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.

抽象的 非小细胞肺癌（NSCLC）每年被诊断出> 187,000人，一直是领先的 美国与癌症有关的死亡率的原因。对于NSCLC患者，放射治疗（RT）或化学放疗 当该疾病留在当地高级或地方区域阶段时，已被用作标准护理。最近， 放射疗法也已被证明是叶切除术和淋巴结清扫术的可行替代品 NSCLC患者。尽管它在NSCLC患者管理中广泛应用，但RT的效率通常会 受到先天或获得的放射性限制的限制。多种辐射激素，例如顺铂，5-FU， 烟酰胺和依托泊苷通常与RT并发用于改善治疗结果。很遗憾， 这些药物也可能引起严重的系统毒性，同时提高肿瘤杀伤效率。 这项研究提案旨在开发基于超小金属的新类别放射敏剂 互级碳点（称为M@CDOTS），旨在实现最小的癌症杀伤效果 全身毒性。我们的M@CDOT具有各种独特功能，包括：1）X-增强的RT治疗效果 Ray：M@CDOTS的金属填充物增强了X射线的光电效应，该X射线与碳结合 表面催化的辐射分解，导致明显的放射敏化作用； 2）细胞毒性有限：由于生物 惰性碳壳，m@cdot不容易受到金属损伤，因为许多常规的高Z纳米颗粒都是 在没有电离照射的情况下，它们几乎没有导致细胞毒性。平均值，由于其超小小的大小（3nm）， m@cdots通过肾脏清除率有效地独占，并具有最小的网状内皮系统（RES）的吸收， 降低对宿主长期毒性的风险。 3）模板合成方法：M@CDOT是通过 介孔模板计算，直径为3 nm。这种独特的方法可以轻松扩展 颗粒的合成，并允许可靠的金属封装而无需广泛重新探索合成 程序。 我们的初步疗法结果非常有前途。在此基础上，我们还将探索主动肿瘤靶向 通过将神经素（NTS）配体结合到M@CDOTS的表面。靶标，神经素受体1（NTSR1）， 在大量肺癌患者中进行更新，但在正常的肺组织中不进行更新。假设 具有出色的肿瘤选择性，有效的放射敏化，最小的金属下降和有效的肾脏清除率， NTS-M@CDOTS将在相同甚至减少辐射剂量下大大改善RT结果 导致最小的全身毒性。尽管当前的研究集中于NSCLC，但该方法也可以 很容易扩展到其他癌症类型的治疗，例如头部和颈部，乳腺癌和前列腺癌。