Multivalent cyclic RGD conjugates for targeted delivery of small interfering RNA.
Multivalent cyclic RGD conjugates for targeted delivery of small interfering RNA.
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DOI：
10.1021/bc200235q
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发表时间：
2011-08-17
影响因子：
4.7
通讯作者：
Juliano, Rudy L.
中科院分区：
文献类型：
--
作者：
Alam, Md Rowshon;Ming, Xin;Fisher, Michael;Lackey, Jeremy G.;Rajeev, Kallanthottathil G.;Manoharan, Muthiah;Juliano, Rudy L.
我们设计、合成和测试了化学修饰的荧光素酶小干扰RNA(Luc-siRNA)与二价、三价和四价环(精氨酸-甘氨酸-天冬氨酸)肽(CRGd)选择性结合到αvβ3整合素上的偶联物。利用稳定转染αvβ3阳性的M21+人黑色素瘤细胞的荧光素酶报告盒，检测连接的Luc siRNA与未连接的对照相比的细胞摄取、亚细胞分布和药理作用。M21+细胞表现出受体介导的摄取cRGD-siRNA结合物，但不摄取未结合的对照siRNA。荧光团标记的cRGD-siRNA偶联物通过空泡内吞途径被摄取，并主要积累在胞液小泡中。二价、三价和四价cRGD结合物被M21+细胞摄取的程度大致相同。然而，它们的药理作用存在显著差异。三价和四价版本的荧光素酶表达呈剂量依赖性的渐进性降低，而二价版本几乎没有影响。这种吸收和效果差异的基础目前尚不清楚。尽管如此，多价cRGD-siRNA结合物的高选择性和实质性的“击倒”效应表明，这种靶向和递送策略值得进一步探索。
We have designed, synthesized and tested conjugates of chemically modified luciferase siRNA (Luc-siRNA) with bi-, tri- and tetravalent cyclic(arginine-glycine-aspartic) peptides (cRGD) that selectively bind to the αvβ3 integrin. The cellular uptake, subcellular distribution and pharmacological effects of the cRGD conjugated Luc-siRNAs as compared to un-conjugated controls were examined using a luciferase reporter cassette stably transfected into αvβ3 positive M21+ human melanoma cells. The M21+ cells exhibited receptor-mediated uptake of cRGD-siRNA conjugates but not of unconjugated control siRNA. The fluorophore-tagged cRGD-siRNA 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 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 ‘knock down’ effects of the multivalent cRGD-siRNA conjugates suggest that this targeting and delivery strategy deserves further exploration.
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影响因子：
4.9
作者：
Juliano R;Bauman J;Kang H;Ming X
通讯作者：
Ming X
影响因子：
16.1
作者：
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影响因子：
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作者：
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有效递送反义和siRNA寡核苷酸的机制和策略。
影响因子：
14.9
作者：
Juliano, Rudy;Alam, Md. Rowshon;Dixit, Vidula;Kang, Hyumin
通讯作者：
Kang, Hyumin
影响因子：
16.6
作者：
Kabanov, Alexander V.;Vinogradov, Serguei V.
通讯作者：
Vinogradov, Serguei V.