Hepatocellular carcinoma (HCC) is the most common primary liver cancer that represents the second most
common cause of cancer-related death worldwide. In addition, the liver the most common site for metastatic
cancer. Transarterial chemo- or radio-embolization (TACE/TARE) for unresectable HCC exploits the hepatic
tumors’ blood supply via the hepatic artery to selectively deliver the embolic agents and therapeutics into
targeted region of the liver. However, these treatments are largely palliative and direct visualization of the
delivery after contrast washout is not possible. Thus, new theranostic modalities are urgently needed. Alpha-
emitting radiopharmaceutical therapy (aRPT) is emerging as a highly potent treatment that effectively targets
single cells, minimal residual disease, and micrometastatic lesions to eradicate cancer cells that exhibit
resistance to conventional treatment. To address diffusion-limited penetration depths of aRPT that may result
in partial tumor irradiation, we propose to develop a dual modality imaging-visible, exosome-mediated
radiotheranostic platform for an alpha emitter delivery. In Specific Aim 1, we will evaluate the imaging visibility
and targeting ability of radiolabeled exosomes in cell monolayers and 3D vascularized spheroids. A selected
aRPT formulation will be tested in ectopic and orthotopic HCC mouse models (Aim 2), allowing us to evaluate
its biodistribution, efficacy and safety via intratumoral and intraarterial delivery. The proposed study brings a
unique combination of expertise in radiosynthesis, dosimetry, medical imaging, and animal model of cancers,
to address the critical challenges for effective HCC treatment. Successful completion of the proposed activities
will have vast ramifications for advancing the development of exosome-mediated aRPT for treating HCC or
other cancers.