R01CA257558

Drug Eluting Injectable Biomaterials for Next Generation Chemoembolization - 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 of 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 (a-PD1, a-PDL1, a-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.

Mayo Clinic Arizona

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Scottsdale, Arizona 852595404 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 367% from $680,198 to $3,173,416.