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: 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
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 42 Issue 18 Pg. 11805-17 (Oct 2014) ISSN: 1362-4962 [Electronic] England
• PMID: 25223783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Peptides, Cyclic
• RNA, Small Interfering
• cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl)
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Cell Line, Tumor
• Cells, Cultured
• Female
• Gene Knockdown Techniques
• HeLa Cells
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (blood supply, therapy)
• Neovascularization, Physiologic
• Peptides, Cyclic (administration & dosage, analysis, chemistry)
• RNA Interference
• RNA, Small Interfering (administration & dosage, chemistry)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, genetics)
• Zebrafish (embryology)