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  • Microcatheter Delivery of Neurotherapeutics: Compatibility with Mesenchymal Stem Cells

    Final Number:
    113

    Authors:
    Visish M. Srinivasan MD; Joy Gumin BS; Kevin M Camstra MS; Frederick F. Lang MD; Peter Kan MD, MPH, FRCSC

    Study Design:
    Laboratory Investigation

    Subject Category:
    Basic Science

    Meeting: AANS/CNS Cerebrovascular Section 2017 Annual Meeting

    Introduction: Mesenchymal stem cells (MSCs) have been used for therapeutic clinical trials for the treatment of Multiple System Atrophy (MSA) and in ischemic/hemorrhagic stroke. A potentially major application of MSCs would be in the delivery of targeted therapeutic agents for the treatment of brain tumors such as malignant gliomas. One such agent, Delta-24-RGD, a tumor-selective oncolytic adenovirus that targets malignant glioma cells in vitro and in vivo, could be delivered in an MSC carrier, which could in turn be using neuroendovascular techniques. Further, bone marrow human MSCs (BM-hMSC) have been shown to have homing capability toward glioma xenografts. Before such endovascular delivery could be tested in an animal model, we sought to test the catheter compatibility with MSCs in vitro.

    Methods: BM-hMSCs were cultured, transfected with Delta-24-RGD, and re-suspended in 1% HSA. Separately, U87 glioma cells were cultured and plated on a Transwell assay. The hMSC-Delta-24 solution was then injected via three different, microcatheters (Marathon, Echelon-14, and Marksman), all widely used neuroendovascular procedures. Cell count and viability was tested versus a baseline control in straight/tortuous configurations and with slow and fast injection. Transwell assay was performed with the injected cells to test the Delta-24-RGD activity against glioma cells.

    Results: BM-hMSC cell count prior to infusion was 0.123 x 106 cells/mL, 98.7% viability. There was no significant difference in cell count after infused through any of the three catheters under standard conditions, with a mean concentration of 0.126 x 106 cells/mL and 97.9% (+/- 1.7%) viability. Injection velocity ranged from 1.01 cc/min to 73.17 cc/min, with no significant difference in cell count or viability. There was no significant difference in cell count or viability in the tortuous or straight configurations. Anti-glioma activity was maintained and did not vary significantly between the non-catheter-infused control and through each of the microcatheters.

    Conclusions: BM-hMSCs are compatible with a wide variety of commonly used microcatheters. Stem cell viability and viral agent activity do not appear to be affected by catheter configuration or injection velocity. Endovascular stem cell delivery is a promising avenue for neurotherapeutics.

    Patient Care: The results of this study will provide crucial preclinical data to support and guide a large animal and then eventual human clinical trial of endovascular delivery of Delta-24-hMSC. This translational research regarding endovascular therapy for GBM is a unique opportunity for collaborative treatment between two neurosurgical subspecialties and is a promising new avenue of practice for cerebrovascular neurosurgeons.

    Learning Objectives: 1) Describe the current applications of mesenchymal stem cells in neurotherapeutics and their potential in neuro-oncology 2) Describe the concerns with intra-arterial endovascular delivery of neurotherapeutics 3) Understand the wide variety of catheters that can be used in IA delivery of stem cells

    References: 1. Jiang Y, Zhu W, Zhu J, Wu L, Xu G, Liu X: Feasibility of delivering mesenchymal stem cells via catheter to the proximal end of the lesion artery in patients with stroke in the territory of the middle cerebral artery. Cell Transplant 22:2291-2298, 2013 2. Lee PH, Lee JE, Kim HS, Song SK, Lee HS, Nam HS, et al: A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol 72:32-40, 2012 3. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, et al: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307-3318, 2005 4. Shinojima N, Hossain A, Takezaki T, Fueyo J, Gumin J, Gao F, et al: TGF-beta mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells. Cancer Res 73:2333-2344, 2013 5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 6. Su YS, Ali R, Feroze AH, Li G, Lawton MT, Choudhri O: Endovascular therapies for malignant gliomas: Challenges and the future. J Clin Neurosci, 2016 7. Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, et al: Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res 69:8932-8940, 2009

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