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

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 ( Conclusions: SSL-0024 overcomes key pharmacokinetic limitations of niclosamide while maintaining potent anti-tumor activity, supporting its further development as an orally bioavailable therapeutic candidate for HCC.