Glycosylated 4-methylumbelliferone as a targeted therapy for hepatocellular carcinoma

GISELA WEIZ; MOLEJON MARIA INES; MARIANA MALVICINI; CAECILIA SUKOWATI; CLAUDIO TIRIBELLI; GUILLERMO MAZZOLINI; JAVIER BRECCIA

LIVER INTERNATIONAL

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2022

1478-3223

Background & Aims: Reaching efficacious drug delivery to target cells/tissues represents a major obstacle in the current treatment of solid malignancies including hepatocellular carcinoma (HCC). This study, we developed a pipeline to selective add complex-sugars to the aglycone 4-methylumbelliferone (4MU), a cholagogue shown to have moderate effect in cancer cells, to help their bioavailability and tumor cell intake. Methods: The therapeutic efficacy of sugar modified rutinosyl-4-methylumbelliferone (4MUR) and 4MU was compared in vitro and in an orthotopic HCC model established in fibrotic livers via intrahepatic inoculation of HCC cells. The mechanistic bases of its selective target to liver tumor cells was evaluated by the interaction with asialoglycoprotein receptor (ASGPR), the mRNA expression of hyaluronan synthases (HAS2 or HAS3) and hyaluronan deposition.Results: 4MUR was mostly incorporated in HCC cells as compared to non-tumoral cells in a dose-dependent manner. Further analysis showed that 4MUR is incorporated mostly into HCC cells by interaction with rhamnose-specific ASGPR, a receptor commonly overexpressed in HCC cells. 4MUR-treatment decreased the levels of HAS2 and HAS3 and the cytoplasmic deposition of hyaluronan. In vivo efficacy showed that 4MUR-treatment displayed a greater tumor growth inhibition and increased survival in comparison to 4MU. Further, 60% of 4MUR treated mice did not present macroscopically tumoral mass post-treatment and more importantly, 4MUR administration was not associated with any signs of tissue damage. Conclusion: Altogether, our results provided evidence that 4MUR may be used as an effective HCC therapy, without damaging non-tumoral cells or other organs, probably due to its specific targeting.