Carbon Dioxide-Derived Biodegradable and Cationic Polycarbonates as a New siRNA Carrier for Gene Therapy in Pancreatic Cancer.

Xinmeng Zhang,Jingyu Yang,Zheng-Ian Lin,Wei-Chung Tsai,Haoqiang Huang,Chih-Kuang Chen,Zulu Hu,Zhourui Xu,Tzu-Hsien Tsai,Xiang Li,Bao-Tsan Ko,Qiqi Liu,Mingze Ma,Chengbin Yang,Ken-Tye Yong,Gaixia Xu,Guan-Lin Liu

doi:10.3390/nano11092312

Abstract

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 CO2 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.

Highlights

These results clearly indicated that cationic poly (cyclohexene carbonate) s (CPCHCs)-44 is capable of effectively protecting siRNA
Utilizing CO2 as one of the constituent materials, CPCHC-44 was successfully synthesized by our developed ring-opening polymerization and thiol-ene modification techniques, which had biodegradability, controlled charge density, and insignificant cytotoxicity
CPCHC-44/siKras NPs were prepared at various CPCHC-44 and siRNA

Summary

Introduction

A number of studies revealed that pancreatic cancer was treated through the use of K-ras protooncogene inhibitors, which are capable of directly targeting mutant K-ras [4,5,6]. The inhibition of K-ras is considered an effective methodology to address the dilemma in treating pancreatic cancer [8]. No therapeutic drugs directly targeting K-ras have been approved for clinical cancer treatment [10]. In this context, RNAi-based gene therapy has been considered a new hope to inhibit K-ras. Due to its efficacy in silencing specified mutated genes, RNAi therapy is thought a promising modality in treating intractable cancer diseases, such as pancreatic cancer. In August 2018, the first-ever RNAi-based drug, Alnylam’s

Methods

Results

Conclusion