Radiotherapy remains a major treatment modality for cancer types such as non-small cell lung carcinoma (or NSCLC). To enhance treatment efficacy at a given radiation dose, radiosensitizers are often used during radiotherapy. Herein, we report a nanoparticle agent that can selectively sensitize cancer cells to radiotherapy. Specifically, we nitrosylated maytansinoid DM1 and then loaded the resulting prodrug, DM1-NO, onto poly(lactide-co-glycolic)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles. The toxicity of DM1 is suppressed by nanoparticle encapsulation and nitrosylation, allowing the drug to be delivered to tumors through the enhanced permeability and retention effect. Under irradiation to tumors, the oxidative stress is elevated, leading to the cleavage of the S-N bond and the release of DM1 and nitric oxide (NO). DM1 inhibits microtubule polymerization and enriches cells at the G2/M phase, which is more radiosensitive. NO under irradiation forms highly toxic radicals such as peroxynitrites, which also contribute to tumor suppression. The two components work synergistically to enhance radiotherapy outcomes, which was confirmed in vitro by clonogenic assays and in vivo with H1299 tumor-bearing mice. Our studies suggest the great promise of DM1-NO PLGA nanoparticles in enhancing radiotherapy against NSCLC and potentially other tumor types.
Keywords: PLGA; maytansinoid; nanoparticles; non-small cell lung carcinoma; radiation therapy; radiosensitizer.