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.

摘要 非小细胞肺癌（NSCLC）是癌症相关死亡率的主要原因。NSCLC占85%， 所有肺癌，在美国每年有234，030人被诊断出。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的功效受到正常组织毒性的限制。为了改善肿瘤控制，放射增敏剂如顺铂 和紫杉醇与RT同时使用，即化学放射疗法（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或完成计划的治疗。 课程迫切需要能够将放射增敏剂位点特异性地递送至肿瘤的方法， 提高RT。 Athna Biotech，Inc.正在开发一种新的CRT方法，利用放射线局部激活全身 递送的治疗剂。具体来说，我们合成了一种辐射响应性前药DM 1-NO， 亚硝基化美登木素DM 1。前药可以负载到聚（丙交酯-共-乙醇酸）-嵌段-聚（乙烯） 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NTSR 1具有高亲和力的配体，NTSR 1在59.7%的肺肿瘤中上调。期间 RT，照射提高了肿瘤中的氧化应激，导致DM 1-NO的解离和DM 1-NO的释放。 DM 1和一氧化氮（NO）。DM 1和NO都是有效的放射增敏剂，协同作用以增强 RT.通过纳米颗粒递送、NTSR 1靶向、适形辐射和辐射响应激活， 该方法与高肿瘤选择性相关，因此允许精确的放射增敏。的方法 可以扩展到治疗其他癌症，如前列腺癌、头颈癌、乳腺癌和结肠癌， 其中NTSR 1也被上调。