Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas.
Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas.
复制标题
DOI：
10.1158/0008-5472.can-08-3873
复制
发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Lang FF
中科院分区：
文献类型：
--
作者：
Yong RL;Shinojima N;Fueyo J;Gumin J;Vecil GG;Marini FC;Bogler O;Andreeff M;Lang FF
Delta-24-RGD 是一种感染力增强、条件复制的溶瘤腺病毒，具有显着的抗神经胶质瘤作用。尽管 Delta-24-RGD 的瘤内递送可能有效，但血管内递送将提高在人类中的成功应用。由于其亲肿瘤特性，我们假设人类间充质干细胞 (hMSC) 可以用作 Delta-24-RGD 至人类神经胶质瘤的血管内递送载体。为了评估细胞事件，将携带 Delta-24-RGD (hMSCs-Delta24) 的 GFP 标记 hMSC 注射到携带原位 U87MG 或 U251-V121 异种移植物的小鼠颈动脉中，并通过免疫荧光分析脑切片中 GFP 和病毒蛋白（E1A 和六邻体）的增加时间。 hMSCs-Delta24选择性地定位于神经胶质瘤异种移植物并释放Delta-24-RGD，随后感染神经胶质瘤细胞。为了确定疗效，小鼠被植入荧光素酶标记的神经胶质瘤异种移植物，用 hMSC-Delta24 或对照处理，并每周通过生物发光成像 (BLI) 进行成像。通过 BLI 对肿瘤大小进行的分析表明，与对照组相比，hMSC-Delta24 治疗的动物可抑制神经胶质瘤生长并根除肿瘤（P<0.0001）。 hMSC-Delta-24治疗动物的中位生存期从对照组的42天增加到75.5天（P<0.0001），并且超过80天的生存期从0%增加到37.5%。我们得出的结论是，动脉内递送的 hMSC-Delta24 选择性地定位于人类神经胶质瘤，并且能够将 Delta-24-RGD 递送和释放到肿瘤中，从而提高小鼠亚群的生存率并消除肿瘤。
Delta-24-RGD is an infectivity-augmented, conditionally-replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta-24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSCs) could be harnessed as intravascular delivery vehicles of Delta-24-RGD to human gliomas. To assess cellular events, GFP-labeled hMSCs carrying Delta-24-RGD (hMSCs-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for GFP and viral proteins (E1A and hexon) at increasing times. hMSCs-Delta24 selectively localized to glioma xenografts and released Delta-24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase-labeled glioma xenografts, treated with hMSCs-Delta24 or controls and imaged weekly by bioluminescence imaging (BLI). Analysis of tumor size by BLI demonstrated inhibition of glioma growth and eradication of tumors in hMSCs-Delta24-treated animals compared with controls (P<0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta-24-treated animals (P<0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSCs-Delta24 selectively localize to human gliomas, and are capable of delivering and releasing Delta-24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.