Dissecting the Role of SMYD2 and Its Inhibitor (LLY-507) in the Treatment of Chemically Induced Non-Small Cell Lung Cancer (NSCLC) by Using Fe₃O₄ Nanoparticles Drug Delivery System

Abstract

Cancer therapies based on nanoparticles with a loaded drug can overcome the problem of the drug’s toxic effects in the traditional chemotherapeutic approach. In this study, we loaded LLY-507, a potent inhibitor of SMYD2, a methyltransferase enzyme, on iron oxide nanoparticles (IONPs). The prepared nanoparticles were characterized by microscopic analysis, loading efficiency, and drug release studies. Microscopic examination revealed an average grain size of 44 nm. The in vitro effect of LLY-507-IONPs, LLY-507, and IONPs was determined by MTT analysis (A549 cells) and hemolysis studies. IONPs have almost negative hemolytic activity in blood. The cell viability assay revealed IC50 values of both LLY-507 alone and LLY-507-loaded IONPs against A549; the lower value of the drug loaded on NPs (0.71 µg/mL alone and 0.53 µg/mL loaded on NPs) shows strong synergistic anticancer potential. We further tested the role of loaded NPs in a urethane-induced lung cancer mouse model (n = 40 mice in three independent trials, 20 mice in control group) to check the role of SMYD2 at various time points of lung cancer development. The loss of SMYD2 due to LLY-507 suppressed tumor growth, emphysema, hemorrhage, and congestion considerably. Hence, it can be concluded that the SMYD2 inhibitor has an anti-inflammatory effect on the mouse lung and suppresses tumor growth by inhibiting the SMYD2 protein.

Keywords

• SMYD2
• LLY-507
• IONPs
• adenocarcinoma
• NSCLC