High intensity focused ultrasound-induced bubbles stimulate the release of nucleic acid cancer biomarkers

Abstract

Recently, several nucleic acid cancer biomarkers, e.g., microRNA and mutant DNA, have been identified and shown promise for improving cancer diagnostics. However, the abundance of these biomarker classes in the circulation is low, impeding reliable detection and adoption into clinical practice. Here, the ability of HIFU-induced bubbles to stimulate release of cancer-associated microRNAs by tissue fractionation or permeabilization was investigated in a heterotopic syngeneic rat prostate cancer model. A 1.5 MHz HIFU transducer was used to either mechanically fractionate subcutaneous tumor with boiling histotripsy (BH) (~20 kW/cm2, 10 ms pulses, and duty factor 0.01) or to permeabilize tumor tissue with inertial cavitation activity (p- = 16 MPa, 1 ms pulses, duty factor 0.001). Blood was collected immediately prior to and serially up to 24-hours after treatments. Plasma concentrations of microRNAs were measured by quantitative RT-PCR. Both exposures resulted in a rapid (within 15 min), short (≤3 h) and dramatic (over ten-fold) increase in relative plasma concentrations of tumor-associated microRNAs, Histologic examination of excised tumor confirmed complete fractionation of targeted tumor by BH and localized areas of intraparenchymal hemorrhage and tissue disruption by cavitation-based treatment. These data suggest a clinically useful application of HIFU-induced bubbles for non-invasive molecular biopsy. [Grant support: NIH 1K01EB015745, R01CA154451, R01DK085714.]