The development of novel radiation-sensitizer based on ultra-small carbon dots

基于超小碳点的新型辐射增敏剂的研制

• 批准号: 10454865
• 负责人: Zibo Li
• 金额: $ 48.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454865
• 关键词: 18F-fluorothymidine; Biodistribution; Biological Assay; Caliber; Cancer Etiology; Cancer Patient; Carbon; Categories; Cisplatin; Development; Diagnosis; Disease; Dose; Elements; Environment; Esophagitis; Etoposide; Extravasation; Failure; Formulation; Gadolinium; Head Cancer; Hematology; In Vitro; Intravenous; Ions; Label; Lead; Ligands; Lobectomy; Lung; Lymph Node Dissections; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metals; Methodology; Methods; Modeling; Mus; Names; Nanoconjugate; Neck Cancer; Neurotensin; Neurotensin Receptors; Newly Diagnosed; Niacinamide; Non-Small-Cell Lung Carcinoma; Patient imaging; Patients; Penetration; Persons; Pharmaceutical Preparations; Positron-Emission Tomography; Procedures; Property; Pulmonary Inflammation; Radiation; Radiation Dose Unit; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Regional Disease; Renal clearance function; Research; Reticuloendothelial System; Risk; Roentgen Rays; Scheme; Silicon Dioxide; Structure of parenchyma of lung; Surface; Tissues; Toxic effect; Toxicity Tests; Treatment Efficacy; Treatment outcome; analog; appropriate dose; base; cancer cell; cancer type; cell killing; chemoradiation; chemotherapy; cytotoxicity; efficacy study; follow-up; image-guided radiation; improved; in vivo; irradiation; malignant breast neoplasm; microPET; molecular imaging; mortality; nanoparticle; novel; particle; patient stratification; radiation resistance; receptor; research clinical testing; scale up; standard care; systemic toxicity; targeted delivery; therapy outcome; tumor; tumor specificity; uptake

Abstract Diagnosed in >187,000 persons each year, non–small cell lung carcinoma (NSCLC) has been a leading cause of cancer-related mortality in the US. For NSCLC patients, radiation therapy (RT) or chemoradiotherapy has been used as the standard care when the disease stays at locally advanced or local regional stage. Recently, radiotherapy have also been proven to be a viable alternative to lobectomy and lymph node dissection in stage I NSCLC patients. Despite its wide application in NSCLC patient management, the efficacy of RT would often be limited by the innate or acquired radioresistance. A wide range of radiosensitizers, such as cisplatin, 5-Fu, nicotinamide, and etoposide, are often used in concurrent with RT to improve treatment outcome. Unfortunately, these drugs could also cause severe systematic toxicities while enhancing tumor killing efficacy. This research proposes to develop a new category of radiosensitizer based on the ultra-small metal- intercalated-carbon dots (named as M@Cdots), aiming to achieve enhanced cancer killing effect with minimal systemic toxicity. Our M@Cdots have various unique features including: 1) enhanced RT therapy effects of X- ray: the metal fillings of M@Cdots enhance photoelectric effects of X-ray, which, in conjunction with the carbon surface catalyzed radiolysis, lead to remarkable radiosensitizing effects; 2) limited cytotoxicity: due to the bio- inert carbon shell, M@Cdots are not susceptible to metal falloff as many conventional high-Z nanoparticles are, and they cause little cytotoxicity in the absence of ionizing irradiation. Meanwhile, due to its ultra-small size (3nm), M@Cdots are efficiently excreted through renal clearance with minimal reticuloendothelial system (RES) uptake, reducing the risk of long-term toxicity to the host. 3) template synthesis methods: M@Cdots are made through mesoporous template calcination and are 3 nm in diameter. This unique approach allows easy scale-up synthesis of particles, and permits reliable metal encapsulation without extensively re-exploring synthetic procedures. Our preliminary therapy results are very promising. On this basis, we will also explore active tumor targeting by conjugating neurotensin (NTS) ligands to the surface of M@Cdots. The target, neurotensi receptor 1 (NTSR1), is upregulated in large numbers of lung cancer patients but not in normal lung tissues. It is hypothesized that with excellent tumor selectivity, efficient radiosensitization, minimal metal falloff, and efficient renal clearance, NTS-M@Cdots will lead to greatly improved RT outcomes at the same or even reduced radiation doses while causing minimal systemic toxicities. Although the current study is focused on NSCLC, the methodology can also be easily extended to treatment of other cancer types, for instance head and neck, breast, and prostate cancer.

摘要 每年在187,000人中确诊的非小细胞肺癌(NSCLC)一直是主要的 美国癌症相关死亡的原因。对于非小细胞肺癌患者，放射治疗(RT)或放化疗 当疾病停留在局部晚期或局部区域阶段时，已被用作标准护理。最近， 放射治疗也被证明是一种可行的替代分期肺叶切除和淋巴清扫的方法。 1例非小细胞肺癌患者。尽管RT在非小细胞肺癌患者管理中得到了广泛的应用，但其疗效往往 受到先天的或后天的辐射抗性的限制。多种放射增敏剂，如顺铂、5-FU、 烟酰胺和依托泊苷经常与RT同时使用，以改善治疗结果。不幸的是， 这些药物在增强肿瘤杀伤力的同时还可能造成严重的全身毒性。 这项研究建议开发一种基于超小金属的新型放射增敏剂-- 插层碳点(简称M@Cdots)，旨在以最小的成本实现增强的杀癌效果 全身毒性。我们的M@Cdots具有各种独特的功能，包括：1)增强X-RT治疗效果 射线：M@Cdots的金属填充增强了X射线的光电效应，这与碳 表面催化辐解，具有显著的辐射增敏作用；2)有限的细胞毒性：由于生物 惰性碳壳，M@Cdots不像许多传统的高Z纳米粒子那样容易受到金属衰减的影响， 在没有电离辐射的情况下，它们几乎没有细胞毒性。同时，由于它的超小尺寸(3 Nm)， M@Cdots通过肾脏清除以最低限度的网状内皮系统(RES)摄取有效地排泄， 降低对宿主的长期毒性风险。3)模板合成方法：M@Cdots通过 介孔模板经焙烧后，直径为3 nm。这一独特的方法允许轻松纵向扩展 颗粒的合成，并允许可靠的金属封装，而无需广泛地重新探索合成 程序。 我们的初步治疗结果非常有希望。在此基础上，我们还将探索主动肿瘤靶向 通过将神经降压素(NTS)配体连接到M@Cdots的表面。靶标神经降压素受体1(NTSR1)， 在大量肺癌患者中表达上调，但在正常肺组织中不表达。据推测， 具有良好的肿瘤选择性、有效的放射增敏、最小的金属衰减和有效的肾脏清除， NTS-M@Cdots将在相同或甚至更低的辐射剂量下极大地改善放疗结果，而 造成最小的全身毒性。虽然目前的研究重点是非小细胞肺癌，但方法学也可以 可以很容易地扩展到其他癌症类型的治疗，例如头颈部、乳腺癌和前列腺癌。