Microcatheter delivery of neurotherapeutics: compatibility with mesenchymal stem cells

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OBJECTIVE

Bone marrow–derived human mesenchymal stem cells (BM-hMSCs) have been used in clinical trials for the treatment of several neurological disorders. MSCs have been explored as a delivery modality for targeted viral therapeutic agents in the treatment of intracranial pathologies. Delta-24-RGD, a tumor-selective oncolytic adenovirus designed to target malignant glioma cells, has been shown to be effective in animal models and in a recent clinical trial. However, the most efficient strategy for delivering oncolytic therapies remains unclear. BM-hMSCs have been shown to home toward glioma xenografts after intracarotid delivery. The feasibility of selective intraarterial infusion of BM-hMSCs loaded with Delta-24-RGD (BM-hMSC-Delta-24) to deliver the virus to the tumor is being investigated. To evaluate the feasibility of endovascular intraarterial delivery, the authors tested in vitro the compatibility of BM-hMSC-Delta-24 with a variety of commercially available, clinically common microcatheters.

METHODS

BM-hMSCs were cultured, transfected with Delta-24-RGD, and resuspended in 1% human serum albumin. The solution was then injected via 4 common neuroendovascular microcatheters of different inner diameters (Marathon, Echelon-14, Marksman, and SL-10). Cell count and viability after injection through the microcatheters were assessed, including tests of injection velocity and catheter configuration. Transwell assays were performed with the injected cells to test the efficacy of BM-hMSC-Delta-24 activity against U87 glioma cells. BM-hMSC-Delta-24 compatibility was also tested with common neuroendovascular medications: Omnipaque, verapamil, and heparin.

RESULTS

The preinfusion BM-hMSC-Delta-24 cell count was 1.2 × 105 cells/ml, with 98.7% viability. There was no significant difference in postinfusion cell count or viability for any of the catheters. Increasing the injection velocity from 1.0 ml/min to 73.2 ml/min, or modifying the catheter shape from straight to tortuous, did not significantly reduce cell count or viability. Cell count and viability remained stable for up to 5 hours when the cell solution was stored on ice. Mixing BM-hMSC-Delta-24 with clinical concentrations of Omnipaque, verapamil, and heparin prior to infusion did not alter cell count or viability. Transwell experiments demonstrated that the antiglioma activity of BM-hMSC-Delta-24 was maintained after infusion.

CONCLUSIONS

BM-hMSC-Delta-24 is compatible with a wide variety of microcatheters and medications commonly used in neuroendovascular therapy. Stem cell viability and viral agent activity do not appear to be affected by catheter configuration or injection velocity. Commercially available microcatheters can be used to deliver stem cell neurotherapeutics via intraarterial routes.

ABBREVIATIONS BM-hMSC = bone marrow–derived hMSC; BM-hMSC-Delta-24 = BM-hMSC loaded with Delta-24-RGD; GFP = green fluorescent protein; hMSC = human MSC; MSC = mesenchymal stem cell.

Downloadable materials

  • Supplemental Tables 1 and 2 (PDF 390 KB)

Article Information

Correspondence Peter Kan: Baylor College of Medicine, Houston, TX. peter.kan@bcm.edu.

INCLUDE WHEN CITING Published online September 6, 2019; DOI: 10.3171/2019.6.JNS19327.

Disclosures Dr. Lang reports being a patent holder with DNAtrix. Dr. Kan reports being a consultant for Stryker Neurovascular and Cerenovus.

© AANS, except where prohibited by US copyright law.

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Figures

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    Cell count before and after infusion via various microcatheters. No significant differences were detected between the preinfusion count and any of the postinfusion counts from the Echelon, Marathon, Marksman, or SL-10 microcatheters (unpaired t-test, p = 0.84, 0.99, 0.29, and 0.47, respectively). Figure is available in color online only.

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    Photograph of bench testing of microcatheters in straight (A) and tortuous (B) configurations. The catheter was meant to simulate a potentially tortuous course of the human internal carotid artery, to assess whether it would affect BM-hMSC-Delta-24 cell count, viability, or function. C: Cell count before and after infusion in the straight or tortuous configuration. No significant differences were detected between the straight and tortuous configurations for any of the microcatheters (see Table 1). Figure is available in color online only.

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    Comparison of the 4 microcatheters with slow or fast infusion. Compared to baseline, other catheters, or within-catheter comparison, no significant change was measured (see Table 2). Additional velocity and transit time data are provided in Supplemental Table 1. Figure is available in color online only.

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    A: Comparative antiglioma activity of Delta-24-MSCs against U87 glioma cells in a Transwell assay, before and after catheter infusion. The catheter-infused Delta-24-MSCs maintained their antiglioma activity. B: Cell count testing after exposure to common neuroendovascular medications (heparin, Omnipaque, and verapamil) in various combinations, and with catheter infusion. C: Postinfusion medication-exposed BM-hMSC-Delta-24 cells were then tested again in a Transwell assay against U87 glioma cells. The catheter-infused Delta-24-MSCs maintained their antiglioma activity. Figure is available in color online only.

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    H & E slides (A, C, E, and G) and corresponding GFP-stained sections (B, D, F, and H) of nude mouse cerebri. Tumor is labeled, and the magnified GFP sections show diffuse localization of the GFP-labeled Delta-24-hMSCs throughout the tumor following intracarotid injection. These cells were used in the preceding experiment of medication exposure before being centrifuged for intracarotid delivery. A, C, E, and G: original magnification ×1. B, D, F, and H: original magnification ×20. Figure is available in color online only.

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    Change in cell count (concentration) while stored on ice over 5 hours. No significant decrement was seen. Rather, a minor increase was observed in cell concentration, likely from some evaporation-based concentration of the diluent over time. There was no significant change in cell viability between baseline and 5 hours (p = 0.6496). Figure is available in color online only.

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