Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Abstract

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.

• Authors: Gireesh B Reddy, David L Kerr, Ivan Spasojevic, Artak Tovmasyan, David S Hsu, Brian E Brigman, Jason A Somarelli, David Needham, William C Eward
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 7 Pg. 1448-1461 (07 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32371588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antinematodal Agents
• Antineoplastic Agents
• Prodrugs
• Stearates
• Niclosamide

Topics

• Animals
• Antinematodal Agents (chemistry, pharmacokinetics, pharmacology)
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Dogs
• Drug Evaluation, Preclinical
• Drug Repositioning
• Humans
• Mice
• Mice, Inbred C57BL
• Niclosamide (chemistry, pharmacokinetics, pharmacology)
• Osteosarcoma (drug therapy, metabolism, pathology)
• Prodrugs (chemistry, pharmacokinetics, pharmacology)
• Stearates (chemistry, pharmacokinetics, pharmacology)
• Tissue Distribution
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays