Alpha-Particle Emitter Radiopharmaceutical Therapy for Liver Cancer

点击翻译按钮获取中文摘要

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide, as well as the second most frequent cause of cancer death. Furthermore, the liver is also the most common site for metastatic cancer. Most patients with advanced disease are offered only non- surgical palliative treatment options. Hepatic tumors derived their blood supply from the hepatic artery whereas normal liver tissue’s blood supply is mainly sourced from the portal vein. Intra-arterial therapies, such as chemoembolization and radioembolization, exploit the hepatic tumors’ blood supply via the hepatic artery to selectively deliver contrast and therapies. Lipiodol is an FDA approved radio-opaque contrast agent used in liver tumor imaging during intra-arterial therapies. Lipiodol accumulates and remains in the tumor while clearing out of normal liver tissue when injected via the hepatic artery, providing a vehicle to deliver therapeutic agents, such as, chemotherapeutics and -emitting radionuclides (188Re and 131I) to liver tumors, but these treatments have limitations, urging the need for development of new therapies. Alpha-emitting radiopharmaceutical therapy (RPT) is highly potent, causing largely irreparable DNA damage to targeted cells. Due to the short range of alpha particles, RPT minimizes damage to nearby healthy cells. The high-energy transfer of alpha particles makes RPT impervious to most resistance mechanisms including pathway redundancy and oxygenation status, a desirable feature for treatment of liver tumors. Lipiodol has detailed information on its pharmacology, formulation and toxicity, due to its FDA-approved status, and its repurposing for RPT can build upon information from previous studies for FDA approval to help rapidly translate a novel RPT agent-Lipiodol emulsion to the clinic. The proposed work is focused on evaluating targeted RPT emulsions for unresectable primary liver cancer as compared to standard of care treatment (Aim 1). A selected RPT emulsion will be tested in a technical rabbit VX2 liver cancer model, allowing us to evaluate these agents’ distribution via the hepatic artery (Aim 2). Finally, the proposed work is focused on the development of a companion imaging agent or the expansion of imaging protocols to allow for a single theranostic agent (Aims 1-3). The successful completion of the proposed research is that an RPT agent-Lipiodol emulsion, based on current FDA approved Lipiodol emulsions, can be repurposed for quick development and evaluation as a therapeutic or theranostic agent for primary and metastatic liver cancer.