Anti-proliferative and Apoptotic Efficacy of Nano-PLGA encapsulated Quercetin Molecules by down-regulation of Akt in K-ras mutated NSCLC cell lines, A549 and H460

Abstract

Abstract To test if encapsulating hydrophobic flavonoids in nanoparticles could offer a new possibility in the therapeutics of non-small cell lung cancer (NSCLC), quercetin was encapsulated in PLGA nanoparticles by solvent displacement technique. The synthesised nanoparticles were then characterised by dynamic light scattering (DLS), Fourier transforms infrared spectroscopy (FTIR), and atomic force microscopy (AFM). The size of the nanoparticles with smooth surface topology was estimated at 110 nm. Treatment with nano-PLGA encapsulated quercetin (NPEQ) triggered the death of K-ras mutated NSCLC cells, A549 and H460, and showed 50% cell cytotoxicity in them at a dose of 406 ng/ml and 306 ng/ml, respectively. NPEQ was able to block uncontrolled cell proliferation by inducing concomitant destruction of BrdU activity and a lower incidence of cell migrations. Cell death was due to the induction of apoptosis rather than necrosis, as revealed by morphological alterations and phosphatidylserine externalisation induced by NPEQ. NPEQ also caused the arrest of A549 and H460 cells at the sub-G1 stage. NPEQ induced down-regulation of Akt, which is usually found to be hyperactive in NSCLC due to K-ras mutation. This indicates that NPEQ caused target-specific apoptotic and antiproliferative activity by targeting the downregulation of Akt. Further, when NPEQ was generated in the tumour-bearing mice model, it showed antitumor efficacy. Besides this, histological alteration of tissue architecture and modulation of an apoptotic marker protein in mice indicates the prospect and advantages of nanoparticulate quercetin delivery in therapeutic formulations against cancer.