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: 10213674
• 负责人: Zibo Li
• 金额: $ 50.71万
• 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/10213674
• 关键词: 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 非小细胞肺癌（NSCLC）每年诊断超过187，000人，已成为肺癌的主要病因。 美国癌症相关死亡的原因。对于NSCLC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，最近， 放射治疗也被证明是一种可行的替代肺叶切除术和淋巴结清扫术的阶段 I NSCLC患者。尽管RT在NSCLC患者管理中应用广泛，但其疗效通常 受到先天或后天辐射抗性的限制。广泛的放射增敏剂，如顺铂，5-Fu， 烟酰胺和依托泊苷通常与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效力的同时也可能引起严重的全身毒性。 本研究提出开发一种基于超小金属微粒的新型放射增敏剂， 嵌入式碳量子点（命名为M@Cdots），旨在以最小的 全身毒性我们的M@Cdots具有各种独特的功能，包括：1）增强X射线的RT治疗效果， 射线：M@Cdots的金属填充物增强了X射线的光电效应， 表面催化辐解，导致显著的辐射增敏效应; 2）有限的细胞毒性：由于生物- 惰性碳壳，M@ Cdot不像许多常规高Z纳米颗粒那样对金属衰减敏感， 并且它们在没有电离辐射的情况下几乎不引起细胞毒性。同时，由于其超小尺寸（3 nm）， M@ Cdot通过肾清除率有效排泄，具有最小的网状内皮系统（RES）摄取， 降低对宿主的长期毒性的风险。3)模板合成方法：M@ Cdot通过 介孔模板煅烧和直径为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，而无需广泛地重新探索合成 程序. 我们初步的治疗结果很有希望。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）配体缀合到M@ Cdot的表面。靶点，神经紧张素受体1（NTSR 1）， 在大量肺癌患者中上调，但在正常肺组织中不上调。它是假设 具有优异的肿瘤选择性、有效的放射增敏性、最小的金属衰减和有效的肾清除， NTS-M@Cdots将在相同或甚至降低的辐射剂量下大大改善RT结果， 引起最小的全身毒性。虽然目前的研究集中在NSCLC，但该方法也可以 很容易扩展到其他癌症类型的治疗，例如头颈癌、乳腺癌和前列腺癌。