ABSTRACT
Drug repurposing is on the rise as an atypical strategy for discovery of new molecules, involving use of pre-existing molecules for a different therapeutic application than the approved indication. Using this strategy, the current study aims to leverage effects of quinacrine (QA), a well-known anti-malarial drug, for treatment of non-small cell lung cancer (NSCLC). For respiratory diseases, designing a QA loaded inhalable delivery system has multiple advantages over invasive delivery. QA-loaded nanoparticles (NPs) were thus prepared using polyethyleneimine (PEI) as a cationic stabilizer. While the use of PEI provided cationic charge on the particles, it also mediated a burst release of QA and demonstrated potential particle toxicity. These concerns were circumvented by coating nanoparticles with bovine serum albumin (BSA), which retained the cationic charge, reduced NP toxicity and modulated QA release. Prepared nanoparticles were characterized for physicochemical properties along with their aerosolization potential. Therapeutic efficacy of the formulations was tested in different NSCLC cells. Mechanism of higher anti-proliferation was evaluated by studying cell cycle profile, apoptosis and molecular markers involved in the progression of lung cancer. BSA coated QA nanoparticles demonstrated good aerosolization potential with a mass median aerodynamic diameter of significantly less than 5 µm. Nanoparticles also demonstrated improved therapeutic efficacy against NSCLC cells in terms of low IC50 values, cell cycle arrest at G2/M phase and autophagy inhibition leading to increased apoptosis. BSA coated QA NPs also demonstrated enhanced therapeutic efficacy in a 3D cell culture model. The present study thus lays solid groundwork for pre-clinical and eventual clinical studies as a standalone therapy and in combination with existing chemotherapeutics.
Subject(s)
Drug Compounding/methods , Drug Delivery Systems/methods , Drug Repositioning/methods , Nanoparticles/chemistry , Quinacrine/chemistry , Serum Albumin, Bovine/chemistry , Administration, Inhalation , Aerosols/chemistry , Aerosols/pharmacology , Animals , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Liberation , Humans , Lung Neoplasms/drug therapy , Nanoparticles/administration & dosage , Particle Size , Polyethyleneimine/chemistry , Quinacrine/administration & dosage , Quinacrine/pharmacologyABSTRACT
This study was aimed at developing a nanoparticle strategy to overcome acquired resistance against erlotinib in non-small cell lung cancer (NSCLC). To load erlotinib on biodegradable PLGA nanoparticles, erlotinib-cyclodextrin (Erlo-CD) complex was prepared using ß-cyclodextrin sulfobutyl ether, which was in turn loaded in the core of PLGA nanoparticles using multiple emulsion solvent evaporation. Nanoparticles were characterized for size distribution, entrapment and loading efficiency, in-vitro release, and therapeutic efficacy against different lung cancer cells. Effect of formulation on cell cycle, apoptosis, and other markers was evaluated using flow cytometry and western blotting studies. The efficacy of optimized nanoformulation was evaluated using a clinically relevant in-vitro 3D-spheroid model. Results showed that Erlo-CD loaded nanoparticles (210⯱â¯8â¯nm in size) demonstrated 3-fold higher entrapment (61.5⯱â¯3.2% vs 21.9⯱â¯3.7% of plain erlotinib loaded nanoparticles) with ~5% loading efficiency and sustained release characteristics. Developed nanoparticles demonstrated significantly improved therapeutic efficacy against NSCLC cells in terms of low IC50 values and suppressed colony forming ability of cancer cells, increased apoptosis, and autophagy inhibition. Interestingly, 3D spheroid study demonstrated better anticancer activity of Erlo-CD nanoparticles compared to plain erlotinib. Present study has shown a premise to improve therapeutic efficacy against erlotinib-resistant lung cancer using modified nanoErlo formulations.
