Nanotechnology Based Repositioning of an Anti-Viral Drug for Non-Small Cell Lung Cancer (NSCLC)
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RESEARCH PAPER
Nanotechnology Based Repositioning of an Anti-Viral Drug for Non-Small Cell Lung Cancer (NSCLC) Vineela Parvathaneni 1 & Mimansa Goyal 1 & Nishant S. Kulkarni 1 & Snehal K. Shukla 1 & Vivek Gupta 1
Received: 7 April 2020 / Accepted: 29 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose 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). Experimental Design 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. Results 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02848-2) contains supplementary material, which is available to authorized users. * Vivek Gupta [email protected] 1
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York 11439, USA
(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. Conclusions 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.
KEYWORDS drug repositioning . nelfinavir . non-small cell lung cancer . 3D spheroid
ABBREVIATIONS DAPI DCM %EE FBS IC50 ICH
4′,6-diamidino-2-phenylindole Dichloromethane Encapsulation efficiency Fetal bovine serum 50% inhibition concentration International council for harmonization of technical requirements for pharmaceuticals for hum
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