DDEL-02. Laser Interstitial Thermal Therapy for Targeted CNS Delivery of Chemotherapy: Pre-Clinical Results and Planned Clinical Trial

Abstract INTRODUCTION Laser Interstitial Thermal Therapy (LITT) is a minimally invasive modality that employs controlled hyperthermia to ablate tumor tissue while transiently disrupting the blood-brain barrier. In a recent phase II trial, low dose doxorubicin infusions following LITT improved survival compared to LITT alone; however, the clinical benefit remains compromised by the systemic toxicities inherent to doxorubicin. Here we utilize LITT and Thermodox, a heat-sensitive liposomal formulation encapsulating doxorubicin, to deliver targeted chemotherapy to the brain. At normal body temperatures, the liposome retains doxorubicin, while above 41.5°C during LITT, it rapidly releases high local doses, thus minimizing systemic exposure. METHODS Using a commercial LITT system, laser fibers were inserted in bilateral frontal lobes of healthy Yucatan mini pigs under image guidance. One hemisphere received LITT alone, while the contralateral side underwent LITT concurrent with Thermodox infusion (50 mg/m2). Animals were sacrificed immediately or at 7 days to assess intraparenchymal drug release and delayed neurotoxicity. Doxorubicin release was evaluated via fluorometric imaging, and histological analysis assessed tissue damage. RESULTS Immediate fluorometric assays demonstrated targeted intraparenchymal doxorubicin release surrounding the zone of ablation in the hemisphere that received LITT + Thermodox. There were no clinical signs of systemic or neurotoxicity during the 7-day monitoring period. No additional cerebral edema was noted on surveillance imaging in the hemisphere that received LITT + Thermodox compared to the hemisphere with LITT alone. DISCUSSION Our findings demonstrate that LITT-mediated, heat-triggered release of doxorubicin from Thermodox enables safe, targeted CNS drug delivery, overcoming the poor CNS penetration and systemic toxicity of conventional doxorubicin. These promising results, together with the established systemic safety of Thermodox in non-CNS trials, support rapid clinical translation. Future studies will refine thermal dosing to maximize drug release using both ablative and sub-ablative temperatures.