Preclinical Efficacy And Safety Evaluation Of Graphene Nanoparticle-based Magneti

石墨烯纳米粒子基磁性材料的临床前疗效和安全性评价

• 批准号: 8646659
• 负责人: Balaji Sitharaman
• 金额: $ 16.05万
• 依托单位: THERAGNOSTIC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646659
• 关键词: Acute; Affect; Anatomy; Animal Model; Biocompatible; Biodistribution; Biological; Blood; Blood Circulation; Blood Circulation Time; Caliber; Carbon; Carbon nanoparticle; Cessation of life; Characteristics; Chemicals; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials; Contracture; Contrast Media; Development; Dextrans; Diagnosis; Diagnostic; Disease; Dose; Drug Formulations; Elements; Evaluation; FDA approved; Fibrosis; Gadolinium; Guidelines; Half-Life; Health; Healthcare; Heart; Hour; Human; Image; In Vitro; Incidence; Injury; Iodine; Joints; Kidney; Kidney Diseases; Kidney Failure; Label; Lead; Lesion; Lethal Dose 50; Link; Liquid substance; Liver; Lung; Magnetic Resonance Imaging; Manganese; Measurable; Modeling; Monitor; Morbidity - disease rate; Nanostructures; Natural graphite; Noise; Onset of illness; Organ; Pain; Pathology; Pathway interactions; Patient Monitoring; Patients; Performance; Phase; Polymers; Process; Rattus; Resources; Rodent; Rodent Model; Safety; Shapes; Signal Transduction; Skin; Small Business Technology Transfer Research; Staging; System; Technology; Testing; Therapeutic; Thick; Time; Tissues; Toxic effect; Translations; Water; Weight; X-Ray Computed Tomography; base; cost; dextran; dosage; gadolinium oxide; hemodynamics; improved; in vivo; mortality; nanoparticle; novel; pre-clinical; preclinical efficacy; preclinical safety; radiologist; residence; technology development

Abstract This STTR phase 1 proposal investigates the safety and efficacy of a novel high-performance carbon nanostructure-based magnetic resonance imaging (MRI) contrast agent for the imaging and monitoring of patients with renal failure. Every year, in the US, approximately 20 million people are treated for mild to severe renal failure. A significant number of cases (greater than 50%) related to renal failure are at an advanced stage, and lead to incidences of morbidity, mortality and increase burden on health care resources and costs. Non-invasive imaging of renal injury or disease especially at advanced stages and /or other pathologies/ lesions in patients with renal failure is still a major challenge in clinic. X-ray computed tomography (CT) and MRI are routinely used in clinic to image the anatomy of kidneys and other organs. Exogenous chemicals called contrast agents (CAs) synthesized using the elements iodine and gadolinium has been widely employed to improve the diagnostic confidence of CT and MRI, respectively. However, in patients with advanced renal failure, these CAs have been linked to the onset of the disease nephrogenic systemic fibrosis (NSF). In these patients, NSF manifests as a severe debilitating condition that hardens and thickens the skin, causes contractures of the joints and restricts joint mobility triggering extreme pain. Furthermore, internal organs such as heart, lungs and liver can be affected, sometimes resulting in death. We have recently developed a novel carbon nanostructure-based MRI CA that comprises of high quality graphene (single sheet of graphite) nanoparticles (disk-shaped, diameter 25 nm, thickness 2-3 nm, 5-7 sheets of graphene, also called graphene nanoplatelets or GNPs) intercalated (chemical species inserted and trapped in the voids between two graphene sheets), and coordinated with graphene trace amounts of manganese (0.1 % w/w (w = weight)) The GNPs are water-solubilized via non-covalent functionalization with the natural biocompatible FDA-approved polymer dextran (hereafter called GNP-Dex). The overall objective of this proposal is to perform key proof-of-principle safety and efficacy studies with the GNP-Dex MRI CA, at potential therapeutic dosages, in a rodent model of renal failure. Successful completion of the studies will demonstrate that the GNP-Dex formulation substantially enhance the contrast (~10 times greater than current clinical MRI CA), and show no NSF like indicators or toxic effects on the various organs at potential therapeutic doses. The proof-of-principle studies detailed in this proposal represent a critical step in accelerating the translation of this technology into clinic, and we anticipate that it will allow us to initiate the safety and efficacy studies in a non- rodent animal model during STTR phase 2, and subsequently prepare for the first-in-human trials. The final commercial product(s) upon the complete development of this technology will be the first FDA-approved MRI CA for patients with renal failure. The GNP-Dex could also due to their high-efficacy be used in clinic for other applications as an alternative off-the-label MRI CA to currently existing gadolinium-basedT1 MRI CAs.

抽象的 该 STTR 第一阶段提案研究了新型高性能碳的安全性和有效性 基于纳米结构的磁共振成像 (MRI) 造影剂，用于成像和监测 肾功能衰竭患者。在美国，每年约有 2000 万人接受轻度至重度的治疗 肾功能衰竭。大量与肾衰竭相关的病例（超过 50%）已处于晚期 阶段，并导致发病率、死亡率的发生，并增加医疗保健资源和费用的负担。 肾损伤或疾病的无创成像，特别是在晚期和/或其他病理情况/ 肾功能衰竭患者的病变仍然是临床上的一大挑战。 X 射线计算机断层扫描 (CT) 和 MRI 在临床上常规用于对肾脏和其他器官的解剖结构进行成像。外源性化学物质 使用碘和钆元素合成的造影剂（CA）已被广泛使用 分别提高CT和MRI的诊断信心。然而，对于晚期肾病患者 如果失败，这些 CA 与肾源性系统性纤维化 (NSF) 疾病的发生有关。在这些 NSF 表现为一种严重的使人衰弱的疾病，使皮肤变硬和增厚，导致 关节挛缩并限制关节活动，引发极度疼痛。此外，内脏器官如 因为心脏、肺和肝脏可能受到影响，有时甚至导致死亡。 我们最近开发了一种新型的基于碳纳米结构的 MRI CA，它由高质量的 石墨烯（单片石墨）纳米粒子（圆盘状，直径25纳米，厚度2-3纳米，5-7片 石墨烯，也称为石墨烯纳米片或 GNP）插层（插入和捕获的化学物质 在两个石墨烯片之间的空隙中），并与石墨烯微量锰（0.1 % w/w (w = 重量)) GNP 通过与天然物质的非共价功能化而溶于水 FDA 批准的生物相容性聚合物右旋糖酐（以下称为 GNP-Dex）。本次活动的总体目标 提议是使用 GNP-Dex MRI CA 进行关键的原理验证安全性和有效性研究，有可能 在肾衰竭啮齿动物模型中的治疗剂量。成功完成研究将证明 GNP-Dex 制剂显着增强了对比度（比当前临床 MRI 强约 10 倍） CA)，并且在潜在治疗剂量下没有显示出类似 NSF 的指标或对各种器官的毒性作用。这 该提案中详细介绍的原理验证研究代表了加速该成果转化的关键一步 技术进入临床，我们预计它将允许我们在非非临床试验中启动安全性和有效性研究 在 STTR 第 2 阶段期间建立啮齿动物模型，并随后为首次人体试验做准备。决赛 该技术完全开发后的商业产品将是第一个获得 FDA 批准的 MRI CA适用于肾功能衰竭患者。由于其高效能，GNP-Dex 还可用于临床治疗其他疾病 作为当前现有基于钆的 T1 MRI CA 的替代品外 MRI CA 的应用。