Local drug delivery of irinotecan with phosphatidyldiglycerol-based thermosensitive liposomes reduces systemic exposure and increases therapeutic efficacy compared to systemic drug and Onivyde®.

Thermosensitive Liposomes (TSL) represent a promising tool for targeted drug delivery in combination with local hyperthermia (HT). Irinotecan (CPT-11) is approved for the treatment of various solid tumors but is rapidly metabolized after i.v. injection impairing intratumoral uptake. CPT-11 was therefore encapsulated in phosphatidyldiglycerol-based TSL (DPPG2-TSL-CPT-11) to extend its blood stability and to intravascularly release CPT-11 in the tumor. In vitro, DPPG2-TSL-CPT-11 demonstrated efficient drug retention at ≤ 39 °C and fast CPT-11 release at > 40 °C in presence of serum. DPPG2-TSL-CPT-11 showed a CPT-11 plasma half-life of 1.57 h in rats compared to 0.71 h for non-liposomal CPT-11 and 18.70 h for PEGylated non-thermosensitive CPT-11 (Onivyde®), respectively. Systemic exposure of the active metabolite SN-38 was reduced by DPPG2-TSL-CPT-11 compared to Onivyde®. One hour of HT treatment in combination with DPPG2-TSL-DOX delivered 24-fold and 36-fold more CPT-11 into tumors than Onivyde® and non-liposomal CPT-11, respectively. DPPG2-TSL-DOX and Onivyde® showed a comparable overall survival, superior (p < 0.005) to non-liposomal CPT-11. DPPG2-TSL-DOX was the only formulation that led to a tumor size reduction. In vivo data indicated an advantage of the intravascular CPT-11 release over systemic drug application or passive tumor accumulation of liposomes.