Ultrasound cavitation therapy: inducing tumor drug delivery and blood flow changes with clinical ultrasound tools

Hepatocellular carcinoma (HCC), the fourth leading cause of cancer-related deaths, remains difficult to treat due to underlying liver disease, abnormal tumor vasculature, elevated interstitial fluid pressure (IFP), and immune suppression. We developed a theranostic approach using ultrasound cavitation with a clinical scanner and FDA-approved microbubbles to enhance vascular permeability and drug delivery in HCC. Acute experiments were performed in a subcutaneous HCC mouse model using a modified Philips EPIQ scanner and S5-1 phased-array probe under two conditions: moderate (1.6 MPa) and high (2.2 MPa) peak negative pressures. Contrast-enhanced ultrasound was acquired before, during, and after treatment, and vascular changes were quantified using a novel maximum intensity projection time area curve (MIP-TAC) analysis. Passive cavitation detection monitored microbubble activity. Doxorubicin extravasation, IFP (with a pressure catheter), and histology were assessed. Both ultrasound conditions induced transient tumor perfusion loss and reduced IFP without significant tissue damage or hemorrhage. The high-pressure treatment caused the greatest perfusion loss, whereas enhanced doxorubicin delivery occurred under moderate pressure. This result is likely due to excessive tumor perfusion loss in the high-pressure group, impeding further drug transport. These results demonstrate the feasibility of therapeutic cavitation with longer than previously evaluated acoustic pulses (1000 cycles) on a clinical scanner and clinically-approved microbubbles in HCC. Moderate-pressure cavitation maximized drug extravasation, underscoring the need to balance transient tumor perfusion loss with drug delivery. This clinically translatable strategy has potential to improve therapeutic outcomes in human HCC.