Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy

Saraswat, A; Vemana, HP; Dukhande, VV; Patel, K

Abstract

This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma. GALARV were prepared using the modified hydration method and characterized for their physicochemical properties as well as anticancer activity using 2D and 3D cell culture models. ARV and GALARV (93.83 +/- 10.05 nm) showed significant in vitro cytotoxicity and apoptosis in hepatocellular carcinoma cells. GALARV also demonstrated a substantially higher intracellular concentration of ARV compared to non-targeted nanoliposomes (similar to 3 fold) and ARV alone (similar to 4.5 fold), showed good physical stability and negligible hemolysis. Immunoblotting results depicted substantial downregulation of target BRD4 protein, oncogenic c-Myc, apoptotic Bcl-2, and survivin proteins. Notably, GALARV treatment resulted in significant apoptosis and subsequent inhibition of the cell viability of 3D tumor spheroids of hepatocellular carcinoma. These results suggest that GALARV is a novel actively targeted PROTAC-based nanotherapeutic approach for hepatocellular carcinoma.

Keywords: ARV-825; BRD4; PROTAC; Galactosylated nanoliposomes; Active drug delivery; Hepatocellular carcinoma

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PROTAC

Hepatocellular carcinoma (HCC) is a primary liver cancer and one of the leading causes of cancer-related deaths worldwide. Traditional treatments like surgery, chemotherapy, and radiation therapy often face limitations due to the aggressive nature of HCC and its resistance to conventional therapies. In recent years, a novel approach called PROTAC (Proteolysis Targeting Chimeras) has emerged as a promising therapeutic strategy. PROTACs are small molecules designed to selectively degrade specific proteins involved in disease processes. Unlike traditional inhibitors that merely block protein function, PROTACs harness the cell’s natural degradation machinery to eliminate target proteins altogether. This approach not only offers greater specificity but also reduces the likelihood of drug resistance. In the context of hepatocellular carcinoma, PROTACs can be tailored to target key proteins driving cancer progression. By degrading these proteins, PROTACs can disrupt critical pathways that tumors rely on for growth and survival. This innovative therapy has the potential to overcome some of the major challenges associated with HCC treatment, offering new hope for patients.