Tumor suppression effect of ultrasound-sensitive nanoparticles with focused ultrasound in a pancreas cancer xenograft model.

BACKGROUND: We investigated the tumor suppression effect of an ultrasound-sensitive doxorubicin-loaded liposome-based nanoparticle, IMP301, to enhance the synergistic effect with focused ultrasound (FUS) in an animal model of pancreatic cancer. METHODS: Thirty nude mice with xenografts of PANC-1 human pancreatic cancer cells were randomly and prospectively allocated to 6 different groups (5 per group) each for Study-1 (dose-response test) and Study-2 (synergistic effect test). Study-1 consisted of control, gemcitabine, Doxil with FUS, and three different doses of IMP301 (2, 4, 6 mg/kg) with FUS groups. Study-2 consisted of control, FUS only, gemcitabine, Doxil with FUS, and IMP301 (4 mg/kg) with or without FUS groups. Differences in tumor volume and growth rate were evaluated by one-way ANOVA and Student-Newman-Keuls test. RESULTS: In Study-1, 4 mg/kg or greater IMP301 with FUS groups showed lower tumor growth rates of 14 ± 4 mm3/day (mean ± standard deviation) or less, compared to the control, gemcitabine, and Doxil with FUS groups with rates exceeding 28 ± 5 (p < 0.050). The addition of FUS in Study-2 decreased the tumor growth rate in the IMP301-treated groups from 36 ± 17 to 9 ± 6, which was lower than the control, FUS only, gemcitabine, and Doxil with FUS groups (p < 0.050). CONCLUSIONS: IMP301 combined with FUS exhibited higher tumor growth suppression compared to the use of a conventional drug alone or the combination with FUS. The present study showed the potential of IMP301 to enhance the synergistic effect with FUS for the treatment of pancreatic cancer. RELEVANCE STATEMENT: This article aims to evaluate the synergistic effect of FUS and ultrasound-responsive liposomal drug in tumor growth suppression by using xenograft mouse model of pancreatic ductal adenocarcinoma. FUS-induced ultrasound-sensitive drug release may be a potential noninvasive repeatable treatment option for patients with locally advanced or unresectable pancreatic cancer. KEY POINTS: • Modification of conventional drugs combined with FUS would maximize tumor suppression. • IMP301 with FUS had higher tumor suppression effect compared to conventional chemotherapy. • This image-guided drug delivery would enhance therapeutic effects of systemic chemotherapy.

Synergistic Effects of Pulsed Focused Ultrasound and a Doxorubicin-Loaded Microparticle-Microbubble Complex in a Pancreatic Cancer Xenograft Mouse Model.

The synergistic effects of a doxorubicin (Dox)-loaded microparticle-microbubble complex (DMMC) and focused ultrasound (FUS) with a short duty cycle (5%) were evaluated in a pancreatic cancer xenograft model established by inoculating immunodeficient mice with CFPAC-1 cells. The efficacy of the DMMC with FUS (study 1), the effect of conjugating the particles as opposed to mixing them (study 2) and the levels of tumor apoptosis and intracellular Dox (study 3) were evaluated. The DMMC with FUS exhibited the lowest tumor growth rate (30.8 mm3/wk) and the highest intracellular Dox uptake (8.8%) and tumor cell apoptosis rate (58.7%) among all treatments. DMMC had a significantly lower growth rate than the mixture of Dox-loaded microparticles and microbubbles (44.2 mm3/wk, p < 0.01) when they were combined with FUS. In conclusion, DMMC with short-duty-cycle FUS holds promise for tumor growth suppression, which may be attributed to high intracellular Dox uptake.