Project Summary/Abstract This proposal focuses on the development of novel liver cancer-targeting small molecules for the treatment of liver cancer. To accomplish this goal, we will create the first radioiodinated variants of indocyanine green (ICG), an FDA-approved fluorescent molecule that found broad use as a fluorescence-guided surgery (FGS) agent. ICG has shown selective uptake in several types of liver cancer, including hepatocellular carcinoma (HCC) and hepatoblastoma (HB). Our prior studies have defined the mechanism of ICG uptake to be dependent on the solute carrier transporter, OATP13B, which is overexpressed on the membrane of hepatocytes and hepatocyte-derived tumors. With these aspects in mind, this proposal aims to repurpose ICG as a therapeutic agent to treat liver cancer. We will accomplish this goal by attaching ICG to the beta-emitting radioisotope 131I and deliver cytotoxic beta particles to the cancerous tissue. This project will uniquely combine the fluorophore synthesis expertise of Dr. Schnermann’s group and the radiolabeling and liver cancer expertise of Dr. Escorcia’s group to develop an innovative small molecule therapeutic agent. The aims in this proposal are as follows: (1) develop novel iodine-bearing ICG conjugates and test their in vitro uptake in liver cancer cell models, (2) radiolabel conjugates with 125I (imaging isotope) for in vivo biodistribution studies in mice bearing liver tumors, and (3) radiolabel conjugates with 131I (therapeutic isotope) and perform efficacy studies in mice bearing liver tumors. We expect that this proposal will lead to a novel therapeutic strategy for the treatment of liver cancer, setting the stage for a new approach to address patients suffering from hepatocellular and hepatoblastoma carcinomas. The goal of this fellowship is for the PI to develop a new skillset and knowledge in the areas of organic chemistry, in vivo imaging, radiolabeling, and therapeutic drug design. These research goals will be accomplished through the outlined proposal. Additionally, this fellowship offers opportunities for mentoring, scientific collaborations and discussions, and networking. Through the resources provide at the National Cancer Institute (NCI), the Chemical Biology Laboratory (CBL), and the Molecular Imaging Branch (MIB), I will have the opportunity to mentor post-baccalaureate students, participate in scientific discussions through the CBL’s annual retreat and Molecular Discovery Seminar Series, and improve my soft laboratory management and teaching skills through courses like the “Becoming a Resilient Scientist” and “Management Boot Camp.” These aspects will help me achieve my overall career goal of becoming a professor and running an independent research group.