A Graphene Nanoparticle-Based X-ray Computed Tomography Contrast Agent ForSubjects At Risk for Contrast Induced Nephropathy

基于石墨烯纳米粒子的 X 射线计算机断层扫描造影剂，适用于有造影剂肾病风险的受试者

• 批准号: 9347832
• 负责人: Jimmy Deon Toussaint
• 金额: $ 16.05万
• 依托单位: THERAGNOSTIC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347832
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Adverse effects; Animal Model; Benzene; Biological Markers; Blinded; Blood; Blood Urea Nitrogen; Carbon; Carbon nanoparticle; Cell Culture Techniques; Cells; Characteristics; Child; Clinical; Computers; Contrast Media; Creatinine; Creatinine clearance measurement; Data; Detection; Deterioration; Development; Dextrans; Diabetes Mellitus; Diagnosis; Dialysis procedure; Disadvantaged; Disease; Dissociation; Dose; Effectiveness; FDA approved; Feasibility Studies; Fibroblasts; Fibrosis; Formulation; Functional disorder; Health Care Costs; Heart failure; Histopathology; Hour; Human; ICAM3 gene; Image; Imaging Phantoms; Impairment; In Vitro; Injury; Investigation; Investigational Drugs; Investigational New Drug Application; Iodine; Iohexol; Ions; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Label; Link; Literature; Magnetic Resonance Imaging; Manganese; Measurable; Measures; Methods; Modeling; Monitor; Morphology; Names; Nanostructures; Nephrotoxic; Noise; Organ; Osmolalities; Osmolar Concentration; Oxides; Pathology; Patient Agents; Patient risk; Patients; Performance; Pharmacology Study; Phase; Polymers; Preventive screening; Procedures; Production; Publishing; Publishing Peer Reviews; Radio; Rattus; Reactive Oxygen Species; Renal Tissue; Renal clearance function; Renal function; Reporting; Risk; Rodent; Rodent Model; Roentgen Rays; Safety; Saline; Scanning; Secure; Serum; Signal Transduction; Small Business Innovation Research Grant; System; Technology; Testing; Therapeutic; Thyroid Gland; Time; Toxic effect; United States National Institutes of Health; Urine; Viscosity; X-Ray Computed Tomography; acute toxicity; base; body system; clinical imaging; cohort; contrast enhanced; covalent bond; cytotoxic; dosage; efficacy study; good laboratory practice; graphene; high risk; imaging agent; improved; in vivo; kidney epithelial cell; microCT; multimodality; nanoparticle; nephrotoxicity; novel; pre-clinical; preclinical study; prevent; radiologist; rat KIM-1 protein; tomography; tool

Abstract This SBIR phase 1 proposal is to demonstrate the pre-clinical safety and efficacy of a novel carbon-nanostructure-based X-ray computer tomography (CT) contrast agent (CA) for imaging and monitoring in patients with renal failure or at risk of contrast induced nephropathy (CIN). Routine contrast enhanced CT scans relays crucial information about diseases and injuries, thus aiding the clinician in improving diagnosis and management of patients. The present day CT CAs available on the market are all based on covalently bonded tri-iodinated benzene rings. However, they are all contraindicated for patients with renal insufficiency, diabetes, heart failure and thyroid dysfunction. Use of these CT CAs in these patient cohorts has been linked to CIN which deteriorates normal or further exacerbate pre-existing kidney functions. These adverse effects have been associated with high osmolality and viscosity CT CAs and the inability of these and even low or iso-osmolar and/or iso-viscous CT CA formulations to be completely eliminated of cytotoxic free iodine ions in solution. The technology detailed in this proposal builds on our previously reported novel carbon- nanoparticle based T1 iso-osmolar, iso-viscous Magnetic Resonance Imaging (MRI) CA. This comprises of manganese (Mn2+) intercalated graphene oxide nanoplatelets (GNP) covalently functionalized with dextran, and named GNP-Dex. This formulation shows low acute toxicity, high blood stability and high renal clearance through the urine. For expanded multimodal use, we intercalated and covalently functionalized iodine ions to the inner graphene sheet layers. This method of sequestration of iodine prevents its dissociation as free ions into solution. This formulation we termed GNP-I. In vitro studies done on kidney epithelial cell culture demonstrated favorable GNP-I cyto-compatibility. Furthermore, at equimolar concentration of iodine, GNP-I showed very high CT (~10 times greater) radio-opacity signals in phantoms compared to the control–Iohexol (Omnipaque™) – a commonly used CT CA. Thus these lower detection limits will allow the same clinical imaging performance at substantially lower dosages, thus lowering healthcare costs. Based on GNP-I characteristics, inclusive of its apparent higher safety and efficacy profiles than that of currently available CT CAs, the thrust in this proposal is to develop it specifically for monitoring and diagnosis of kidney and other vital organs for patients at risk of CIN. Thus, thereby overcoming the limitations of present day CT CAs. For this, we will conduct pre-clinical safety and efficacy feasibility studies in a well validated rodent model of acute kidney injury, that is, the 5/6 Nephrex rat. Successful completion of the aims outlined in this proposal will lead to submission of a SBIR phase 2 proposal to perform safety and efficacy pre-clinical studies in a suitable large animal model under good laboratory practice (GLP) followed by Investigational New Drug (IND) application to the FDA. Furthermore, successful development will lead to the first FDA- approved CT CA specifically for use in these high risks, distinctly disadvantaged patient groups.

