Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou 350025, China.
Mater Sci Eng C Mater Biol Appl. 2018 Feb 1;83:210-217. doi: 10.1016/j.msec.2017.08.075. Epub 2017 Aug 18.
Stanniocalcin 2 (STC2) overexpression in hepatocellular carcinoma (HCC) could lead to poor prognosis, which might be due to its induced P-glycoprotein and Bcl-2 protein expression level increase. P-glycoprotein or membrane pump induced drug efflux and altered prosurvival Bcl-2 expression are key mechanisms for drug resistance leading to failure of chemotherapy in HCC. However, current strategy to overcome both P-glycoprotein and Bcl-2 protein induced drug resistance was rarely reported. In this work, we utilized an amphiphilic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) cationic polyester to encapsulate chemotherapeutic paclitaxel (PTX) in hydrophobic PHB domain and Bcl-2 convertor Nur77/ΔDBD gene (Nur77 without DNA binding domain for mitochondria localization) by formation of polyplex due to cationic PDMAEMA segment, to effectively inhibit the drug resistant HepG2/STC2 and SMCC7721/STC2 liver cancer cell growth. Thanks to the cationic nanoparticle complex formation ability and high transfection efficiency to express Bcl-2 conversion proteins, PHB-PDMAEMA/PTX@polyplex could partially impair P-glycoprotein induced PTX efflux and activate the apoptotic function of previous prosurvival Bcl-2 protein. This is the pioneer report of cationic amphiphilic polyester PHB-PDMAEMA to codeliver anticancer drug and therapeutic plasmid to overcome both pump and non-pump mediated chemotherapeutic resistance in liver cancer cells, which might be inspiring for the application of polyester in personalized cancer therapy.
Stanniocalcin 2（STC2）在肝细胞癌（HCC）中的过表达可导致不良预后，这可能是由于其诱导的 P-糖蛋白和 Bcl-2 蛋白表达水平增加所致。P-糖蛋白或膜泵诱导的药物外排和改变的促生存 Bcl-2 表达是导致 HCC 化疗失败的耐药关键机制。然而，克服 P-糖蛋白和 Bcl-2 蛋白诱导的耐药性的当前策略很少有报道。在这项工作中，我们利用两亲性聚[(R)-3-羟基丁酸酯]（PHB）-b-聚（2-（二甲氨基）乙基甲基丙烯酸酯）（PDMAEMA）阳离子聚酯将化疗药物紫杉醇（PTX）包裹在疏水性 PHB 域中，并通过阳离子 PDMAEMA 段形成聚集体将 Bcl-2 转化基因 Nur77/ΔDBD（Nur77 无 DNA 结合域用于线粒体定位）封装在疏水 PHB 域中，以有效抑制耐药性 HepG2/STC2 和 SMCC7721/STC2 肝癌细胞的生长。由于阳离子纳米颗粒复合物形成能力和高转染效率来表达 Bcl-2 转换蛋白，PHB-PDMAEMA/PTX@聚集体可以部分破坏 P-糖蛋白诱导的 PTX 外排并激活先前促生存 Bcl-2 蛋白的凋亡功能。这是阳离子两亲聚酯 PHB-PDMAEMA 首次用于共递抗癌药物和治疗性质粒以克服肝癌细胞中泵和非泵介导的化疗耐药性的报告，这可能为聚酯在个性化癌症治疗中的应用提供启示。
