Antiproliferative and Apoptotic Efficacy of Nano-PLGA Encapsulated Quercetin Molecules by Downregulation of Akt in K-ras Mutated NSCLC Cell Lines, A549 and H460.

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 Poly(lactic-co-glycolic acid) (PLGA) nanoparticles by the solvent displacement technique. The synthesized nanoparticles were then characterized by dynamic light scattering (DLS), Fourier transform 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 and 347 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 externalization induced by NPEQ. NPEQ also caused the arrest of A549 and H460 cells at the sub-G1 stage. Through network analysis, AKT was identified as a key gene target of quercetin in NSCLC. Moreover, we found that NPEQ induced downregulation of Akt, which is usually 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 also modulating the Akt expression along with upregulation in cleaved caspase 3 activation. Besides this, histological alteration of tissue architecture and reduction in tumor volume was also found. This as a whole indicates the prospects and advantages of nanoparticulate quercetin delivery in therapeutic formulations against cancer.