Nanoencapsulation of etoposide promotes increased long-term DNA damage, greater induction of senescence and reduces population regrowth of lung cancer cells

Abstract

Lung cancer is the most common type of cancer and the leading cause of cancer-related deaths worldwide. The nanoencapsulation of etoposide, a topoisomerase II inhibitor and widely used chemotherapeutic drug, may overcome the limitations related to low aqueous solubility and non-specific toxicity, in addition to enabling a sustained release of etoposide and promoting long-term effects. Here we developed etoposide-loaded lipid-core nanocapsules (ETO NC) having unimodal particle size (∼150 nm), drug content of 0.5 mg mL−1 and encapsulation efficiency of ∼99 %. The formulation remained stable for 28 days at 5 °C. The release experiment showed 70 % of drug dialyzed from ETO NC within 72h in a biexponential curve characterized by a burst phase (60 %, t½ = 1.3 h) followed by a sustained phase (33 %, t½ = 173.2 h). Exposure of A549 lung adenocarcinoma cells to 10 μmol L−1 of drug (ETO NC) produced a threefold reduction in cell viability after 48h. Etoposide (ETO or ETO NC) produced DNA double-strand breaks, as indicated by nuclear foci in A549 cells stably expressing 53BP1-mApple. However, ETO NC significantly promoted nuclear damage over the long-term (20 days), consequently enhancing the induction of senescence and significantly reducing the proliferative subpopulation compared to etoposide in solution. Our findings reveal that ETO NC can enhance the long-term effects of etoposide in inducing DNA damage and inducing senescence, being an innovative strategy to overcome the limitations of this treatment, and strongly encouraging future investigations in in vivo models.