Cavitation-induced release of liposomal chemotherapy in orthotopic murine pancreatic cancer models: A feasibility study

Targeted and triggered release of liposomal drug using ultrasound (US) induced cavitation represents a promising treatment modality to increase the therapeutic-toxicity ratio of encapsulated chemotherapy. Objectives: To study the feasibility and efficacy of a combination of focused US and liposomal doxorubicin (US-L-DOX) release in orthotopic murine models of pancreatic cancer. Material and methods: A confocal US setup was developed to generate US inertial cavitation delivery in a controlled and reproducible manner and designed for two distinct murine orthotopic pancreatic cancer models. Controlled cavitation at 1 MHz was applied within the tumors after L-DOX injection according to a preliminary pharmacokinetic study. Results: In vitro studies confirmed that L-DOX was cytostatic. In vivo pharmacokinetic study showed L-DOX peak tumor accumulation at 48h. Feasibility of L-DOX injection and US delivery was demonstrated in both murine models. In a nude mouse model, at W9 after implantation (W5 after treatment), US-L-DOX group (median [IQR] 51.43 mm(3) [35.1-871.95]) exhibited significantly lower tumor volumes than the sham group (216.28 [96.12-1202.92]), the US group (359.44 [131.48-1649.25]), and the L-DOX group (255.94 [84.09-943.72]), and a trend, although not statistically significant, to a lower volume than Gemcitabine group (90.48 [42.14-367.78]). Conclusion: This study demonstrates that inertial cavitation can be generated to increase the therapeutic effect of drug-carrying liposomes accumulated in the tumor. This approach is potentially an important step towards a therapeutic application of cavitation-induced drug delivery in pancreatic cancer. (C) 2019 Elsevier Masson SAS. All rights reserved.