Development of a radiation-activatable nanoparticle for lung cancer therapy

摘要 非小细胞肺癌(NSCLC)是癌症相关死亡的主要原因。非小细胞肺癌占85% 所有肺癌，在美国每年有234,030人被诊断为肺癌。对于大多数患有 局部晚期或局部区域性疾病，放射治疗(RT)是标准治疗。然而，剂量和 RT的疗效受到正常组织毒性的限制。为了改善肿瘤控制，顺铂等放射增敏剂 和紫杉醇与放疗同时使用，即放化疗(CRT)。然而，CRT与 高水平的急性和全身毒性。许多患者不适合接受CRT或完成计划的 课程。迫切需要一种能够将放射增敏剂定点输送到肿瘤的方法学 增强RT。 Athna Biotech，Inc.正在开发一种新的CRT方法，这种方法利用辐射来局部系统性激活 提供治疗方法。具体地说，我们已经合成了一种辐射反应前药DM1-NO，a 亚硝化的美丹素DM1。前药可以负载到聚丙交酯-乙交酯共聚-嵌段-聚乙烯中 乙二醇纳米粒，并将其输送至肿瘤。为了提高输送效率，纳米颗粒被偶联。 对于NTSmut，一种与NTSR1具有高亲和力的配体，NTSR1在59.7%的肺癌中上调。在.期间 RT，辐射增加肿瘤氧化应激，导致DM1-NO解离和释放 DM1和一氧化氮(NO)。DM1和NO都是有效的放射增敏剂，它们协同工作以增强 RT.通过纳米颗粒递送、NTSR1靶向、适形辐射和辐射响应激活，这 入路与肿瘤的高选择性有关，因此可以进行准确的放射增敏。方法论 可扩展到其他癌症的治疗，如前列腺癌、头颈部、乳腺癌和结肠癌， 其中NTSR1也被上调。

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.