAktl复合物导致有效的自噬和凋亡，其可用于引起细胞死亡。过量自噬的诱导可导致II型细胞死亡，并可增加化疗对肿瘤细胞的敏感性。在这种情况下，自噬和凋亡的结合对于肿瘤治疗是有意义的。在本研究中，PEI-GA/DOX/shAkt 1显示出良好的肿瘤靶向能力，副作用小，具有理想的抗肿瘤效果。
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/shAktl 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.