Abstract Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a major worldwide public health concern because it is often detected at advanced stages where treatment options are limited. According to the World Health Organization, each year there are ~750,000 new HCC cases resulting in 700,000 deaths worldwide. While historically systemic chemotherapy has been the cornerstone to cancer treatment, inability to achieve uniform drug delivery to tumors, collateral toxicity to the non-cancerous liver and systemic side-effects have limited progress in the development of novel therapies for liver cancer. Recently, novel immunotherapeutic agents (immune checkpoint inhibitors (ICI), CAR-T cells, oncolytic virus) have been developed, but there are still limitations to their use due to systemic side effects and difficulty to deliver to solid tumors. Although transcatheter arterial chemoembolization (TACE), a procedure performed using an X-ray guided catheter to deliver chemotherapy coupled to embolization beads into the blood vessels that perfuse the liver tumor has shown success in liver cancer management, the embolization efficiency is relatively low as the beads cannot be readily delivered into downstream microvasculature to achieve uniform ischemia and chemotherapy delivery. Here we propose a transformative technology that uses a catheter-based locoregional approach to deliver X-ray visible bioengineered biomaterial, i.e. next-generation TACE, to induce a more efficient ischemic cell death within the tumor microvasculature coupled with efficient chemo- and immunotherapy delivery. We aim to combine TACE with both chemo- and immuno-therapeutics (e.g. ICIs) in order to enhance the anti-tumor immune response. Maintaining and even enhancing the inflammatory response induced after chemotherapy may potentially yield improved tumor regression assisted by localized ICI delivery. To achieve this goal we will mix doxorubicin (DOX) and / ICI (α-PD1, α-PDL1, α-CTLA-4) within an injectable shear-thinning hydrogel (STH) to enhance tumor ablation. We hypothesize that STH, a semi-solid gel like embolic material, which is composed of gelatin and nanosilicate, will achieve more efficient endovascular embolization reaching vessels as small as 50 microns than the current TACE beads. Simultaneously, DOX/ICI delivery will be used to locally ablate the liver cancer cells. Our preliminary data demonstrates exciting results showing our ability to synthesize and deliver STHs using catheters, to release drugs controllably from STHs, as well as in vitro and rabbit liver cancer models. In Aim 1, we will optimize STH compositions for effective endovascular chemoembolization. In Aim 2, we will develop the novel drug-eluting STH (DESTH) for endovascular Immuno-chemoembolization. In Aim 3 we will evaluate the in vivo performance of the DESTH.

Narrative The 5-year survival rate of liver cancer patients is as low as 9.9% in the United States and 6.2% in Europe. Nearly 2 billion people worldwide infected with hepatic viral diseases are at risk for developing liver cancer and dying owing to limited therapeutic options. While historically systemic chemotherapy has been the cornerstone to cancer treatment, inability to achieve uniform drug delivery to tumors, collateral toxicity to non- cancerous liver and systemic side-effects have limited progress in the development of novel therapies for liver cancer. We propose a transformative platform technology that uses a catheter based locoregional approach to deliver X-ray visible bioengineered biomaterial, i.e. next generation TACE, to induce a more efficient ischemic cell death within the tumor microvasculature that can be coupled with chemo- and immunotherapy. We believe that our approach will prevent progression of cancer providing time to bridge more patients to the curative liver transplantation and extend lives.