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

基本信息

批准号：
10059478
负责人：
Zibo Li
金额：
$ 52.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10059478
关键词：
Biodistribution Biological Assay Caliber Cancer Etiology Cancer Patient Carbon Categories Cisplatin Development Diagnosis Disease Dose Elements Environment 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 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

项目摘要

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) 每年有超过 187,000 人被诊断出来，一直是主要的癌症对于美国非小细胞肺癌 (NSCLC) 患者，放射治疗 (RT) 或放化疗是导致癌症相关死亡的原因。最近，当疾病处于局部晚期或局部区域阶段时，已被用作标准护理。放疗也被证明是阶段性肺叶切除术和淋巴结清扫术的可行替代方案 I NSCLC 患者尽管放疗在 NSCLC 患者管理中广泛应用，但其疗效通常会受到影响。受到先天或获得性放射抗性的限制多种放射增敏剂，例如顺铂、5-Fu、不幸的是，烟酰胺和依托泊苷通常与 RT 同时使用以改善治疗结果。这些在增强肿瘤杀伤功效的同时还可能导致严重的系统毒性药物。这项研究提出开发一种基于超小型金属的新型放射增敏剂插层碳点（命名为M@Cdots），旨在以最小的成本实现增强的杀癌效果我们的 M@Cdots 具有各种独特的功能，包括：1) 增强 X- 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，与碳结合表面催化放射分解，导致显着的放射增敏作用；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脱落的影响，在没有电离辐射的情况下，它们几乎不会产生细胞毒性，同时，由于其尺寸超小（3nm）， M@Cdots 通过肾清除有效排泄，网状内皮系统 (RES) 的摄取量最小， 3）模板合成方法：M@Cdots是通过M@Cdots制成的。介孔模板煅烧，直径为 3 nm，这种独特的方法可以轻松放大。颗粒的合成，并允许可靠的金属封装，而无需重新探索合成程序。我们的初步治疗结果非常有前景，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) 配体缀合至 M@Cdots 的目标神经降压素受体 1 (NTSR1) 表面，在大量肺癌患者中表达上调，但在正常肺组织中不表达。具有出色的肿瘤选择性、高效的放射增敏、最小的金属脱落和高效的肾脏清除率， NTS-M@Cdots 将在相同甚至减少辐射剂量的情况下大大改善 RT 效果，同时尽管目前的研究主要针对非小细胞肺癌，但该方法也可以引起最小的全身毒性。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。