Comparison of mechanical and thermal effects of focused ultrasound on drug delivery efficiency and toxicity for pancreatic cancer treatment.

Abstract

Pancreatic cancer remains one of the most lethal malignancies due to low response to chemotherapy. Focused ultrasound (FUS) has emerged as a promising strategy for enhancing tumor-specific drug delivery. However, chemotherapy in combination with FUS has still been limited by the unique tumor environment of pancreatic cancer. Thus, FUS application to clinical trials has been sufficiently considerable by several side effect. Therefore, many preclinical and clinical trials have been conducted to accelerate clinical application. This study demonstrates the effects of FUS-induced mechanical and thermal energies on drug delivery efficiency and safety in a PANC-1 xenografted BALB/c mouse model. Reflected acoustic pressure from tumors were analyzed to quantify cavitation effects, and enhancement of drug delivery investigated by fluorescence imaging. Anti-tumor efficacy with FUS exposure was compared using FOLFIRINOX. H&E, TUNEL assay and serum biochemistry were evaluated for the comparison of toxicity. The results demonstrated that increase of cavitation dose was dominantly dependent on the intensity, not duty cycle inducing thermal effect for the enhancement of drug accumulation to tumor. Mechanical effects by 2.0 kW/cm²-I_SPPA and 1 % duty cycle enhanced drug accumulation to tumor by 1.57-fold without tissue damage. Also, FOLFIRINOX combined with mechanical effects achieved superior antitumor efficacy, with 83.0 % tumor inhibition compared to 48.0 % with FOLFIRINOX alone. And mechanical effect was validated as a non-toxic energy for tumor treatment by H&E, TUNEL assay and serum biochemistry analysis. In conclusion, FUS-mediated mechanical effects can be one of candidate as a safe and effective strategy for tumor-specific drug delivery.