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

Pharm Res. 2020 Jun 8;37(7):123. doi: 10.1007/s11095-020-02848-2.

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.

Keywords: 3D spheroid; drug repositioning; nelfinavir; non-small cell lung cancer.

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell Proliferation
  • Drug Compounding / methods
  • Drug Liberation
  • Drug Repositioning
  • Drug Stability
  • Gene Expression Regulation / drug effects
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Nanocapsules / chemistry*
  • Nanotechnology / methods*
  • Nelfinavir / chemistry*
  • Nelfinavir / pharmacology
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry*

Substances

  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • Nanocapsules
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Nelfinavir