A Novel Niclosamide Sulfate Prodrug with Enhanced Bioavailability Suppresses Hepatocellular Carcinoma via Inhibition of Multiple Signaling Pathways

Abstract Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for effective therapies. The FDA-approved anthelmintic, niclosamide, is a promising repurposed drug candidate for HCC; however, its clinical application in solid tumors is hampered by poor aqueous solubility and resulting low bioavailability. Methods We designed and screened eight novel niclosamide prodrug candidates for solubility, stability, and anti-proliferative activity in HCC cell lines. The lead compound, SSL-0024, was evaluated for pharmacokinetics and anti-tumor efficacy in an orthotopic patient-derived xenograft (PDX) model, and for cytotoxicity in patient-derived organoids (PDOs). Mechanistic studies assessed AKT–mTOR–STAT3 and other related signaling pathways. Results The O-sulfate derivative, SSL-0024, demonstrated improved solubility and pH stability, and a sustained release of niclosamide over ∼48 h. Once-daily oral administration of SSL-0024 (100 mg/kg) achieved ∼60% tumor growth inhibition in PDX models at ∼46.8% of the niclosamide ethanolamine dose, with minimal toxicity. It also induced significantly greater cytotoxicity than sorafenib ( p