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

2022-02-14T17:14:08Z

2022-02-14T17:14:08Z

2020-07

2022-02-14T17:14:07Z

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.

1535-7163.MCT-19-0689

1535-7163

1538-8514

https://hdl.handle.net/10161/24488

eng

American Association for Cancer Research (AACR)

Molecular cancer therapeutics

10.1158/1535-7163.mct-19-0689

Tumor Cells, Cultured

Animals

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

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

Journal article

Spasojevic, Ivan|0000-0001-9890-6246

Somarelli, Jason A|0000-0003-1510-9343

Needham, David|0000-0002-0082-9148

1448

1461

7

Duke

Nicholas School of the Environment

Pratt School of Engineering

School of Medicine

Clinical Science Departments

Institutes and Centers

Medicine

Orthopaedics

Pediatrics

Medicine, Medical Oncology

Duke Cancer Institute

Marine Science and Conservation

Published

19