开发一种兔子人类脑胶质母细胞瘤模型，用于测试内血管选择性动脉内输注（ESIA）新型基于干细胞的治疗方法。
Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics.
发表日期：2023 Aug 21
作者：
Peter Kan, Visish M Srinivasan, Joy Gumin, Roberto Garcia, Stephen R Chen, Jeremiah N Johnson, Dalis E Collins, Melissa M Chen, Daniel Ledbetter, Jason Huse, Zean Aaron Evan Luna, Ariadna Robledo, Viren Vasandani, Abhijit Rao, Sanjay K Singh, Elizabeth J Shpall, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang
来源：
NEURO-ONCOLOGY
摘要：
内血管选择性动脉内注射（ESIA）细胞治疗法是治疗胶质母细胞瘤的一种快速发展的策略。评估ESIA注射需要一个独特的动物模型。我们的目标是创建一个兔人胶质母细胞瘤模型，以测试细胞治疗的IA注射，并通过使用临床级微导管和注射方法来测试其效用，将富含溶瘤腺病毒Delta-24-RGD的间充质干细胞注入其中。采用MMF、地塞米松和他克莫司进行小鼠免疫抑制。将人类胶质母细胞瘤细胞系（U87、MDA-GSC-17和MDA-GSC-8-11）通过定向异种移植注入右额叶。通过磁共振成像、组织病理学和免疫组织化学分析确认肿瘤形成。通过同侧颈内动脉选择性微导管注射MSC-D24，评估模型的效用以及该方法的疗效和安全性。共植入25只兔子（U87 18只，MDA-GSC-17 2只，MDA-GSC-8-11 5只）。68%的兔子形成肿瘤（U87 77.8%，MDA-GSC-17 50.0%，MDA-GSC-8-11 40.0%）。在磁共振成像上，肿瘤在T2加权成像上呈高信号，有不同程度的强化（证据显示了血脑屏障的破坏）。组织学上，肿瘤显示出人类胶质母细胞瘤的表型特征，包括不同程度的血管生成。在该模型中，通过内颈动脉远端选择性注射2毫升MSCs-D24（107个细胞）是安全的。注射后检查结果表明，MSCs-D24在24小时内定位到植入的肿瘤中。颅内免疫抑制的兔人胶质母细胞瘤模型可以以临床相关的方式测试新型治疗方法（例如MSC-D24）的ESIA注射。© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model in order to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24).Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach.Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (10 7 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours.The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (e.g., MSC-D24) in a clinically relevant fashion.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.