Akciğer Kanserine Yönelik siRNA Taşıyıcı Polimerik Nanopartiküllerin Geliştirilmesi ve Etkinliklerinin İn Vitro Değerlendirilmesi

Abstract

. Lung cancer, one of the most common type of cancers, has the highest mortality rate among all types of cancer, The low effectiveness of current therapies and serious side and toxic effects lead researchers to develop targeted treatment approaches with minimal systemic effects and increased specific effects. It is known that the Kirsten Rat Sarcoma Viral Oncogene (Kras) protein has an important role in lung cancers, and this pathway is activated in most of the cases in lung adenocarcinoma. The purpose of this study was to design and developed KRAS silencing small interfering RNA (siRNA) loaded poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticle formulations and evaluate in the treatment of KRAS mutant lung cancer. The nanoparticles prepared by the double emulsion solvent evaporation method were modified with dioleoyl-3-trimethylammonium propane (DOTAP) and polyethyleneimine (PEI) to impart cationic surface potential, and also modified with hyaluronic acid for active targeting. The siRNA loaded nanoparticles with particle sizes in the range of 190-245 nm, zeta potential in the range of (-12) - (+14) mV and polydispersity index around 0.1 were obtained. Encapsulation efficiency was found between %80-100. In addition, the cytotoxic and KRAS gene silencing effects of the siRNA loaded nanoparticles on A549 human lung adenocarcinoma and BEAS-2B human healthy lung cell were investigated. In vitro studies have shown that the nanoparticles do not affect cell viability of the cancer and healthy lung cells after 72 hours. A decrease of the expression of the target gene up to 50% and a decrease of protein level more than 90% was occurred. In addition, metabolomic analyzes were performed to evaluate the changes in metabolic profiles of the cells after nanoparticles treatment. The formulated siRNA delivery nanoparticles can be promising treatment in lung cancer.