Development of a radiation-activatable nanoparticle for lung cancer therapy

ABSTRACT Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality. NSCLC accounts for 85% of all lung cancers, and is diagnosed in 234,030 persons each year in the US. For the majority of patients with locally advanced or local regional disease, radiation therapy (RT) is the standard care. However, the dose and efficacy of RT is limited by normal tissue toxicity. To improve tumor control, radiosensitizers such as cisplatin and paclitaxel are used in concurrent with RT, i.e. chemoradiotherapy (CRT). However, CRT is associated with high levels of acute and systemic toxicity. Many patients are unfit to receive CRT or complete the planned courses. There is an urgent need of methodologies that can deliver radiosensitizers site-specifically to tumors to enhance RT. Athna Biotech, Inc. is developing a new CRT approach where radiation is utilized to locally activate systemically delivered therapeutics. Specifically, we have synthesized a radiation-responsive prodrug, DM1-NO, a nitrosylated maytansinoid DM1. The prodrug can be loaded into poly(lactide-co-glycolic)-block-poly(ethylene glycol) nanoparticles and delivered to tumors. To improve delivery efficiency, the nanoparticles are conjugated with NTSmut, a ligand that has high affinity towards NTSR1, which is up-regulated in 59.7% lung tumors. During RT, irradiation elevates oxidative stress in tumors, resulting in the disassociation of DM1-NO and the release of DM1 and nitric oxide (NO). Both DM1 and NO are effective radiosensitizers, working synergistically to enhance RT. With nanoparticle delivery, NTSR1 targeting, conformal radiation, and radiation-responsive activation, this approach is associated with high tumor selectivity thus permitting accurate radiosensitization. The methodology can be extended to treatment of other cancers, such as prostate, head and neck, breast, and colon cancer, where NTSR1 is also upregulated.PROJECT NARRATIVE This project aims to develop a new chemo-radiotherapy approach for non-small cell lung cancer. Briefly, nitrosylated mertansine, a prodrug, is encapsulated into poly(lactide-co-glycolic) or PLGA nanoparticles, and delivered to tumors in the lung. Under radiation, the prodrug is activated, producing mertansine and nitric oxide that synergistically enhance radiotherapy efficacy.