SURG-05. Evaluating liposomal topotecan for use in improving drug penetration within brain parenchyma for pediatric brain tumors

Background The permeability of drugs across the blood-brain barrier, a microvascular unit that selectively regulates entry into the brain, is one of the greatest challenges in the treatment of pediatric brain tumors. Low-intensity focused ultrasound (LIFU) is a non-invasive and acoustic method that delivers energy pulses to a spatial coordinate to transiently open the blood-brain barrier (BBB). The application of LIFU-mediated blood-brain barrier (BBB) disruption results in increased drug accumulation and immune activation in the brain. Results In this study, we employ topotecan encapsulated within sonosensitive liposomes. These specialized liposomes release topotecan upon exposure to the targeted acoustic energy of LIFU, enabling precise drug accumulation within the tumor in combination with targeted BBB opening. Unlike the standardized DSPC, cholesterol, and PEG-DSPE ratios or the hydrophilic polymer-modified lipid mixture in other topotecan liposomes, our formulation mimics the first FDA approved liposomal formulation of the chemotherapeutic doxorubicin. The half-maximal inhibitory concentrations of free and liposomal topotecan in the pediatric glioma cell line, STN10049, at 72 hours are 0.12μM and 0.60μM, respectively. In-situ brain perfusions were performed in mice using physiological buffers with liposomal or free topotecan in order to determine the unidirectional uptake of topotecan. Liposomal topotecan did not have linear uptake at the same time points of free topotecan, therefore, the unidirectional uptake coefficient (Kin) was not determined. The Kin of free topotecan is 4.9 ± 1.2x10-4 mL/s/g. In a preliminary mouse study, we observe increased topotecan and texas red dye within the LIFU-targeted regions of STN10049 intracranial tumors. Further analyses are being conducted to determine the pharmacodynamic effect of the increased topotecan delivery. Conclusion The combination of LIFU and liposomal release of topotecan in orthotopic murine models offers a promising avenue for enhancing pediatric brain tumor treatment.