Stem-04. Mechanism of Dysregulation and Efficacy of Pharmacologically Targeting the Apc/C in Glioblastoma

Abstract

INTRODUCTION:Pre-clinical interventions to the CNS require direct cranial administration of drugs for relevant therapeutic concentrations since the efficacy of systemic administration is hindered by the blood-brain barrier (BBB). We used MR-guided Focused Ultrasound (MRgFUS) to deliver primary-patient derived mesenchymal stem cells (hMSCs) for the first time, with sub-millimeter precision, in preselected areas. This method is a revolutionary way to deliver cellular therapy to delicate or inoperable regions obviating the need for invasive surgical intervention. METHOD: MRgFUS mediates BBB opening when low intensity FUS is applied to brain vasculature containing circulating microbubbles. This causes high intensity oscillation leading to a pore formation in BBB. hMSCs were injected intracardially in mice as a proof-of-principal delivery system. Under guidance of MRI, 0.4-1MPa in situpressures at 1 MHz, 1ms bursts and 1Hz pulse repetition frequency for 120 seconds were administered on the left hemisphere. Each animal's contralateral brain served as its own control RESULTS: We demonstrate that MRgFUS augments permeability of BBB. Each animal (n=3) received 3 cavitation parameters ranging from .4-1MPa in situ pressures at time points 2, 6 and 24hrs. Immunohistochemistry identified hMSC localization on sonicated points. Further analysis showed blood cell extravasation and capillary damage due to higher pressures and increased shear force from microbubble stream. The consequence is a cavitation pore larger than intended, necessitating further optimization. There were no observed behavioral complications after sonication and no hMSCs localization in non-pulsed regions demonstrating precise localization and no off-target delivery. CONCLUSION: The global hurdle of systemic therapy due to the BBB makes access of cellular therapy to the brain parenchyma, nearly impossible. This study investigates for the first time the utility of FUS to non-destructively permeabilize the BBB by creating a transient pore big enough for hMSC access.