title: Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA.
abstract: 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.
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Guangzhou RiboBio Co., Guangzhou 510663, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Guangzhou RiboBio Co., Guangzhou 510663, China.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Samarsky
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Guangdong Shuanglin Bio-pharmaceutical Co.,Ltd, Zhanjiang 524005, China.
authors.forename: Guangzu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Xialin
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Houliang
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Zhuomin
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Witspool Biopharmaceutical Co., Wuhan 430079, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Center for Drug Non-clinical Evaluation and Research (National Guangzhou Key Laboratory for New Drug Safety Evaluation and Research), Guangzhou General Pharmaceutical Research Institute, Guangzhou 510240, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China zhang_biliang@gibh.ac.cn.
authors.forename: Biliang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China Department of Cell Biology, Southern Medical University, Guangzhou 510515, China aiminji@163.com.
authors.forename: Aimin
authors.initials: A
authors.lastname: Ji
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy*; D018919:Neovascularization, Physiologic; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000032:analysis / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D015027:Zebrafish / Q000196:embryology
chemical_list: D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D040301:Vascular Endothelial Growth Factor Receptor-2