Advanced Manufacturing Process for High Performance MRI Contrast Agents

高性能 MRI 造影剂的先进制造工艺

• 批准号: 8714201
• 负责人: Valeriy Bezmelnitsyn
• 金额: $ 22.5万
• 依托单位: LUNA INNOVATIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714201
• 关键词: Accounting; Acute; Affect; Animals; Arterial Fatty Streak; Atherosclerosis; Biodistribution; Biological Assay; Biological Markers; Blood; Capital; Chemicals; Chemistry; Clinical; Collection; Contrast Media; Cost Analysis; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Kinetics; Encapsulated; Environmental Impact; Equipment; Exposure to; Film; Foundations; Fullerenes; Gadolinium; Goals; Half-Life; Health; Image; Immune system; Intervention; Investigational Drugs; Investigational New Drug Application; Ionizing radiation; Kilogram; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Marketing; Methods; Modeling; Mus; One-Step dentin bonding system; Organic solvent product; Outcome; Patients; Penetration; Performance; Phase; Plasma; Preclinical Testing; Preparation; Process; Production; Productivity; Property; Protocols documentation; Quality Control; Resolution; Safety; Solid; Solvents; Soot; Staging; Sterility; Structure; Technology; Tissues; Toxic effect; Training; base; caged molecule; cancer imaging; clinical Diagnosis; clinically relevant; cost; gadolinium oxide; imaging probe; immunogenicity; improved; in vitro testing; manufacturing process; molecular imaging; novel; pressure; programs; research clinical testing; research study; solvent extraction; sound; sublimation; tool; vapor; wasting

DESCRIPTION (provided by applicant): Contrast-enhanced magnetic resonance imaging is widely used for non-invasive diagnosis of a variety of diseases. However due to the intrinsic properties of existing gadolinium-chelate contrast agents, there exist clinical needs of improved MRI contrast agents that render extended circulatory half-life enabling blood pool imaging with favorable biodistribution and enabling tissue-specific imaging; reduce Gd associated long term safety concerns; have greater relaxivity and generate positive contrast enhancement. Luna is developing metallofullerene-based T1 agents for both blood pool imaging and targeted imaging of cancer and atherosclerotic plaque. We have conducted extensive animal studies demonstrating substantially improved imaging sensitivity at lower does, and no acute toxicity was found. It is a very promising new T1 contrast agent platform technology. However, to be cost competitive and capable of producing clinically relevant quantities, it is necessary to improve the existing manufacturing process for metallofullerenes. Luna proposes to develop a high-volume train sublimation process in place of the existing batch extraction-purification processes allowing direct collection of high purity metallofullerenes from as-produced reactor soot. Fundamental improvements will be made in existing manufacturing processes that deliver substantial productivity, quality, and environmental benefits. These improvements will overcome challenges facing the high cost purification, a significant barrier in the realization of metallofullerene-based MRI contrast agents. In vitro testing will be conducted following the proposed production process to demonstrate that the physiochemical and magnetic properties are not affected. We will also extrapolate information from the structure-activity (relaxivity) relationship and optimize the relaxivity property to maximize the clinical potential of our Hydrochalarone agents. Along with stability studies and quality control assays, the Phase I results will provide a sound foundation to proceed to Phase II for IND- enabling pharmacokinetics, toxicity and imaging studies.

描述（由申请人提供）：对比增强的磁共振成像被广泛用于各种疾病的非侵入性诊断。然而，由于现有的Gadolinium-Chelate对比剂具有内在特性，因此存在改进的MRI对比剂的临床需求，这些临床需求使循环的半衰期扩展，从而使血池成像具有良好的生物分布并实现组织特异性成像；减少与GD相关的长期安全问题；具有更大的放松性并产生正对比度增强。露娜（Luna）正在开发基于金属的T1剂，用于血液池成像和癌症和动脉粥样硬化斑块的靶向成像。我们已经进行了广泛的动物研究，证明了Low的成像敏感性大大提高，并且没有发现急性毒性。这是一种非常有前途的新T1对比剂平台技术。但是，要具有成本竞争力并能够生产临床相关的数量，有必要改善金属脂烯的现有制造过程。露娜（Luna）建议开发一个大容量的火车升华过程，以代替现有的批次提取纯化过程，允许直接收集从ASPROPUSE的反应器烟灰中收集高纯度金属氟烯烯。在现有的制造过程中，将进行基本的改进，这些工艺可带来可观的生产力，质量和环境利益。这些改进将克服高成本净化面临的挑战，这是实现基于金属氟烷的MRI对比剂的重大障碍。在提出的生产过程之后，将进行体外测试，以证明生理化学和磁性不受影响。我们还将从结构活动（松弛）关系中推断信息，并优化放松性特性，以最大程度地提高水chalarone剂的临床潜力。除稳定性研究和质量控制测定外，I期结果还将为II阶段提供良好的基础，以促进药代动力学，毒性和成像研究。