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.

摘要 本SBIR I期提案旨在证明一种新的药物的临床前安全性和有效性。 用于成像的基于碳纳米结构的X射线计算机断层摄影（CT）造影剂（CA） 以及在肾衰竭或有造影剂诱发肾病（CIN）风险的患者中进行监测。 常规对比增强CT扫描传递了有关疾病和损伤的重要信息， 从而帮助临床医生改进对患者的诊断和管理。今天 市售的CT CA均基于共价键合的三碘化苯环。 但是，它们都禁忌用于肾功能不全、糖尿病、心力衰竭患者 和甲状腺功能紊乱在这些患者队列中使用这些CT CA与CIN相关 其使正常的肾功能恶化或进一步恶化预先存在的肾功能。这些不良 影响与高渗透压和粘度CT CA以及 这些以及甚至低或等渗和/或等粘性的CT CA制剂完全 消除溶液中的细胞毒性游离碘离子。 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、等粘磁共振成像（MRI）CA。这 包括锰（Mn 2+）共价插层的氧化石墨烯纳米片（GNP）， 用葡聚糖官能化，并命名为GNP-Dex。该制剂显示出低急性毒性， 高血液稳定性和通过尿液的高肾清除率。对于扩展的多模式使用， 我们将碘离子插入并共价官能化到内部石墨烯片层。 碘的这种螯合方法防止其作为游离离子解离到溶液中。这 我们称之为GNP-I。对肾上皮细胞培养进行的体外研究 显示出有利的GNP-I细胞相容性。此外，在等摩尔浓度下， 碘，GNP-I在体模中显示非常高的CT（约10倍）射线不透性信号 与对照-碘海醇（Omnipaque™）-一种常用的CT CA相比。因此，这些较低 检测极限将允许在基本上较低的剂量下具有相同的临床成像性能， 从而降低医疗保健成本。 基于GNP-I的特征，包括其安全性和疗效明显高于 目前可用的CT CA，本提案的重点是专门针对 监测和诊断有CIN风险的患者的肾脏和其他重要器官。因此，在本发明中， 从而克服了当前CT CA的局限性。为此，我们将进行临床前 在经过充分验证的急性肾损伤啮齿动物模型中进行的安全性和有效性可行性研究， 是5/6肾鼠成功完成本提案中概述的目标将导致 提交SBIR II期提案，以在 根据药物非临床研究质量管理规范（GLP）建立合适的大型动物模型，然后进行研究 向FDA提交新药（IND）申请。此外，成功的开发将导致 第一个FDA批准的CT CA专门用于这些高风险，明显不利的 患者群体。