Acid Degradable Zinc Oxide Nanoparticle Loaded Etoposide Nanoformulation for Targeting Lung Adenocarcinoma via Drug Metabolism and Crosstalk Between Angiogenesis and Akt Pathways

Lung Cancer is a leading cause of death worldwide, and if diagnosed at later stages, it can be lethal and incurable. Lung cancer is conventionally treated using chemotherapy. Among the chemotherapeutic drugs used, topoisomerase-II inhibitor etoposide is mainly used first-line chemotherapeutic drug for lung adenocarcinoma treatment. Due to its fast and extensive metabolism by the cytochrome-P 450 system, etoposide shows limited efficacy and reduced bioavailability. Our study examines the zinc oxide nanoparticle-loaded etoposide activity on drug metabolism and crosstalk between angiogenesis and Akt pathways. The Dynamic light scattering analysis revealed that after drug loading to Zinc oxide nanoparticles, particle size increased to 49 nm from 4 nm. The developed etoposide-loaded zinc oxide nanoparticles showed sustainable drug release with respect to tumor microenvironment. Zinc oxide nanoparticles loaded with etoposide showed enhanced anticancer effects at lower concentrations compared to pure etoposide. The etoposide nanoformulation showed decreased cytochrome P4503A4 expression in A549 lung adenocarcinoma cells, leading to decreased drug excretion and enhanced anticancer efficiency of etoposide. The developed nanoformulation promoted the apoptosis of A549 cells by stimulating the expressions of caspase 7 and caspase 9, along with the reduction in phosphorylated Akt and ERK signaling molecules. It also showed inhibition of angiogenesis and migration of A549 cells by inhibiting the expressions of vascular endothelial growth factor -A & C, HIF-α, Fibroblast growth factor, Angiogenin, Transforming growth factor -β and Matrix metalloproteinases -2, 9 &13.

Etoposide loaded zinc oxide nanoparticles and their in vitro activity.