DIPG-43. PROLONGED CONVECTION-ENHANCED DELIVERY IN THE PONS WITH SN-38 LOADED NANOPARTICLES AND IRINOTECAN

INTRODUCTION: Inadequate drug delivery due to an intact blood-brain barrier (BBB) could explain part of the resistance to chemotherapeutic agents in diffuse intrinsic pontine glioma (DIPG). Convection-enhanced delivery (CED) is an alternative mode of local delivery and irinotecan, and its active compound SN‐38, are potentially effective agents. In this study we aim to perform prolonged CED in the pontine area of rats using irinotecan and newly designed SN‐38 loaded polymer nanoparticles (NPs). METHODS: Efficacy of irinotecan and SN‐38 against patient-derived HSJD-DIPG-007 cells was determined in vitro. Stability and release of SN‐38 from the NPs was tested with a dialysis chamber. Prolonged CED (200 μL in 24 hours using an Alzet Osmotic pump) was performed in naïve rats, and maximum tolerated dose (MTD) was determined by neurological follow-up using Rota-rod testing. Orthotopic HSJD-DIPG-007 xenografts were treated with the MTD of SN-38NPs, irinotecan, or vehicle (NaCl 0.9%). RESULTS: IC50 of SN‐38 against HSJD‐DIPG-007 cells was in the nanomolar range. IC50 of irinotecan was 1000 fold higher. Rota-rod scores in rats with HSJD-DIPG-007 tumors declined significantly before weight loss could be objectified. Stability of SN‐38 and release from NPs was adequate for the aimed experiment. Prolonged CED with SN-38 and irinotecan in the pontine area was tolerated at 1.2 μg (~8 μg/kg) and 0.08 mg (~5 mg/kg), respectively. These dosages did not show efficacy against HSJD-DIPG-007 tumors. DISCUSSION: This study shows that prolonged CED in the rat pons using potent chemotherapeutic agents is feasible and safe; it validates stability of newly‐designed NPs containing SN38 in the used vehicle, and it shows Rota-rod testing to be an effective tool for studying transitory functional changes related to toxicity in the pons and cerebellum of rats. The lack of efficacy in treating HSJD-DIPG-007 tumors identifies important new starting points for further research.