Enhancing the therapeutic effect via elimination of hepatocellular carcinoma stem cells using Bmi1 siRNA delivered by cationic cisplatin nanocapsules

• Published in: Nanomedicine 2018-10, Vol.14 (7), p.2009-2021
• Main Authors: Yang, Tan, Chen, Yuyuan, Zhao, Pengxuan, Xue, Huiying, You, Jia, Li, Bin, Liu, Yong, He, Chuanchuan, Zhang, Xiaojuan, Fan, Lingling, Lee, Robert J., Li, Lei, Ma, Xiang, Xu, Chuanrui, Xiang, Guangya
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Bmi1 siRNA; Cancer stem cell; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cations; Cell Cycle; Cell Proliferation; Cisplatin - administration & dosage; Cisplatin - pharmacology; Co-delivery; Combined Modality Therapy; Drug Resistance, Neoplasm; Hepatocellular carcinoma; Humans; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Mice; Mice, Inbred BALB C; Mice, Nude; Nanocapsules; Nanocapsules - administration & dosage; Nanocapsules - chemistry; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Polycomb Repressive Complex 1 - antagonists & inhibitors; Polycomb Repressive Complex 1 - genetics; RNA, Small Interfering - genetics; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2018.05.012

Resistance of hepatocellular carcinoma (HCC) to systemic chemotherapy is partially due to presence of drug-resistant cancer stem cells. Bmi1 protein is essential for survival and proliferation of HCC cancer stem cells (CSCs). Here, we report that Bmi1 siRNA (Bmi1siR) loaded in cationic nanocapsules of cisplatin (NPC) eliminated stem cells in situ HCC in mice. NPC/Bmi1siR was fabricated via electrostatic complexation of Bmi1 siRNA to NPCs, which had cores composed of cisplatin and were coated with cationic lipids. In vivo, NPC/Bmi1siR showed higher anti-tumor activity in HCC bearing mice compared with cisplatin or NPC. Critically, both flow cytometry (FACS) analysis in vitro and histological examination in vivo revealed that side population or CD133+ HCC cells were dramatically decreased by NPC/Bmi1siR treatment, suggesting that HCC CSCs were eliminated. Altogether, our results suggest that drug resistance of HCC can be overcome by co-delivering Bmi1 siRNA with cisplatin in cationic nanocapsules. An illustration of intracellular trafficking of NPC/Bmi1siR nanocapsules. After injection, NPC/Bmi1siR nanocapsules escape from blood vessel and enter to the tumor. NPC/Bmi1siR is then transported by early endosome to the late endosome. Then the cisplatin and Bmi1 siRNA are released from late endosome to the cytoplasm. Released cisplatin binds to DNA and induces apoptosis, whereas released Bmi1 siRNA inhibits Bmi1 expression and further inhibits the growth of CD133+ cancer stem cells. [Display omitted]