Yong Raymund L, Shinojima Naoki, Fueyo Juan, Gumin Joy, Vecil Giacomo G, Marini Frank C, Bogler Oliver, Andreeff Michael, Lang Frederick F
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2009 Dec 1;69(23):8932-40. doi: 10.1158/0008-5472.CAN-08-3873. Epub 2009 Nov 17.
Delta24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta24-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 (hMSC) could be harnessed as intravascular delivery vehicles of Delta24-RGD to human gliomas. To assess cellular events, green fluorescent protein-labeled hMSCs carrying Delta24-RGD (hMSC-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Delta24 selectively localized to glioma xenografts and released Delta24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Delta24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-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-Delta24-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 hMSC-Delta24 selectively localize to human gliomas and are capable of delivering and releasing Delta24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.
Delta24-RGD是一种感染性增强的、条件性复制的溶瘤腺病毒，具有显著的抗胶质瘤作用。尽管瘤内注射Delta24-RGD可能有效，但血管内注射将改善其在人体中的成功应用。鉴于其肿瘤靶向特性，我们推测人间充质干细胞（hMSC）可作为Delta24-RGD向人胶质瘤进行血管内递送的载体。为了评估细胞事件，将携带Delta24-RGD的绿色荧光蛋白标记的hMSC（hMSC-Delta24）注入患有原位U87MG或U251-V121异种移植瘤的小鼠颈动脉，并在不同时间通过免疫荧光分析脑切片中的绿色荧光蛋白和病毒蛋白（E1A和六邻体）。hMSC-Delta24选择性地定位于胶质瘤异种移植瘤并释放Delta24-RGD，随后Delta24-RGD感染胶质瘤细胞。为了确定疗效，给小鼠植入荧光素酶标记的胶质瘤异种移植瘤，用hMSC-Delta24或对照进行治疗，并每周通过生物发光成像进行成像。通过生物发光成像分析肿瘤大小显示，与对照组相比，hMSC-Delta24治疗的动物中胶质瘤生长受到抑制且肿瘤被根除（P < 0.0001）。中位生存期从对照组的42天增加到hMSC-Delta24治疗动物的75.5天（P < 0.0001），存活超过80天的比例分别从0%增加到37.5%。我们得出结论，动脉内递送的hMSC-Delta24选择性地定位于人胶质瘤，并且能够将Delta24-RGD递送至肿瘤并释放到肿瘤中，从而提高了部分小鼠的生存率并根除了肿瘤。
