Image-Guided Treatment of Primary Liver Cancer in Mice Leads to Vascular Disruption and Increased Drug Penetration

Abstract

Despite advances in interventional procedures and chemotherapeutic drug development, hepatocellular carcinoma (HCC) is still the fourth leading cause of cancer-related deaths worldwide with a <30% 5-year survival rate. This poor prognosis can be attributed to the fact that HCC most commonly occurs in patients with pre-existing liver conditions, rendering many treatment options too aggressive. Patient survival rates could be improved by a more targeted approach. Ultrasound-induced cavitation can provide a means for overcoming traditional barriers defining drug uptake. The goal of this work was to evaluate preclinical efficacy of image-guided, cavitation-enabled drug delivery with a clinical ultrasound scanner. To this end, ultrasound conditions (unique from those used in imaging) were designed and implemented on a Philips EPIQ and S5-1 phased array probe to produced focused ultrasound for cavitation treatment. Sonovue ® microbubbles which are clinically approved as an ultrasound contrast agent were used for both imaging and cavitation treatment. A genetically engineered mouse model was bred and used as a physiologically relevant preclinical analog to human HCC. It was observed that imageguided and targeted microbubble cavitation resulted in selective disruption of the tumor blood flow and enhanced doxorubicin uptake and penetration. Histology results indicate that no gross morphological damage occurred as a result of this process. The combination of these effects may be exploited to treat HCC and other challenging malignancies and could be implemented with currently available ultrasound scanners and reagents.

Effects of contrast-enhanced ultrasound treatment on neoadjuvant chemotherapy in breast cancer

“…Additionally, carboplatin was mostly detected close to larger and more mature vessels, which might be less affected by oscillating or collapsing microbubbles. This hypothesis is also supported by other studies in hepatocellular carcinoma 34 and the brain 38 . Thus, the smaller disrupted vessels may have only contributed to a minor extent to the overall carboplatin accumulation, whereas drugs that accumulate in the considerably large extravascular space of larger vessels can still slowly diffuse through the stromal compartment towards necrotic areas and tumor cells might be the dominant delivery mechanism.…”

“…Next to the frequency and pressure that are applied on the tumor, pulse length, duration and duty cycle also influence the behavior of microbubbles resulting in different biological effects on the tumor tissue. Thus, for a systematic discussion despite the highly variable settings, we roughly categorize the experiments in approaches using sonopermeation to enhance drug delivery in tumors without damaging the vasculature 2 , 3 , 8 , 30 , 31 , 35 and strategies that focus on improving retention of drugs by inducing a vascular breakdown 32 - 34 .…”

“…The alternative approach to induce a vascular breakdown to trap chemotherapeutics was successfully demonstrated in murine breast 32 , prostate 33 , and liver 34 tumors. All of these studies were performed at high acoustic pressures of 1.65-3 MPa, where destruction of microbubbles is assumed.…”

“…All of these studies were performed at high acoustic pressures of 1.65-3 MPa, where destruction of microbubbles is assumed. It could be shown that tumor perfusion was reduced 32 - 34 and that the overall amount of chemotherapy accumulation in tumors was enhanced 34 .…”

“…Additionally, in mice, tumor blood vessels are approximately ten times smaller than those of human tumors. In smaller vessels, the effects of high MI CDUS on the endothelium are expected to be much stronger, as the collapse of microbubbles occurs closer to the vessel wall 34 . This hypothesis may also explain the results of Dimcevski et al on pancreatic carcinomas that, like our murine tumors, are known to have more and smaller vessels than human breast carcinomas 41 .…”