DDEL-28. Systemic delivery of lipid nanoparticles into infiltrating zone of brain tumors following opening the BBB via Magnetic Resonance-Guided Focused Ultrasound in a Swine Model

Abstract Current therapeutic for GBM have limited effect on patients’ survival. Previous publications demonstrated that RNAi / CRISPR –PKL1 LNPs effectively delivered locally into glioma rat model. The majority of clinical trials during the last two decades using a local delivery of innovative drugs to patients with GBM have failed. We used LIFUS to open the BBB mediated by intravascular microbubble oscillations. Published data in a rat model demonstrated that ΔR2 MR values reflected the parenchymal LNPs concentrations OBJECTIVES Establish brain tumor model in a big animal, explore the impact of sonication on ct-DNA extraction using LIFUS, evaluate the feasibility of systemic delivery of LNPs into the surrounding brain tumor of pigs bearing glioma following opening of the BBB via Magnetic LIFUS and the efficacy of LNPs carrying CRISPR / SiRNA MATERIALS AND METHODS Female domestic pigs 1 -3 months, 10 - 28 kg Human GBM U87MG will be transplanted with 10 million cells / 20 microliters of DMEM Cyclosporine (15 mg/kg) orally twice a day to prevent rejection Desired tumor volume 3cc. The ExAblate InSightec, Ltd (MRgLIFUS) 4000 Type 2 System is used for BBB disruption. liposomes conjugated to gadolinium will be delivered. Sonication parameters, micro-bubble concentrations based on our previous experience in published data Liquid biopsy: qPCR, electrophoresis determines amount of ct-cf DNA RESULTS U87 implantation following immunotherapy established a measurable infiltrating lobar enhancing glioma in four pigs. Liquid biopsy demonstrated elevation of cf DNA following sonication of the peritumoral edges along 6 hours. Liposomes remain in the brain parenchyma for at least 2 weeks Higher microbubble concentration correlate with higher Liposomes signal CONCLUSIONS Opening the BBB via LIFUS in a Swine brain tumor model is feasible supported by liquid biopsy. LNPs remain in the brain parenchyma as potential carrier for targeted drug delivery. FUTURE Validate the efficacy of delivered RNAi / CRSPR loaded LNPs. Tumor core ablation using LIFUS is under investigation. Potential clinical trials as a new therapeutic modality for GBM.