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

Abstract

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. Cavitation is 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 doxorubicin (Dox) penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active versus passive drug diffusion). For both types, the pHIFU exposures which were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized Dox concentration by up to 4.5 fold compared to controls. Furthermore, normalized Dox concentration was associated with the cavitation metrics (p < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, i.e., Dox infusion 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 tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors.

Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy

“…Chevillet et al pulsed focused ultrasound-aided drug and gene delivery applications, with and without ultrasonographic (US) contrast agents (17)(18)(19). The latter is collectively referred to as histotripsy.…”

“…After subsequent blood draws at 30 minutes and 1 hour, the animal was recovered from anesthesia and returned to its cage. The animal was briefly reanesthetized for two subsequent blood draws (ie, at 3-hour and 24-hour time (18). To confirm consistent cavitation activity throughout exposure, broadband emissions that resulted from each focused ultrasound pulse were detected with a passive cavitation detector, and the signals were processed with a method similar to that in our previous studies to obtain the level of broadband noise emitted by cavitation bubbles (25).…”

Enhancement of High-Intensity Focused Ultrasound Heating by Short-Pulse Generated Cavitation

“…Cavitation bubbles can not only accelerate ultrasonic heating but make mechanical tissue treatment such as histotripsy possible. They can also induce chemical effects and enhance drug delivery, both of which are useful in sonodynamic therapy (SDT) [51,73,74]. The forced oscillation and collapse of cavitation bubbles in a trigger HIFU sequence is also effective for SDT [75,76].…”

Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines

“…In vitro and preclinical studies to validate US-and/or cavitation-mediated delivery have shown substantial improvements to the accumulation and distribution of small molecule, 6,7 antibody, 8 nanoparticle 9,10 and gene-and viralbased medicines. 11,12 Indeed, an optimized system which can achieve targeted, sustained cavitation was recently shown to provide up to 10,000-fold enhancement in the tumor infection achieved by an oncolytic vaccinia virus (VV).…”