Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against Osteosarcoma

Reddy, Gireesh B.; Kerr, David L.; Spasojevic, Ivan; Tovmasyan, Artak; Hsu, David S.; Brigman, Brian E.; Somarelli, Jason A.; Needham, David; Eward, William C.

Abstract

Therapeutic advances for osteosarcoma (OS) 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 OS 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 anti-cancer 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, intracellular-signaling by western blot; ex vivo pulmonary metastatic assay model; and in vivo PK and lung mouse metastatic model of OS. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t1/2 ~5 h; reduces cell-viability and cell-proliferation in human and canine OS cells in vitro at 0.2 - 2 µM IC50; inhibits recognized growth pathways, and induces apoptosis at 20µM; eliminates metastatic lesions in the ex-vivo lung metastatic model; and, when injected intravenously (i.v.) at 50mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of OS over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected i.v. at 50mg/kg (1.9mM). 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 OS patients.

Citation

Reddy, G. B., Kerr, D. L., Spasojevic, I., Tovmasyan, A., Hsu, D. S., Brigman, B. E., …Eward, W. C. (2020). Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against Osteosarcoma. Molecular Cancer Therapeutics, 19(7), 1448-1461. https://doi.org/10.1158/1535-7163.mct-19-0689

• Journal Article Type: Article
• Acceptance Date: Apr 21, 2020
• Online Publication Date: May 5, 2020
• Publication Date: Jul 1, 2020
• Deposit Date: May 18, 2020
• Publicly Available Date: May 6, 2021
• Journal: Molecular Cancer Therapeutics
• Print ISSN: 1535-7163
• Electronic ISSN: 1538-8514
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 19
• Issue: 7
• Pages: 1448-1461
• DOI: https://doi.org/10.1158/1535-7163.mct-19-0689
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/4395809
• Publisher URL: https://mct.aacrjournals.org/content/early/2020/05/05/1535-7163.MCT-19-0689