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.
Type
Journal articleSubject
Tumor Cells, CulturedAnimals
Mice, Inbred C57BL
Dogs
Humans
Mice
Osteosarcoma
Bone Neoplasms
Niclosamide
Stearates
Antineoplastic Agents
Prodrugs
Antinematodal Agents
Drug Evaluation, Preclinical
Xenograft Model Antitumor Assays
Apoptosis
Cell Proliferation
Tissue Distribution
Drug Repositioning
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https://hdl.handle.net/10161/24488Published Version (Please cite this version)
10.1158/1535-7163.mct-19-0689Publication Info
Reddy, Gireesh B; Kerr, David L; Spasojevic, Ivan; Tovmasyan, Artak; Hsu, David S;
Brigman, Brian E; ... Eward, William C (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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Brian Eugene Brigman
Professor of Orthopaedic Surgery
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.
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 T
Jason Andrew Somarelli
Assistant Professor in Medicine
Ivan Spasojevic
Associate Professor in Medicine
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