Zhang Xinmeng, Lin Zheng-Ian, Yang Jingyu, Liu Guan-Lin, Hu Zulu, Huang Haoqiang, Li Xiang, Liu Qiqi, Ma Mingze, Xu Zhourui, Xu Gaixia, Yong Ken-Tye, Tsai Wei-Chung, Tsai Tzu-Hsien, Ko Bao-Tsan, Chen Chih-Kuang, Yang Chengbin
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China.
Polymeric Biomaterials Laboratory, Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
Nanomaterials (Basel). 2021 Sep 6;11(9):2312. doi: 10.3390/nano11092312.
Pancreatic cancer is an aggressive malignancy associated with poor prognosis and a high tendency in developing infiltration and metastasis. K-ras mutation is a major genetic disorder in pancreatic cancer patient. RNAi-based therapies can be employed for combating pancreatic cancer by silencing K-ras gene expression. However, the clinical application of RNAi technology is appreciably limited by the lack of a proper siRNA delivery system. To tackle this hurdle, cationic poly (cyclohexene carbonate) s (CPCHCs) using widely sourced CO as the monomer are subtly synthesized via ring-opening copolymerization (ROCOP) and thiol-ene functionalization. The developed CPCHCs could effectively encapsulate therapeutic siRNA to form CPCHC/siRNA nanoplexes (NPs). Serving as a siRNA carrier, CPCHC possesses biodegradability, negligible cytotoxicity, and high transfection efficiency. In vitro study shows that CPCHCs are capable of effectively protecting siRNA from being degraded by RNase and promoting a sustained endosomal escape of siRNA. After treatment with CPCHC/siRNA NPs, the K-ras gene expression in both pancreatic cancer cell line (PANC-1 and MiaPaCa-2) are significantly down-regulated. Subsequently, the cell growth and migration are considerably inhibited, and the treated cells are induced into cell apoptotic program. These results demonstrate the promising potential of CPCHC-mediated siRNA therapies in pancreatic cancer treatment.
胰腺癌是一种侵袭性恶性肿瘤，预后较差，且具有较高的浸润和转移倾向。K-ras突变是胰腺癌患者的主要基因紊乱。基于RNA干扰的疗法可通过沉默K-ras基因表达用于对抗胰腺癌。然而，RNA干扰技术的临床应用因缺乏合适的小干扰RNA递送系统而受到明显限制。为克服这一障碍，以广泛来源的CO为单体的阳离子聚（环己烯碳酸酯）（CPCHCs）通过开环共聚（ROCOP）和硫醇-烯官能化巧妙合成。所开发的CPCHCs能够有效地包裹治疗性小干扰RNA以形成CPCHC/小干扰RNA纳米复合物（NPs）。作为小干扰RNA载体，CPCHC具有生物可降解性、可忽略的细胞毒性和高转染效率。体外研究表明，CPCHCs能够有效地保护小干扰RNA不被核糖核酸酶降解，并促进小干扰RNA持续从内体逃逸。用CPCHC/小干扰RNA NPs处理后，胰腺癌细胞系（PANC-1和MiaPaCa-2）中的K-ras基因表达均显著下调。随后，细胞生长和迁移受到显著抑制，且处理后的细胞被诱导进入细胞凋亡程序。这些结果证明了CPCHC介导的小干扰RNA疗法在胰腺癌治疗中的潜在前景。
