Efficacy and mechanisms of cisplatin and sulforaphane nanoparticles in alleviating cisplatin resistance in non-small cell lung cancer.

[BACKGROUND] Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and its morbidity and mortality rates continue to increase, placing tremendous pressure on global public health systems. Cisplatin (DDP), also known as diamminedichloroplatinum (II), is a traditional chemotherapy drug widely used in the treatment of NSCLC; however, it has serious side effects and can easily lead to drug resistance, which seriously limits its efficacy. The mechanism of DDP resistance is closely related to ferroptosis. Tumor cells evade the killing effect of drugs by regulating iron metabolism, anti-oxidant responses, and lipid metabolism. Sulforaphane (SFN) is a classic ferroptosis activator with potent anti-tumor effects. This study aims to develop a novel NSCLC-targeted nanoplatform loaded with cisplatin and sulforaphane, which is expected to reverse the drug resistance induced by cisplatin monotherapy.

[METHODS] This study was conducted on three levels: materials science, cytology and zoology. First, nanostructured SFN and DDP particles (nSDDPs) with NSCLC-targeting functions were synthesized. The distribution characteristics and safety characteristics were evaluated through cell experiments and animal experiments using immunofluorescence imaging, in vivo imaging technology, and hematoxylin and eosin (H&E) staining. To explore the efficacy of the nSDDPs, we tested the cell activity, cell proliferation rate, cell scratch, and ferroptosis-related indicators. To further test the DDP resistance-improving effect and anti-tumor effect of the nSDDPs, we conducted subcutaneous tumor-bearing experiments to detect tumor size, assess histological status, investigate metastasis-related factors and ferroptosis-related indicators.

[RESULTS] The synthesized nSDDPs showed good targeting and biocompatibility in cell and animal models of NSCLC. In the cell experiments, the nSDDPs exerted a significant inhibitory effect on cell activity, reduced the cell proliferation rate, and exerted a strong growth inhibition effect in the cell scratch assays. In addition, the nSDDPs also exerted a significant activation effect on the ferroptosis-related indicators, further enhancing the anti-tumor effect. In the animal experiments, the nSDDPs significantly inhibited tumor growth. The tumor volume and weight were smaller, and the necrosis and apoptosis of the tumor tissue were more obvious in the nSDDP group than in the DDP group. The expression of metastasis-related factors was also significantly decreased, indicating that the nSDDPs had a strong effect in improving DDP resistance and inhibiting tumor metastasis. The nSDDPs exerted good anti-tumor effects and overcame DDP resistance to a certain extent, providing a new strategy for the treatment of NSCLC.

[CONCLUSIONS] The nSDDPs which were successfully synthesized in this study improved DDP resistance by activating the ferroptosis pathway and also exerted anti-tumor effects. Our findings provide new insights into the study of DDP drug resistance.