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.

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Citation

Published Version (Please cite this version)

10.1158/1535-7163.mct-19-0689

Publication Info

Reddy, Gireesh B, David L Kerr, Ivan Spasojevic, Artak Tovmasyan, David S Hsu, Brian E Brigman, Jason A Somarelli, David Needham, et al. (2020). Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma. Molecular cancer therapeutics, 19(7). pp. 1448–1461. 10.1158/1535-7163.mct-19-0689 Retrieved from https://hdl.handle.net/10161/24488.

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Scholars@Duke

Brigman

Brian Eugene Brigman

Professor of Orthopaedic Surgery
Somarelli

Jason Andrew Somarelli

Assistant Professor in Medicine
Needham

David Needham

Professor Emeritus in the Thomas Lord Department of Mechanical Engineering and Materials Science

Professor Needham has been at Duke since 1987 and over the years has developed many collaborative and scholarly relationships across the campus and Medical School. He holds Faculty and membership appointments as: Associate Professor of Biomedical Engineering; Center for Bioinspired Materials and Material Systems; Center for Biomolecular and Tissue Engineering; Duke Comprehensive Cancer Center; and the Duke Cancer Institute.  Internationally, he holds a joint appointment as Professor of Translational Therapeutics in the School of Pharmacy, at the University of Nottingham, UK.  He also collaborates with preclinical researchers at the Erasmus University Medical Center, in Rotterdam, NL. 
For the past 35 years Needham's Lab has developed and used a platform technology of micropipette manipulation to manipulate single and pairs of micro bubbles, droplets and particles in order to assess their behavior in well-defined fluids and solution conditions.  Recently his research and development has focused on nucleation, growth and stability of nanoparticles.  Applications of these fundamental particle and interfacial studies have primarily focused on advanced drug delivery treatments for cancer and now COVID19 with a nasal and throat spray prophylactic and early treatment regimen.

Eward

William Curtis Eward

Frank H. Bassett III, M. D. Associate Professor of Orthopaedic Surgery

I am an Orthopaedic Oncologist, with dual clinical degrees (MD and DVM).  I treat complex sarcomas in people and animals.  My laboratory studies comparative oncology - discoveries we can make about cancer by analyses across different species.


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