Combination of DNA demethylation and chemotherapy to trigger cell pyroptosis for inhalation treatment of lung cancer
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, an inhaled poly (lactic-co-glycolic acid) (PLGA) porous microspheres loading Decitabine (DAC) and Doxorubicin (DOX) (denoted as CO-MPs) was prepared to induce cell pyroptosis for orthotopic lung cancer therapy with minimal systemic side effects. The CO-MPs appeared as hollow and porous spherical morphology, exhibited excellent aerodynamic property, lung distribution and 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 immune system. The CO-MPs could lead to the suppression of lung tumor, decrease of the lung metastatic nodules in tumor-bearing mice and induction of immunological memory that provide continuous protection from the tumor rechallenge. The inhalable microspheres loaded with DAC and DOX could be an effective strategy for lung cancer treatment via pyroptosis mechanism.