Nanoparticles Encapsulating Nitrosylated Maytansine to Enhance Radiation Therapy

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 (EPR) 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 peroxynitrite...