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 1阶段提案研究了新型高性能碳的安全性和功效 基于纳米结构的磁共振成像（MRI）对比剂，用于成像和监测 肾衰竭的患者。每年，在美国，约有2000万人受到轻度至重度的治疗 肾衰竭。与肾衰竭有关的大量病例（大于50％）处于高级 阶段，导致发病率，死亡率的发生，并增加医疗资源和成本的负担。 肾脏损伤或疾病的非侵入性成像，尤其是在高级阶段和 /或其他病理学 /或 肾衰竭患者的病变仍然是诊所的主要挑战。 X射线计算机断层扫描（CT）和 MRI通常在诊所中用于成像肾脏和其他器官的解剖结构。外源化学物质 使用碘和gadolin元素合成的称为对比剂（CAS）已广泛使用 分别提高CT和MRI的诊断信心。但是，在晚期肾脏患者中 失败，这些CAS与疾病肾脏发质全身纤维化（NSF）的发作有关。在这些 NSF患者表现为严重的衰弱状况，使皮肤变硬并增厚 关节和限制关节迁移率会引发极端疼痛。此外，内部器官这样 作为心脏，肺和肝脏可能会受到影响，有时会导致死亡。 我们最近开发了一种新型的基于碳纳米结构的MRI CA，由高质量组成 石墨烯（石墨单片）纳米颗粒（磁盘形，直径25 nm，厚度2-3 nm，5-7张 石墨烯，也称为石墨烯纳米片或GNP）（化学物种插入和捕获） 在两个石墨烯片之间的空隙中），并与石墨烯痕量的锰配位（0.1 ％w/w（w =重量））GNP通过自然化的非共价功能化水溶解化 生物相容性FDA批准的聚合物葡萄糖（以下称为GNP-DEX）。总体目标 建议是在潜在的 治疗剂量，在肾衰竭模型中。成功完成研究将证明 GNP-DEX公式大大增强了对比度（大约是当前临床MRI的10倍 Ca），并且没有任何NSF如潜在治疗剂量的各种器官的指标或有毒作用。这 本提案中详细介绍的原则研究证明是加速翻译的关键步骤 进入诊所的技术，我们预计这将使我们能够在非 - 在STTR 2期间，啮齿动物模型，随后为第一次人类试验做准备。决赛 该技术完整开发后的商业产品将是FDA批准的第一个MRI 肾衰竭患者的CA。 GNP-DEX也可能是由于其高效率用于其他诊所的 作为目前现有的基于Gadolinium的T1 MRI CAS的替代标签MRI CA的应用。