Active targeting of RGD-conjugated bioreducible polymer for delivery of oncolytic adenovirus expressing shRNA against IL-8 mRNA.
Active targeting of RGD-conjugated bioreducible polymer for delivery of oncolytic adenovirus expressing shRNA against IL-8 mRNA.
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DOI：
10.1016/j.biomaterials.2011.03.084
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发表时间：
2011-08
期刊：
影响因子：
14
通讯作者：
Kim, Sung Wan
中科院分区：
文献类型：
--
作者：
Kim, Jaesung;Nam, Hye Yeong;Kim, Tae-il;Kim, Pyung-Hwan;Ryu, Jihoon;Yun, Chae-Ok;Kim, Sung Wan
尽管溶瘤腺病毒（Oncolytic adenovirus，Ad）已成为肿瘤基因治疗领域的研究热点，但其转导靶向和免疫豁免仍是一个难题。最近的报道已经注意到用聚合物屏蔽腺病毒表面以克服其实际应用的限制的增加的趋势。我们先前报道了可生物降解的聚合物聚（CBA-DAH）（CD）作为有效基因递送的有希望的候选物的潜力。为了将肿瘤脉管系统的选择性靶向部分赋予CD，使用异源双功能交联剂SM（PEG）n将cRGDfC（众所周知的肿瘤内皮细胞表面整联蛋白的配体）缀合至CD。与裸Ad相比，聚合物包被的溶瘤Ad选择性地对癌细胞的致病变作用明显增强，并呈剂量依赖性。最重要的是，在所有癌细胞中用Ad/CD-PEG 500-RGD治疗评估最有效的溶瘤作用。Ad/RGD偶联聚合物的增强的细胞病变效应被针对整合素的阻断抗体特异性抑制，但不被针对CAR的阻断抗体抑制。Ad/CD-PEG 500-RGD处理的HT 1080细胞具有较强的凋亡诱导作用，并能抑制IL-8和VEGF的表达。这些结果表明，RGD偶联的生物可还原聚合物可用于安全有效地递送溶瘤Ad用于肿瘤治疗。
Even though oncolytic adenovirus (Ad) has been highlighted in the field of cancer gene therapy, transductional targeting and immune privilege still remain difficult challenges. The recent reports have noted the increasing tendency of adenoviral surface shielding with polymer to overcome the limits of its practical application. We previously reported the potential of the biodegradable polymer, poly(CBA-DAH) (CD) as a promising candidate for efficient gene delivery. To endow the selective-targeting moiety of tumor vasculature to CD, cRGDfC well-known as a ligand for cell-surface integrins on tumor endothelium was conjugated to CD using hetero-bifunctional cross-linker SM(PEG)n. The cytopathic effects of oncolytic Ad coated with the polymers were much more enhanced dose-dependently when compared with that of naked Ad in cancer cells selectively. Above all, the most potent oncolytic effect was assessed with the treatment of Ad/CD-PEG500-RGD in all cancer cells. The enhanced cytopathic effect of Ad/RGD-conjugated polymer was specifically inhibited by blocking antibodies to integrins, but not by blocking antibody to CAR. HT1080 cells treated with Ad/CD-PEG500-RGD showed strong induction of apoptosis and suppression of IL-8 and VEGF expression as well. These results suggest that RGD-conjugated bioreducible polymer might be used to deliver oncolytic Ad safely and efficiently for tumor therapy.
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