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

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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 (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.

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Abbreviations

DAPI:

4′,6-diamidino-2-phenylindole

DCM:

Dichloromethane

%EE:

Encapsulation efficiency

FBS:

Fetal bovine serum

IC50 :

50% inhibition concentration

ICH:

International council for harmonization of technical requirements for pharmaceuticals for human use

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NFV:

Nelfinavir

NFV NPs:

NFV loaded PLGA nanoparticles

NSCLC:

Non-small-cell lung cancer

PBS:

Phosphate-buffered saline

PDI:

Polydispersity index

PLGA:

Poly (lactic-co-glycolic acid)

PS:

Particle size

PVA:

Poly (vinyl alcohol)

RH:

Relative humidity

TEM:

Transmission electron microscopy

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Acknowledgments

The author(s) would like to acknowledge the Imaging Facility of CUNY Advanced Science Research Center for instrument use, scientific and technical assistance; and Dr. Aaron Muth, Assistant Professor at St. John’s university for providing EVOS FL fluorescence microscope. The author(s) would also like to acknowledge Dr. Yong Yu (Associate Professor & Graduate Director, Biological Sciences, St. John’s University, NY, USA) for providing porcine kidney proximal tubule cell line (LLC-PK1).

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  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York, 11439, USA

    Vineela Parvathaneni, Mimansa Goyal, Nishant S. Kulkarni, Snehal K. Shukla & Vivek Gupta

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  1. Vineela Parvathaneni
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  2. Mimansa Goyal
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Correspondence to Vivek Gupta.

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Financial Disclosure and Conflict of Interest

This study was supported by start-up funds to VG from College of Pharmacy and Health Sciences (CPHS), St. John’s University. VP was supported by teaching assistantships from CPHS. MG was supported by graduate assistantship from University Learning Commons (ULC) at St. John’s University. SKS and NSK were supported with the research assistantship by National Institutes of Health (NIH) (Grant #1R15HL138606-01A1) to Vivek Gupta.

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Parvathaneni, V., Goyal, M., Kulkarni, N.S. et al. Nanotechnology Based Repositioning of an Anti-Viral Drug for Non-Small Cell Lung Cancer (NSCLC). Pharm Res 37, 123 (2020). https://doi.org/10.1007/s11095-020-02848-2

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