BACKGROUND Delta-24-RGD, an oncolytic adenovirus, shows promise against glioblastoma. To enhance virus delivery, we recently demonstrated that human bone marrow-derived mesenchymal stem cells loaded with Delta-24-RGD (hMSC-D24) can eradicate glioblastomas in mouse models. There are no studies examining the safety of endovascular selective intra-arterial (ESIA) infusions of MSC-D24 in large animals simulating human clinical situations. OBJECTIVE To perform canine preclinical studies testing the feasibility and safety of delivering increasing doses of hMSCs-D24 via ESIA infusions. METHODS ESIA infusions of hMSC-D24 were performed in the cerebral circulation of 10 normal canines in the target vessels (internal carotid artery [ICA]/P1) via transfemoral approach using commercially available microcatheters. Increasing concentrations of hMSC-D24 or particles (as a positive control) were injected into 1 hemisphere; saline (negative control) was infused contralaterally. Toxicity (particularly embolic stroke) was assessed on postinfusion angiography, diffusion-weighted magnetic resonance imaging, clinical exam, and necropsy. RESULTS ESIA injections were performed in the ICA (n = 7) or P1 (n = 3). In 2 animals injected with particles (positive control), strokes were detected by all assays. Of 6 canines injected with hMSC-D24 through the anterior circulation, escalating dose from 2 × 106 cells/20 mL to 1 × 108 cells/10 mL resulted in no strokes. Two animals had ischemic and hemorrhagic strokes after posterior cerebral artery catheterization. A survival experiment of 2 subjects resulted in no complications detected for 24-h before euthanization. CONCLUSION This novel study simulating ESIA infusion demonstrates that MSCs-D24 can be infused safely at least up to doses of 1 × 108 cells/10 mL (107 cells/ml) in the canine anterior circulation using commercially available microcatheters. These findings support a clinical trial of ESIA infusion of hMSCs-D24.

中文翻译：

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犬模型中装载有 Delta-24 的间充质干细胞的血管内选择性动脉内输注

背景 Delta-24-RGD 是一种溶瘤腺病毒，显示出对抗胶质母细胞瘤的前景。为了增强病毒传递，我们最近证明了装载有 Delta-24-RGD (hMSC-D24) 的人骨髓间充质干细胞可以根除小鼠模型中的胶质母细胞瘤。没有研究检查在模拟人类临床情况的大型动物中血管内选择性动脉内 (ESIA) 输注 MSC-D24 的安全性。目的 进行犬临床前研究，以测试通过 ESIA 输注增加剂量的 hMSCs-D24 的可行性和安全性。方法 使用市售微导管通过经股方法在 10 只正常犬科动物的脑循环中对目标血管（颈内动脉 [ICA]/P1）进行 ESIA 输注。将增加浓度的 hMSC-D24 或颗粒（作为阳性对照）注射到 1 个半球；对侧输注生理盐水（阴性对照）。通过输注后血管造影、弥散加权磁共振成像、临床检查和尸检评估毒性（尤其是栓塞性中风）。结果 ESIA 注射在 ICA (n = 7) 或 P1 (n = 3) 中进行。在注射颗粒的 2 只动物（阳性对照）中，所有测定均检测到中风。在通过前循环注射 hMSC-D24 的 6 只犬中，将剂量从 2 × 106 细胞/20 mL 增加到 1 × 108 细胞/10 mL，未导致中风。两只动物在大脑后动脉插管后出现缺血性和出血性中风。2 名受试者的生存实验导致在安乐死前 24 小时内未检测到并发症。结论 这项模拟 ESIA 输注的新研究表明，使用市售微导管，MSCs-D24 可以安全地输注至犬前循环中至少高达 1 × 108 个细胞/10 mL（107 个细胞/ml）的剂量。这些发现支持 ESIA 输注 hMSCs-D24 的临床试验。