Drug-Eluting, Radiopaque, Tumor-Casting Hydrogels for Endovascular Locoregional Therapy of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. For patients with unresectable disease, locoregional therapies, such as transarterial chemoembolization (TACE), are the standard of care. However, even with this treatment, the average survival rate is only 27% at 5 years. Recent studies have demonstrated the potential of novel approaches to improve responses through more complete embolization and targeting ischemia-induced molecular dependencies. To build on these findings, we developed an injectable chitosan-based hydrogel system (AuNP-Lys05-gel) that we hypothesized might be a more effective embolic material by (i) enabling a more complete filling of tumor feeding blood vessels in a cast-like manner, (ii) encapsulating Lys05, a potent autophagy inhibitor, and (iii) providing X-ray contrast for direct visualization of the embolization. Chitosan hydrogels of varying composition were formed and characterized. We found that Lys05 could be loaded in this type of hydrogel and that it was released gradually over 7 days. We found that AuNP was better retained by the hydrogel than iopamidol, an FDA-approved contrast agent, indicating that AuNP would provide longer-lasting CT monitoring. In a rat model of HCC, AuNP-Lys05-gel reduced tumor growth and resulted in a 67% objective response rate vs 26% for a clinically used particle embolic. Histology indicated effective vascular occlusion by the gel. These findings indicate that AuNP-Lys05-gel merits further investigation as a treatment for HCC.