Development of a radiation-activatable nanoparticle for lung cancer therapy

开发用于肺癌治疗的辐射激活纳米颗粒

• 批准号: 10259278
• 负责人: Zhi Liu
• 金额: $ 40万
• 依托单位: ATHNA BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259278
• 关键词: Address; Affinity; Agreement; Antimitotic Agents; Binding; Biotechnology; Canada; Cancer Etiology; Cancer Model; Cancer cell line; Capital; Cells; Cisplatin; Cleaved cell; Clinic; Colon Carcinoma; Conformal Radiotherapy; Coupled; DNA; Data; Development; Diagnosis; Dose; Drug Kinetics; Encapsulated; Etoposide; External Beam Radiation Therapy; Failure; Future; Goals; Growth; Head Cancer; Histopathology; In Situ; In Vitro; Incidence; Interruption; Label; Legal patent; Licensing; Ligands; Lipids; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Methodology; Microtubules; Mus; Neck Cancer; Neoplasm Metastasis; Neurotensin Receptors; Nitric Oxide; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oryctolagus cuniculus; Oxidative Stress; Paclitaxel; Patients; Peroxonitrite; Persons; Phase; Platinum; Positron-Emission Tomography; Prodrugs; Production; Prognosis; Property; Proteins; Pulmonary Inflammation; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radio; Radiosensitization; Reactive Oxygen Species; Regional Disease; Safety; Schedule; Scheme; Site; Surface; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxicity Tests; Treatment Efficacy; Treatment outcome; Tumor Suppression; Up-Regulation; acute toxicity; base; bioluminescence imaging; cancer therapy; cancer type; chemoradiation; chemotherapy; commercial application; commercialization; ethylene glycol; improved; in vivo; inhibitor/antagonist; innovation; irradiation; malignant breast neoplasm; meetings; mortality; nanoparticle; nanoparticle delivery; neuroendocrine differentiation; new technology; poly(lactide); preclinical study; scale up; standard care; systemic toxicity; tumor; tumor growth

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.

抽象的 非小细胞肺癌 (NSCLC) 是癌症相关死亡的主要原因，占 NSCLC 死亡的 85%。 所有肺癌，在美国每年有 234,030 人被诊断出患有肺癌。 局部晚期或局部区域疾病，放射治疗（RT）是标准护理，但剂量和。 放疗的疗效受到正常组织毒性的限制。为了改善肿瘤控制，使用顺铂等放射增敏剂。 和紫杉醇与放化疗同时使用，即放化疗 (CRT)。 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。 迫切需要能够将放射增敏剂特异性地递送至肿瘤的方法。 增强 RT。 Athna Biotech, Inc. 正在开发一种新的 CRT 方法，利用辐射进行局部全身激活 具体来说，我们合成了一种辐射响应前药 DM1-NO，一种 亚硝基化的美登木素生物碱DM1可以被负载到聚(丙交酯-共-乙醇)-嵌段-聚(乙烯)中。 乙二醇）纳米颗粒并递送至肿瘤 为了提高递送效率，纳米颗粒被缀合。 NTSmut 是一种对 NTSR1 具有高亲和力的配体，在 59.7% 的肺部肿瘤中表达上调。 RT、辐射会升高肿瘤中的氧化应激，导致 DM1-NO 解离并释放 DM1 和一氧化氮 (NO) DM1 和 NO 都是有效的放射增敏剂，协同作用以增强放射增敏作用。 RT。通过纳米粒子递送、NTSR1 靶向、适形辐射和辐射响应激活，这 该方法与高肿瘤选择性相关，因此可以实现精确的放射增敏。 可以扩展到其他癌症的治疗，例如前列腺癌、头颈癌、乳腺癌和结肠癌， 其中 NTSR1 也上调。