Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer

Abstract

Pyroptosis is an inflammation-dependent and self-cascade amplifying type of programmed cell death, serving as an effective means for activating the local immune response and improving the anticancer efficacy. As the effector of pyroptosis, gasdermin-E (GSDME) is silenced in most tumor cells. The gene silencing can be reversed by DNA demethylation, but the systemic side effects and toxicity of chemotherapeutic agents are inevitable. In this work, inhaled poly(lactic-co-glycolic acid) (PLGA) porous microspheres loaded with Decitabine (DAC) and Doxorubicin (DOX) (denoted as CO-MPs) were prepared to induce cell pyroptosis for orthotopic lung cancer therapy with fewer systemic side effects. The CO-MPs showed a hollow and porous spherical morphology and exhibited an excellent aerodynamic property, lung distribution and a sustained release effect. The CO-MPs could reverse GSDME silencing and elevate the expression of cleaved-caspase 3 in tumor cells. The cleaved-caspase 3 protein cleaved the GSDEM protein to obtain GSDME-N protein, causing the rupture of cell plasma membranes, release of cell contents and activation of the immune system. The CO-MPs could lead to the suppression of lung tumors, the decrease of the lung metastatic nodules in tumor-bearing mice and the induction of immunological memory that provides continuous protection from the tumor rechallenge. The inhalable microspheres loaded with DAC and DOX could be an effective strategy for lung cancer treatment via the pyroptosis mechanism.