抽象的 SBIR 1阶段的建议是证明新颖的临床前安全性和效率 基于碳纳米结构的X射线计算机断层扫描（CT）对比剂（CA）用于成像 并监测肾衰竭或面临造影剂诱发肾病（CIN）的风险。 常规对比增强了CT扫描中继有关疾病和伤害的关键信息， 这有助于改善患者的诊断和管理。今天 市场上可用的CT CAS都是基于共价键合的三碘苯环。 但是，对于肾功能不全，糖尿病，心力衰竭的患者，它们都是禁忌的 和甲状腺功能障碍。在这些患者队列中使用这些CT CAS已与CIN相关 这决定了正常或进一步加剧预先存在的肾脏功能。这些对手 效果与高渗透压和粘度CT CAS有关，并且无法 这些甚至是低或iso-osmolar和/或iSo-viscous ct Ca公式 消除溶液中的细胞毒性无碘离子。 该提案中详细介绍的技术建立在我们先前报道的新颖碳 - 基于纳米颗粒的T1 ISO渗透性，等音磁共振成像（MRI）Ca。这 包括锰（MN2+）插量的石墨烯氧化石墨烯纳米片（GNP）共价 用葡萄糖官能化，并命名为gnp-dex。该配方显示低急性毒性， 高血稳定性和高肾脏清除通过尿液。用于扩展的多模式使用， 我们将碘化离子与内部石墨烯片层插入并共价化。 这种碘会议方法可阻止其解离作为溶液中的自由离子。 我们称为GNP-I的公式。对肾上皮细胞培养进行的体外研究 证明了有利的GNP-I细胞兼容性。此外，在等摩尔浓度的 碘，GNP-I在幻像中显示出很高的CT（〜10倍）放射性信号 与对照 - iohexol（Omnipaque™）相比 - 常用的CT CA。这些较低 检测极限将使相同的临床成像性能在较低的剂量下进行， 因此降低了医疗保健成本。 基于GNP-I特征，包括其明显更高的安全性和效率概况 当前可用的CT CAS中，该提案的推力是专门针对 对有CIN风险的患者监测和诊断肾脏和其他重要器官。那， 从而克服了当今CT CAS的局限性。为此，我们将进行临床前 在经过良好验证的急性肾脏损伤模型中的安全性和效率可行性研究， IS，5/6 Nephrex大鼠。该提案中概述的目标成功完成将导致 提交SBIR 2阶段的提案，以在A中进行安全性和有效性前研究 在良好的实验室实践（GLP）下进行合适的大动物模型，然后进行研究 新药（IND）应用于FDA。此外，成功的发展将导致 首先专门用于这些高风险的FDA-批准的CT CA，这显然处于不利地位 患者群体。