RNAi technology is taking strong position among the key therapeutic modalities,with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development.To further explore potentials of RNAi technology as therapeutics,we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-D-Phe-Lys”PEG-MAL”) (cRGD) peptide,known to bind αvβ3 integrin receptors.cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC).Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth.In tumor-bearing mice,intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues.Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55% and 45%) and protein (65% and 45%) in tumors,as well as in overall reduction of tumor volume (90% and 70%).These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.
Xiaoxia Liu Wei Wang Dmitry Samarsky Li Liu Qian Xu Wenqing Zhang Guangzu Zhu Ping Wu Xialin Zuo Houliang Deng Jingjing Zhang Zhuomin Wu Xiaohui Chen Lingfeng Zhao Zhiyong Qiu Zhongyi Zhang Qiyi Zeng Wei Yang Biliang Zhang Aimin Ji
Department of Pharmacy,Zhujiang Hospital,Southern Medical University,Guangzhou 510282,China Guangzhou RiboBio Co.,Guangzhou 510663,China Department of Cell Biology,Southern Medical University,Guangzhou 510515,China Guangdong Shuanglin Bio-pharmaceutical Co.,Ltd,Zhanjiang 524005,China Witspool Biopharmaceutical Co.,Wuhan 430079,China Department of Pediatrics,Zhujiang Hospital,Southern Medical University,Guangzhou 510282,China Center for Drug Non-clinical Evaluation and Research(National Guangzhou Key Laboratory for New Drug Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China Department of Pharmacy,Zhujiang Hospital,Southern Medical University,Guangzhou 510282,China;Departme