Nanotechnology Based Repositioning of an Anti-Viral Drug for Non-Small Cell Lung Cancer (NSCLC)

Autor: Vineela Parvathaneni, Nishant S. Kulkarni, Vivek Gupta, Snehal K. Shukla, Mimansa Goyal
Rok vydání: 2020
Předmět:
Cell Membrane Permeability
Lung Neoplasms
Anti-HIV Agents
Drug Compounding
Pharmaceutical Science
non-small cell lung cancer (NSCLC)
Apoptosis
02 engineering and technology
030226 pharmacology & pharmacy
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Drug Stability
Nanocapsules
Polylactic Acid-Polyglycolic Acid Copolymer
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Autophagy
medicine
Humans
Nanotechnology
HIV Protease Inhibitor
Pharmacology (medical)
Cell Proliferation
Pharmacology
Tumor microenvironment
Activating Transcription Factor 3
Nelfinavir
Organic Chemistry
Drug Repositioning
HIV Protease Inhibitors
021001 nanoscience & nanotechnology
medicine.disease
Drug Liberation
PLGA
Gene Expression Regulation
chemistry
Cancer cell
Cancer research
Molecular Medicine
Growth inhibition
0210 nano-technology
Microtubule-Associated Proteins
Biotechnology
medicine.drug
Zdroj: Pharmaceutical Research. 37
ISSN: 1573-904X
0724-8741
DOI: 10.1007/s11095-020-02848-2
Popis: Nelfinavir (NFV), a FDA approved antiretroviral drug, has been reported to exhibit cancer cells growth inhibition and increased apoptosis. However, it requires a higher dose leading to toxicity, thus limiting its potential clinical translation. We aim to develop biodegradable (poly (lactic-co-glycolic acid)) PLGA nanoparticles of nelfinavir and determine their efficacy to treat non-small cell lung cancer (NSCLC). HIV protease inhibitor, NFV, was loaded into PLGA nanoparticles by double emulsion/solvent evaporation method; and nanoparticles were characterized for physicochemical characteristics including morphology and intracellular uptake. Their anti-cancer efficacy in NSCLC was assessed by in vitro assays including cytotoxicity, cellular migration, colony formation; and 3D spheroid culture mimicking in-vivo tumor microenvironment. Studies were also conducted to elucidate effects on molecular pathways including apoptosis, autophagy, and endoplasmic stress. NFV loaded PLGA nanoparticles (NPs) were found to have particle size: 191.1 ± 10.0 nm, zeta potential: −24.3 ± 0.9 mV, % drug loading: 2.5 ± 0.0%; and entrapment efficiency (EE): 30.1 ± 0.5%. NFV NP inhibited proliferation of NSCLC cells compared to NFV and exhibited significant IC50 reduction. From the caspase-dependent apoptosis assays and western blot studies (upregulation of ATF3), it was revealed that NFV NP significantly induced ER stress marker ATF3, cleaved PARP and further caused autophagy inhibition (LC3BII upregulation) leading to increased cellular death. In addition, NFV NP were found to be more efficacious in penetrating solid tumors in ex-vivo studies compared to plain NFV. Nelfinavir, a lead HIV protease inhibitor can be repositioned as a NSCLC therapeutic through nanoparticulate delivery. Given its ability to induce apoptosis and efficient tumor penetration capability, NFV loaded PLGA nanoparticulate systems provide a promising delivery system in NSCLC treatment.
Databáze: OpenAIRE
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