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 image-guided 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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the fourth leading cause of cancer-related deaths (El-Serag and Rudolph, 2007; Global Burden of Disease Liver Cancer Collaboration et al, 2017)
Enhanced drug penetration and immediate tumor vascular shutdown were observed in animals treated with focused ultrasound and microbubbles compared to those receiving free drug
We observed that microbubble cavitation at moderate ultrasound pressures between 2 and 3 MPa exhibits a high degree of anti-vascular action selectively within the tumors of mice. This was first seen qualitatively, in which it was observed that there was a clear reduction of contrast in the tumor post-USCTx that was not observed in healthy tissue. When this was analyzed quantitatively using Time intensity curve (TIC) analysis, we found a significant increase in contrast rise time (RT) and a significant decrease in peak intensity (PI) in the tumor cores of USCTx mice
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the fourth leading cause of cancer-related deaths (El-Serag and Rudolph, 2007; Global Burden of Disease Liver Cancer Collaboration et al, 2017). Emerging therapies have focused on more precise tumor targeting while sparing nontumor liver (Mavros et al, 2014; Liang et al, 2016) One such approach is the use of vascular disruption agents (VDAs) to restrict blood flow to the tumor (Liu et al, 2017). It has been shown that cavitation-induced vascular disruption can be selectively applied to the tumor microvascular network, while avoiding damage to surrounding tissue (Wang et al, 2015). Several studies have shown significant blood flow restriction to tumor neovessels with cavitating microbubbles at modest ultrasound pressures (1–5 MPa) with minimal non-tumorous tissue damage. Liu et al observed complete cessation of tumor blood flow after therapy with 4.8 MPa that could last as long as 24 h, which resulted in widespread necrosis to the tumor region (Liu et al, 2012)
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