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  • Endovascular Microcatheter Delivery of Neurotherapeutics in Mesenchymal Stem Cells: Compatibility and Viability

    Final Number:

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

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2018 Annual Meeting

    Introduction: Based on preclinical studies, we have developed a tumor-selective oncolytic adenovirus (Delta-24-RGD) which has been shown to kill malignant gliomas. This virus can be loaded into a bone marrow human mesenchymal stem cell (BM-hMSC) as a tumor-tropic carrying vehicle. In preparation for clinical trials we sought to test the compatibility of several micro catheters with MSCs in vitro. We previously assessed and reported on microcatheter compatibility with the cells and testing injection parameters. For clinical application, we sought to establish hMSC-Delta-24 compatibility with endovascular medications and confirm post-injection tropic activity.

    Methods: Delta-24-BM-hMSCs were prepared per our previous protocol. hMSC-Delta-24 cells were mixed with various combinations endovascular medications (heparin, verapamil, and Omnipaque) and assessed for cell count and viability. hMSC-Delta-24 solution was then injected via microcatheter and cells were collected from the distal end. hMSC-Delta-24 that were not passed through the catheter were used as a control. Separately, we took an identically prepared cell solution that had been passed through a microcatheter and injected into the carotid artery of a U87 mouse model. The murine brains were analyzed for localization of the hMSCs and virus based on green fluorescence protein (GFP) labeling.

    Results: BM-hMSC cell count was 1.12 x x 106 cells/mL (±0.069 x 106) with 98.7% viability prior to infusion. Mean concentration and viability for each medication mixture were: Heparin+Omnipaque, 1.35 x 106 cells/mL (±0.160 x 106) and 95.5%, Heparin+Verapamil, 1.16 x 106 cells/mL (±0.125 x 106), and Heparin+Verapamil+Omnipaque, 1.10 x 106 cells/mL (±0.176 x 106). None of these were significant differences. Cells were found to retain tropic activity to the tumor in the mouse model as identified by GFP staining.

    Conclusions: Delta-24-hMSCs retain their tumor-tropic and tumor-lytic functions after microcatheter passage and appear to be compatible with endovascular medications. Endovascular microcatheter delivery of hMSC appears to be viable and practical.

    Patient Care: This work represents the initial steps to prove the viability of endovascular therapy with mesenchymal stem cells. As a concept, this line of work has implications in treating a whole breath of pathologies from stroke to Parkinsons to tumors.

    Learning Objectives: 1) Understand the background of mesenchymal stem cell use in neurosurgical pathologies 2) Appreciate the challenges and issues associated with endovascular delivery of mesenchymal stem cells 3) Understand the next steps involved in bringing endovascular MSC delivery to a clinical reality

    References: 1. 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 2. 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 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. Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al: Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J Clin Oncol:JCO2017758219, 2018 5. 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

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