Abstract 2524: Lipid-based nanoparticles for the theranostic treatment of brain tumors using focused ultrasound

Abstract Glioblastoma is an extremely aggressive brain tumor and currently has limited effective treatment options, with a median survival of 14 months. This low survival is partially attributed to the blood-brain barrier (BBB), especially in early-stage glioblastoma. An emerging clinically approved technology to non-invasively and transiently open the BBB is focused ultrasound (FUS) in combination with microbubble cavitation. In this study, we formulated a dual-imageable drug-loaded lipid-based nanoparticle (ActNano) and tested their efficacy against U87-MG in vitro and in vivo (subcutaneous). In addition, we performed focused ultrasound (FUS) induced BBB opening to deliver ActNano into both healthy mice brains and mice bearing orthotopic brain tumors (U87-MG). ActNano uptake was determined and quantified in vivo and ex vivo using MRI and near-infrared fluorescence (NIRF) imaging, respectively. In addition, drug uptake enhancement following FUS BBB opening in orthotopic tumours was also determined using HPLC (SN-38) and ICP MS (carboplatin). ActNano was loaded with SN-38 (1.11 ± 0.08 mg/ml) and carboplatin (0.84 ± 0.14 mg/ml). The ability of ActNano to supress tumor growth was investigated with single treatments against a U87-MG subcutaneous flank xenograft model (10 mg/kg SN-38 & carboplatin). FUS-induced BBB opening was performed in mice (peak-negative pressure = 320 kPa, number of cycles = 500, pulse repetition frequency = 5 Hz, number of pulses = 600). SonoVue microbubbles (2 ml/kg) and ActNano (8 ml/kg, 10 mg/kg SN-38) were administered intravenously during FUS treatment. T1-weighted MRI was performed in a 9.4-T MRI 4 hours after BBB opening, to allow time for ActNano to accumulate in the brain/tumors for optimal T1 contrast. NIRF imaging, H&E staining and drug quantification was performed on perfused and excised brains after the final time point, to confirm successful liposome delivery into the sonicated volume. ActNano was successfully formulated with both MRI and NIRF contrast. ActNano (10 mg/kg SN-38) treatment caused an increase in survival of mice with xenograft tumours when administered alone and a significant increase in survival and tumor uptake when combined with FUS. MRI and NIRF imaging confirmed localized increased uptake of ActNano where FUS-induced BBB opening was performed compared to the contralateral control side. Quantification of Gd, carboplatin and SN-38 confirmed a significant increase in drug concentration in the tumor following BBB opening. These results suggest that MRI/NIRF-tagged drug loaded lipid-nanoparticles are suitable drug carriers for the treatment of glioblastoma in combination with FUS-induced BBB opening. Future work includes evaluation of the survival benefit of ActNano in tumor-bearing mice. Citation Format: Paul Cressey, Chris Payne, Amelia Claxton, Benedetta Arno, Christopher Ireson, Maral Amrahli, David Thurston, Antonios Pouliopoulos, Maya Thanou. Lipid-based nanoparticles for the theranostic treatment of brain tumors using focused ultrasound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2524.