Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Biomaterials. 2011 Aug;32(22):5158-66. doi: 10.1016/j.biomaterials.2011.03.084. Epub 2011 Apr 30.
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-PEG(500)-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-PEG(500)-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.
尽管溶瘤腺病毒（Ad）在癌症基因治疗领域备受关注，但转导靶向和免疫豁免仍然是难以克服的挑战。最近的报告指出，通过聚合物对腺病毒表面进行遮蔽，以克服其实际应用的限制，这种趋势越来越明显。我们之前曾报道过可生物降解聚合物聚（CBA-DAH）（CD）作为高效基因传递的有前途的候选物的潜力。为了将肿瘤血管的选择性靶向部分赋予 CD，将 cRGDfC（一种已知的肿瘤内皮细胞表面整合素的配体）用杂双功能交联剂 SM（PEG）（n）连接到 CD 上。与裸 Ad 相比，用聚合物包裹的溶瘤 Ad 在癌细胞中具有更强的剂量依赖性细胞病变效应。最重要的是，在用 Ad/CD-PEG（500）-RGD 处理所有癌细胞时，评估了最强的溶瘤作用。Ad/RGD 偶联聚合物的增强细胞病变效应可被整合素阻断抗体特异性抑制，但不能被 CAR 阻断抗体抑制。用 Ad/CD-PEG（500）-RGD 处理的 HT1080 细胞表现出强烈的诱导凋亡和抑制 IL-8 和 VEGF 表达的作用。这些结果表明，RGD 偶联的生物还原聚合物可用于安全有效地传递溶瘤腺病毒进行肿瘤治疗。
