Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.

Pancreatic cancer is characterized by extensive stromal desmoplasia, which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity— cavitation. Cavitationis also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicinpenetration using ultrasound-induced cavitationin a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitationin pancreatic tumors, pulsed high-intensity focused ultrasound(pHIFU) was used either during or before doxorubicinadministration to elucidate the mechanisms of enhanced drug delivery (active vs. passive drug diffusion). For both types, the pHIFU exposures that were associated with high cavitationactivity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized doxorubicinconcentration by up to 4.5-fold compared with controls. Furthermore, normalized doxorubicinconcentration was associated with the cavitationmetrics ( P < 0.01), indicating that high and sustained cavitationresults in increased chemotherapy penetration. No significant difference between the outcomes of the two types, that is, doxorubicininfusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumorswhen resulting in high and sustained cavitationcan efficiently enhance chemotherapy delivery to pancreatic tumors. Cancer Res; 75(18); 3738–46. ©2015 AACR .