Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice

Abstract

Yi Liu,1 David Quintanar Guerrero,2 David Lechuga-Ballesteros,3 Mingdian Tan,1 Faiz Ahmad,1 Bilal Aleiwi,4 Edmund Lee Ellsworth,4 Bin Chen,4 Mei-Sze Chua,1 Samuel So1 1Department of Surgery, School of Medicine, Stanford University, Stanford, CA, USA; 2Laboratorio de Investigación y Posgrado en Tecnologías Farmacéuticas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, CP, 54745, Mexico; 3AstraZeneca Pharmaceuticals, Ltd. 4222 Emperor Boulevard, Durham, NC, USA; 4Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USACorrespondence: Mei-Sze Chua, Email [email protected]: We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS).Methods: Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control.Results: Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice.Conclusion: We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.Keywords: niclosamide, self-microemulsifying drug delivery system, SMEDDS, oral bioavailability, drug repurposing, hepatocellular carcinoma

Keywords

• niclosamide
• self-microemulifying drug delivery system
• smedds
• oral bioavailability
• drug repurposing
• hepatocellular carcinoma