Inhibiting tumor growth by targeting liposomally encapsulated CDC20siRNA to tumor vasculature: Therapeutic RNA interference
Inhibiting tumor growth by targeting liposomally encapsulated CDC20siRNA to tumor vasculature: Therapeutic RNA interference
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DOI：
10.1016/j.jconrel.2014.02.012
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发表时间：
2014-04-28
影响因子：
10.8
通讯作者：
Chaudhuri, Arabinda
中科院分区：
文献类型：
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作者：
Majumder, Poulami;Bhunia, Sukanya;Chaudhuri, Arabinda
许多癌细胞过度表达 CDC20（细胞分裂周期同源物 20），这是从酵母到人类等生物体完成有丝分裂所需的关键细胞周期调节因子。最近的一项体外研究表明，使用CDC20siRNA特异性敲除CDC20表达可以显着抑制人胰腺癌细胞的生长。然而，旨在证明CDC20siRNA抑制肿瘤生长的治疗潜力的临床前研究才刚刚开始。使用同源 C57BL/6 J 小鼠肿瘤模型，本文中我们表明，静脉注射封装在聚乙二醇化 RGDK-脂肽的 α5β1 整联蛋白受体选择性脂质体中的 19 bp 合成 CDC20siRNA 可抑制黑色素瘤肿瘤生长。研究发现，在体外环境下，脂质体封装的 CDC20siRNA 在 mRNA 和蛋白质水平上都能有效沉默肿瘤和内皮细胞中 CDC20 的表达。流式细胞术研究的结果证实，在用脂质体封装的 CDC20siRNA 处理的细胞中，G2/M 期群体的存在显着增强。对用脂质体封装的荧光标记的siRNA处理的小鼠的肿瘤冷冻切片进行免疫组织化学染色，揭示了本脂质体制剂的肿瘤脉管系统靶向能力。肿瘤冷冻切片中 TUNEL 和 VE-钙粘蛋白阳性细胞的共定位与通过肿瘤内皮细胞凋亡介导的肿瘤生长抑制一致。总之，目前公开的CDC20siRNA的脂质体制剂是用于抗血管生成癌症治疗的有前途的RNA干扰工具。 (C) 2014 Elsevier B.V. 保留所有权利。
Many cancer cells over express CDC20 (Cell Division Cycle homologue 20), a key cell cycle regulator required for the completion of mitosis in organisms from yeast to human. A recent in vitro study showed that specific knockdown of CDC20 expression using CDC20siRNA can significantly inhibit growth of human pancreatic carcinoma cells. However, preclinical study aimed at demonstrating therapeutic potential of CDC20siRNA in inhibiting tumor growth has just begun. Using a syngeneic C57BL/6 J mouse tumor model, herein we show that intravenous administration of a 19 bp synthetic CDC20siRNA encapsulated within alpha 5 beta 1 integrin receptor selective liposomes of pegylated RGDK-lipopeptide inhibits melanoma tumor growth. Liposomally encapsulated CDC20siRNA was found to be efficient in silencing the expression of CDC20 in tumor and endothelial cells at both mRNA and protein levels under in vitro settings. Findings in the flow cytometric studies confirmed the presence of significantly enhanced populations of the G2/M phase in cells treated with liposomally encapsulated CDC20siRNA. Immunohistochemical staining of tumor cryosections from mice treated with liposomally encapsulated fluorescently labeled siRNAs revealed tumor vasculatures targeting capabilities of the present liposomal formulations. The colocalizations of the TUNEL and VE-cadherin positive cells in tumor cryosections are consistent with tumor growth inhibition being mediated via apoptosis of the tumor endothelial cells. In summary, the presently disclosed liposomal formulation of CDC20siRNA is a promising RNA interference tool for use in anti-angiogenic cancer therapy. (C) 2014 Elsevier B.V. All rights reserved.