Nitric oxide- and cisplatin-releasing amine-modified mesoporous silica nanoparticles for the treatment of non-small cell lung cancer

Purpose: Lung cancer is the leading cause of cancer related death in the United States; non-small cell lung cancer (NSCLC) is the most common type and it is a challenge to treat in the clinic. Studies have shown that cisplatin-loaded nanoparticles are efficacious against NSCLC and can reduce the nephrotoxicity associated with cisplatin. Previously, nitric oxide (NO) was shown to enhance the efficacy of chemo- and radiotherapies in vivo; thus, the aim of this study was to develop a NO- and cisplatin-releasing wrinkle-structured amine-modified mesoporous silica (AMS) nanoparticle for improved NSCLC therapy. Methods: The AMS and NO- and cisplatin-loaded AMS materials were prepared and characterized. Platinum (Pt) drug loading was analyzed using inductively coupled plasma-mass spectrometry (ICP-MS), and NO release and in vitro release of cisplatin from AMS materials were investigated. Cytotoxicity of functionalized AMS nanoparticles were tested against human NSCLC cell lines, H596 and A549, and compared with that against normal lung cell lines, WI-38 and BEAS-2B. Pt cellular uptake studies were then performed using these four cell lines. The results were then compared to those obtained for cisplatin. Results: For both NSCLC cell lines, the toxicity of NO- and cisplatin-loaded silica nanoparticles (NO-Si-DETA-cisplatin-AMS) was significantly higher than that of silica nanoparticles loaded with only cisplatin (Si-DETA-cisplatin-AMS). In contrast, the toxicity of NO-Si-DETA-cisplatin-AMS toward normal lung cell lines was not significantly different from that of Si-DETA-cisplatin-AMS (normal lung fibroblast cells WI-38) or was lower than that of Si-DETA-cisplatin-AMS (normal lung epithelial cells BEAS-2B). The calculated therapeutic index of NO-Si-DETA-cisplatin-AMS was higher than that of Si-DETA-cisplatin-AMS and free cisplatin, based on both WI-38 and BEAS-2B data. When treated with Si-DETA-cisplatin-AMS, Pt cellular uptake was highest in BEAS-2B, then H596, WI-38 and A549, which corresponds to the toxicity data, and Pt uptake was higher in NSCLC cells when treated with NO-Si-DETA-cisplatin-AMS, compared to Si-DETA-cisplatin-AMS; however, differences in Pt uptake were not statistically significant. Conclusions: The NO-induced sensitization of tumor cell death demonstrates that NO is a promising enhancer of platinum-based lung cancer therapy, and our new therapy may be useful to enhance efficacy of Pt therapy in the clinic.