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Title
  • RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system
Creator

Sakurai, Yu

Hatakeyama, Hiroto

Sato, Yusuke

Hyodo, Mamoru

Akita, Hidetaka

Ohga, Noritaka

Hida, Kyoko

Harashima, Hideyoshi

Subject
  • Other siRNA
  • Other Liposome
  • Other Anti-angiogenic therapy
  • Other Cyclic RGD
  • Other Active targeting
  • NDC 499
Description
Other
  • Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to alpha(V)beta(3) integrin, which is selectively expressed at high levels in TECs. We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0 mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy. (C) 2013 Elsevier B.V. All rights reserved.
PublisherElsevier science bv
Date Issued 2014-01-10
Languageeng
NIItypejournal article
VersiontypeAM
Identifier URI http://hdl.handle.net/2115/57252
Relation
  • isIdenticalTo PMID 24120854
  • isIdenticalTo DOI https://doi.org/10.1016/j.jconrel.2013.10.003
Journal
    • ISSN 0168-3659
    • Journal of controlled release
    173, 110-118
File
Oaidate2019-03-15T05:20:26Z