新型脂包被顺铂/磷酸钙共载Bmi1 siRNA纳米粒抑制肝癌干细胞并协同治疗肝癌的实验研究

Resistance of hepatocellular carcinoma (HCC) to systemic chemotherapy is partially due to existence of cancer stem cell in HCC cells and tissues. Literature and our previous study have revealed that oncogene Bmi1 is overexpressed in HCC patients and silencing Bmi1 can block cell cycle progression in HCC cells and inhibit HCC growth. Furthermore, knockdown of Bmi1 in HCC stem cells can block their growth and restrain their initiating capability. In addition, our previous study also showed that co-delivery of Bmi1 siRNA and doxorubicin (DOX) by folate targeting liposome can enhance the cytotoxicity of DOX in KB cells. We speculate that Bmi1 siRNA promote the cytotoxicity of DOX by eliminating drug-resistant and cancer stem cells in KB cells. To validate this hypothesis, we designed a novel lipid-coated cisplatin/Ca3(PO4)2/Bmi1 siRNA nanoparticle to explore whether co-delivery of Bmi1 siRNA and cisplatin into HCC cells can inhibit HCC stem cells, block cell cycle progression, overcome drug resistance and hence produce synergetic efficacy in HCC treatment. Altogether, our study will help explore the feasibility of HCC treatment by delivering Bmi1 siRNA through nanoparticle delivery system and feasibility of treating HCC by eliminating HCC stem cells.

肝癌中肿瘤干细胞的存在是导致肝癌细胞耐药的重要因素之一。文献及本团队研究表明，癌基因Bmi1在肝癌中普遍高表达，沉默Bmi1基因可以抑制肝癌干细胞增殖并明显降低其成瘤能力。同时，沉默Bmi1可以明显阻断肝癌细胞周期进行，抑制其增殖。前期研究还表明，利用脂质体联合递送Bmi1 siRNA和阿霉素可有效增强阿霉素对口腔癌KB细胞的杀伤作用。据此我们推测Bmi1 siRNA沉默Bmi1基因后，抑制了肿瘤干细胞增殖并阻断肿瘤细胞周期进行，进而克服肿瘤细胞耐药并与阿霉素产生协同治疗作用。在本研究中，我们设计了新型脂包被顺铂/磷酸钙共载Bmi1 siRNA纳米递送系统，来探索沉默Bmi1基因抑制肝癌干细胞增殖、阻断肝癌细胞周期进而协同顺铂治疗肝癌的可行性。本研究的实施，有助于深入探索利用核酸药物抑制肿瘤干细胞克服肿瘤耐药，并协同化学药物进行综合治疗的可行性，进而向临床研究转化。

肝癌中肿瘤干细胞的存在是导致肝癌细胞耐药的重要因素之一。文献及本团队研究表明，癌基因Bmi1在肝癌中普遍高表达，沉默Bmi1基因可以抑制肝癌干细胞增殖并明显降低其成瘤能力。同时，沉默Bmi1可以明显阻断肝癌细胞周期进行，抑制其增殖。前期研究还表明，利用脂质体联合递送Bmi1 siRNA和阿霉素可有效增强阿霉素对口腔癌KB细胞的杀伤作用。据此我们推测Bmi1 siRNA沉默Bmi1基因后，抑制了肿瘤干细胞增殖并阻断肿瘤细胞周期进行，进而克服肿瘤细胞耐药并与阿霉素产生协同治疗作用。在本研究中，我们设计了新型脂包被顺铂/磷酸钙共载Bmi1 siRNA纳米递送系统，来探索沉默Bmi1基因抑制肝癌干细胞增殖、阻断肝癌细胞周期进而协同顺铂治疗肝癌的可行性。本研究的实施，有助于深入探索利用核酸药物抑制肿瘤干细胞克服肿瘤耐药，并协同化学药物进行综合治疗的可行性，进而向临床研究转化。