Abstract
Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. Many patients are not eligible for curative therapies, such as surgical resection of the tumor or a liver transplant. Transarterial embolization is one therapy clinically used in these cases; however, this requires a long procedure and careful placement of an intraarterial catheter. Gas embolization has been proposed as a fast, easily administered, more spatially selective, and less invasive alternative. Here, we demonstrate the feasibility and efficacy of using acoustic droplet vaporization to noninvasively generate gas emboli within vasculature. Intravital microscopy experiments were performed using the rat cremaster muscle to visually observe the formation of occlusions. Large gas emboli were produced within the vasculature in the rat cremaster, effectively occluding blood flow. Following these experiments, the therapeutic efficacy of gas embolization was investigated in an ectopic xenograft model of hepatocellular carcinoma in mice. The treatment group exhibited a significantly lower final tumor volume (ANOVA, p = 0.008) and growth rate than control groups – tumor growth was completely halted. Additionally, treated tumors exhibited significant necrosis as determined by histological analysis. To our knowledge, this study is the first to demonstrate the therapeutic efficacy of gas embolotherapy in a tumor model.
Highlights
Liver cancer is the third most common cause of cancer-related death globally; in addition to the high mortality rate, incidence rates are continuing to rise[1,2]
Gas embolotherapy (GE) has been proposed as a less invasive, highly spatially selective embolization method, with the intention of circumventing the issues presented by transarterial embolization (TAE) and TACE10,11
GE utilizes focused ultrasound (FUS) and a phenomenon known as acoustic droplet vaporization (ADV) to produce gas emboli directly within a tumor’s vasculature
Summary
Liver cancer is the third most common cause of cancer-related death globally; in addition to the high mortality rate, incidence rates are continuing to rise[1,2]. TACE is the combination of a technique known as bland transarterial embolization (TAE), which utilizes an intraarterial catheter to deposit an embolizing agent directly into the vasculature of a tumor, with local delivery of a chemotherapeutic agent The intent of these therapies is to induce targeted ischemia and subsequent tumor necrosis due to lack of blood flow. Droplets can be produced with a mean diameter of 1–3 μm, which enables them to flow freely through capillaries; upon vaporization, the droplets undergo a 125-fold volumetric expansion, rendering them large enough to embolize small vessels[20] They can be targeted to specific cell receptors (e.g., αvβ3) to increase their local concentration, thereby increasing the likelihood of forming a large embolus during insonation, and to increase the stability of a developed occlusion by increasing its resistance to dislodging. A complete cessation of tumor growth was observed, thereby rendering this the first study, to our knowledge, to demonstrate the therapeutic efficacy of GE in a tumor model
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