Treatment of malignant gliomas with nanoliposomal CPT-11 following both systemic administration or convection-enhanced delivery

1489 We have developed a stable nanoliposomal formulation of the topoisomerase I inhibitor CPT-11 / irinotecan (nLs-CPT-11) for treatment of brain tumors. Two modes of administration were evaluated in rat intracranial U87 xenografts: bolus i.v. injection (systemic) and convection-enhanced delivery (CED) (local-regional). Following i.v. injection, tissue PK of free CPT-11 or nLs-CPT-11 (both at 50 mg/ml) reveal similar brain tissue Cmax of 10.2 μg/g and 11.8 μg/g respectively. However, tumor AUC for nLs-CPT-11 was 13-fold greater than free CPT-11 demonstrating extended tumor exposure. Additionally, nLs-CPT-11 showed significantly higher tumor t 1/2 and MRT (5.6-fold and 5.5-fold greater, respectively) than free CPT-11. Tumor selectivity was demonstrated for free CPT-11 and nLs-CPT-11, as the maximum drug concentration was >12 fold higher in the tumor than surrounding healthy striatum for both formulations following i.v. injection. CED of nLs-CPT-11 was associated with dose-dependent clearance in healthy rat brains, with doses of 60 μg, 0.8 mg, and 1.6 mg resulting in tissue t 1/2 of 6.7, 10.7, and 19.7 d, respectively. CED of 0.8 mg nLs-CPT-11 resulted in tumor t 1/2 of 43 d indicating even greater retention in tumors. At equivalent CED doses of 60 μg, nLs-CPT-11 increased healthy brain tissue AUC by 25-fold and tissue t 1/2 by 22-fold over free CPT-11. MTD for CED of free CPT-11 was 60 μg while no MTD was reached with nLs-CPT-11 at the highest tested dose of 1.6 mg. Preliminary efficacy data following i.v. treatment with nLs-CPT-11 was collected in the intracranial U87 tumor model. 50 mg/kg of nLs-CPT-11 administered on days 5, 8, 11, and 14 post-tumor implantation resulted in a 66 d median survival, and 3 of 6 rats surviving until study end at day 100. Rats in the control group all reach terminal morbidity at 19-22 d (median = 20 d, p = 100 d) as compared to CED of control liposomes (19.5 d, p =