Multivalent Cyclic RGD Conjugates for Targeted Delivery of Small Interfering RNA

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• 作者：Md. Rowshon Alam ; Xin Ming ; Michael Fisher ; Jeremy G. Lackey ; Kallanthottathil G. Rajeev ; Muthiah Manoharan ; Rudy L. Juliano
• 刊名：Bioconjugate Chemistry
• 出版年：2011
• 出版时间：August 17, 2011
• 年：2011
• 卷：22
• 期：8
• 页码：1673-1681
• 全文大小：1033K
• 年卷期：v.22,no.8(August 17, 2011)
• ISSN：1520-4812

文摘

We have designed, synthesized, and tested conjugates of chemically modified luciferase siRNA (Luc-siRNA) with bi-, tri-, and tetravalent cyclic(arginine-glycine-aspartic) (cRGD) peptides that selectively bind to the 伪v尾3 integrin. The cellular uptake, subcellular distribution, and pharmacological effects of the cRGD-conjugated Luc-siRNAs compared to those of unconjugated controls were examined using a luciferase reporter cassette stably transfected into 伪v尾3 positive M21⁺ human melanoma cells. The M21⁺ cells exhibited receptor-mediated uptake of cRGD鈥搒iRNA conjugates but not of unconjugated control siRNA. The fluorophore-tagged cRGD鈥搒iRNA conjugates were taken up by a caveolar endocytotic route and primarily accumulated in cytosolic vesicles. The bi-, tri-, and tetravalent cRGD conjugates were taken up by M21⁺ cells to approximately the same degree. However, there were notable differences in their pharmacological effectiveness. The tri- and tetravalent versions produced progressive, dose-dependent reductions in the level of luciferase expression, while the bivalent version had little effect. The basis for this divergence of uptake and effect is currently unclear. Nonetheless, the high selectivity and substantial 鈥渒nock down鈥?effects of the multivalent cRGD鈥搒iRNA conjugates suggest that this targeting and delivery strategy deserves further exploration.