Hepatocellular carcinoma (HCC), the commonest primary liver cancer, is the fifth most frequently diagnosed cancer worldwide. At the time of diagnosis most patients have advanced disease, greatly limiting their options for treatment beyond non-surgical palliative care.Thisalpha-particle emitting radioembolization for the treatment of HCC. A DOTA chelator was modified and radiolabeled with Actinium-225, an α-particle emitting radionuclide. The resulting agent [225Ac]Ac-DOTA-TDA was emulsified with Lipiodol®, an FDA-approved radio-opaque agent, yielding the radioembolic agent [225Ac]Ac-Lipiodol®. Lipiodol® can be targeted to hepatic tumors through the hepatic artery, where it is able to embolize hepatic tumors, accumulating and remaining in the tumors while clearing out of normal liver tissue, making it an excellent vehicle for the selective delivery of therapeutic radionuclides. To confirm retention in HCC tumors of the modified chelator, we initially determined that [111In]In-DOTA-TDA was retained to a greater degree within HEPG2 tumors in a mouse model when emulsified with Lipiodol® (216±145 %ID/g) as compared to [111In]In-DOTA-TDA alone (20.0±15.9 %ID/g) 48 hours post-injection. [225Ac]Ac-Lipiodol® showed significant improvement in the survival of HEPG2 tumor-bearing mice to as compared to controls (p&lt;0.005). Selective delivery of [225Ac]Ac-Lipiodol® to hepatic tumors via the hepatic artery was confirmed in the VX2 rabbit model. The rabbit model allowed us to monitor [225Ac]Ac-Lipiodol® with SPECT-imaging of Actinium-225’s daughters, Francium-221 and Bismuth-213; distinguishing between [225Ac]Ac-Lipiodol® (Francium-221) and the relocation of the longer lived Bismuth-213. [225Ac]Ac-Lipiodol® demonstrated high retention within the VX2 tumor (40.6 %ID/g) 6-days post-injection as compared to the normal liver (0.23 %ID/g). Finally, maximum tolerated activity (MTA) studies are currently underway with no evident short-term toxicities (3-month) in healthy rats administered [225Ac]Ac-Lipiodol® via the hepatic artery. Overall these works are supportive of [225Ac]Ac-Lipiodol® as a promising therapeutic agent for HCC.

Preliminary evaluation of alpha-emitting radioembolization in animal models of Hepatocellular Carcinoma

ACS Spring 2022

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