Carbon Dioxide-Derived Biodegradable and Cationic Polycarbonates as a New siRNA Carrier for Gene Therapy in Pancreatic Cancer.
Carbon Dioxide-Derived Biodegradable and Cationic Polycarbonates as a New siRNA Carrier for Gene Therapy in Pancreatic Cancer.
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二氧化碳衍生的可生物降解的阳离子聚碳酸酯作为胰腺癌基因治疗的新型 siRNA 载体
DOI：
10.3390/nano11092312
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Yang C
中科院分区：
文献类型：
--
作者：
Zhang X;Lin ZI;Yang J;Liu GL;Hu Z;Huang H;Li X;Liu Q;Ma M;Xu Z;Xu G;Yong KT;Tsai WC;Tsai TH;Ko BT;Chen CK;Yang C
胰腺癌是一种侵袭性恶性肿瘤，预后差，易发生浸润和转移。K-ras突变是胰腺癌患者的主要遗传疾病。基于rnai的治疗方法可以通过沉默K-ras基因表达来对抗胰腺癌。然而，由于缺乏合适的siRNA递送系统，RNAi技术的临床应用明显受到限制。为了解决这一难题，以广泛来源的二氧化碳为单体，通过开环共聚（ROCOP）和巯基功能化巧妙地合成了阳离子聚碳酸环己烯（CPCHCs）。所制备的CPCHC可以有效地包封治疗性siRNA，形成CPCHC/siRNA纳米复合物（NPs）。CPCHC作为siRNA载体，具有可生物降解性，细胞毒性可忽略不计，转染效率高。体外研究表明，CPCHCs能够有效保护siRNA不被rna酶降解，并促进siRNA的持续内体逃逸。经CPCHC/siRNA NPs处理后，两种胰腺癌细胞系（PANC-1和MiaPaCa-2）中K-ras基因的表达均显著下调。随后，细胞的生长和迁移受到明显抑制，并诱导细胞凋亡。这些结果证明了cpchc介导的siRNA疗法在胰腺癌治疗中的巨大潜力。
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.
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DOI：
10.1016/j.jconrel.2015.10.006
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Hickey JW;Santos JL;Williford JM;Mao HQ
通讯作者：
Mao HQ
影响因子：
16.6
作者：
Hamarsheh S;Groß O;Brummer T;Zeiser R
通讯作者：
Zeiser R
影响因子：
3.4
作者：
Hosseinkhani, Hossein;Domb, Abraham J.
通讯作者：
Domb, Abraham J.
影响因子：
4.6
作者：
Chang, Chi-Hang;Tsai, Chen-Yen;Ko, Bao-Tsan
通讯作者：
Ko, Bao-Tsan
影响因子：
19
作者：
Scharfenberg, Markus;Hilf, Jeannette;Frey, Holger
通讯作者：
Frey, Holger