PACM-11 LASER INTERSTITIAL THERMAL THERAPY ENABLES TARGETED INTRAPARENCHYMAL DELIVERY OF HEAT-SENSITIVE DRUGS WITH REAL-TIME SPATIAL MONITORING
Armin Tavakkoli, Beverly Petusseau, David Hunter, Katherine Onk, David Needham, Andrew Sloan, Linton EvansAbstract
Introduction
Laser Interstitial Thermal Therapy (LITT) is a minimally invasive technique that uses controlled hyperthermia to ablate tumor tissue. A recent phase II trial found that low-dose doxorubicin after LITT improved survival versus LITT alone, but systemic doxorubicin toxicities and poor CNS penetration limit clinical benefit.
Objective
We investigated Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), a thermosensitive formulation of doxorubicin, for targeted CNS chemotherapy during LITT. We hypothesized that predictable release of LTLD above 41.5 °C, coupled with MRI-based LITT thermography, would enable spatiotemporal monitoring and control of drug delivery, achieving high local concentrations while minimizing systemic exposure.
Methods
We induced U87 gliomas in immunosuppressed Yucatan minipigs and used a commercial LITT system to ablate the tumors following LTLD infusion (50 mg/m²). Animals were sacrificed immediately or at 7 days for drug release and neurotoxicity assays, respectively. Doxorubicin release was quantified by fluorometric & MALDI imaging, whereas tissue damage was assessed radiographically and histologically. To support clinical translation, we optimized macroscopic and microscopic intraoperative imaging systems for real-time visualization of doxorubicin release.
Results
Immediate ex-vivo fluorometric & MALDI assays demonstrated targeted doxorubicin release surrounding the zone of ablation following LITT + LTLD. There were no clinical signs of systemic or neurological toxicity during the 7-day monitoring period. No additional cerebral edema was noted on surveillance MRI following LITT + LTLD compared to LITT alone. The in-vivo imaging systems successfully visualized doxorubicin release at wide-field and cellular scales.
Conclusions
We demonstrate that LITT-mediated, heat-triggered release of doxorubicin from LTLD enables safe, targeted CNS drug delivery, overcoming the poor CNS penetration and systemic toxicity of conventional doxorubicin. Coupled with the established systemic safety of LTLD in non-CNS trials, these findings support rapid clinical translation. Ongoing pre-clinical studies in tumor models will refine thermal dosing to maximize drug release at both ablative and sub-ablative temperatures.