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 该 SBIR 第一阶段提案旨在证明一种新型药物的临床前安全性和有效性 基于碳纳米结构的 X 射线计算机断层扫描 (CT) 成像造影剂 (CA) 并对肾功能衰竭或有造影剂肾病 (CIN) 风险的患者进行监测。 常规对比增强 CT 扫描可传递有关疾病和损伤的重要信息， 从而帮助临床医生改善当今患者的诊断和管理。 市场上的CT CA都是基于共价键合的三碘苯环。 但肾功能不全、糖尿病、心力衰竭患者禁用。 在这些患者群体中使用这些 CT CA 与 CIN 相关。 这会恶化正常肾功能或进一步恶化已有的肾功能。 影响与高渗透压和粘度 CT CA 以及无法 这些甚至低或等渗透和/或等粘度的 CT CA 制剂都可以完全 消除溶液中具有细胞毒性的游离碘离子。 该提案中详细介绍的技术建立在我们之前报道的新型碳- 基于纳米颗粒的 T1 等渗、等粘性磁共振成像 (MRI) CA。 由锰 (Mn2+) 共价插层氧化石墨烯纳米片 (GNP) 组成 用葡聚糖进行功能化，并命名为 GNP-Dex 该制剂显示出低急性毒性， 高血液稳定性和高肾清除率，用于扩大多模式使用， 我们将碘离子嵌入并共价功能化到内部石墨烯片层上。 这种碘隔离方法可防止其以自由离子形式解离到溶液中。 我们将这种制剂称为 GNP-I，在肾上皮细胞培养物上进行体外研究。 进一步证明，在等摩尔浓度下，GNP-I 具有良好的细胞相容性。 碘，GNP-I 在体模中显示非常高的 CT（约高 10 倍）射线不透明信号 与对照——碘海醇（Omnipaque™）——一种常用的 CT CA 相比，这些值较低。 检测限将允许以低得多的剂量实现相同的临床成像性能， 从而降低医疗费用。 基于 GNP-I 的特征，包括其明显高于 就目前可用的 CT CA 而言，该提案的主旨是专门为 对有 CIN 风险的患者的肾脏和其他重要器官进行监测和诊断。 克服当今 CT CA 的局限性，为此，我们将进行临床前研究。 在经过充分验证的急性肾损伤啮齿动物模型中进行安全性和有效性可行性研究， 也就是说，5/6 Nephrex 大鼠成功完成本提案中概述的目标将导致 提交 SBIR 第 2 阶段提案，以进行安全性和有效性临床前研究 在良好实验室规范 (GLP) 下建立合适的大型动物模型，然后进行研究 此外，成功的开发将带来新药（IND）申请。 第一个 FDA 批准的 CT CA 专门用于这些高风险、明显弱势的人群 患者群体。