Biodegradable macromolecular Blood pool contrast agents

可生物降解高分子血池造影剂

• 批准号: 7777331
• 负责人: ZHENG-RONG LU
• 金额: $ 27.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777331
• 关键词: Abbreviations; Acids; Acute; Amides; Animal Model; Biodistribution; Blood; Blood Circulation Time; Blood Vessels; Cardiovascular system; Clinical; Complex; Contrast Media; Cystamine; Cystine; Detection; Development; Diagnosis; Diphosphates; Disease; Drug Kinetics; Early Diagnosis; Early treatment; Electron Transport Complex III; Esters; Gadolinium; Gadolinium DTPA; Generations; Glutathione Disulfide; Goals; Image; Lead; Life; MS-325; Macromolecular Complexes; Magnetic Resonance Imaging; Malignant Neoplasms; Maximum Tolerated Dose; Modification; Molecular Weight; Osmolalities; Patient Care; Patients; Pentetic Acid; Pharmacologic Substance; Physicians; Plasma; Property; Research; Research Personnel; Research Project Grants; Safety; Sodium Chloride; Structure; Testing; Thermodynamics; Tissues; Toxic effect; Vascular Permeabilities; alkyl group; base; cancer imaging; chemical stability; clinical application; clinical practice; copolymer; design; diethylenetriaminepentaacetate; disulfide bond; gadofosveset trisodium; hemodynamics; improved; in vivo; mortality; novel; pre-clinical; programs; tumor

DESCRIPTION (provided by applicant): The objectives of this research project are to design and develop novel biodegradable macromolecular Gd(lll) complexes as safe, effective magnetic resonance imaging (MRI) blood pool contrast agents. Polydisulfide Gd(lll) complexes are non-toxic, have prolonged blood circulation time, can degrade and rapidly eliminate from the body as shown in animal models. They are promising for further preclinical and clinical development. The proposed research will focus on the optimization of the structure of polydisulfides to develop a new generation of non-ionic polydisulfide Gd(lll) complexes with controllable in vivo degradation rate and pharmacokinetics, and improved in vivo contrast enhancement. The novel non-ionic agents will have minimal tissue accumulation, low osmolality and broad applications in clinical practice. The specific aims are to design, synthesize and characterize novel non-ionic polydisulfide Gd(lll) complexes with controllable degradation rate and controllable plasma pharmacokinetics; to study their physicochemical properties including relaxivities, degradability and the thermodynamic stability of Gd(lll) chelates and chemical stability of the macromolecular agents; to investigate the plasma pharmacokinetics, elimination and biodistribution, hemodynamic safety, acute and subacute tolerance and maximum tolerated dose of the novel agents; to investigate efficacy of the biodegradable macromolecular contrast agents in tumor imaging in animal models with conventional and dynamic contrast enhanced MRI; and to identify a lead agent with controllable degradation rate, effective contrast enhancement, minimal body retention and optimal safety profiles for further preclinical and clinical development. The long-term goal of this project is to develop a safe, effective biodegradable macromolecular blood pool MRI contrast agent for clinical applications in cancer imaging. This research project is proposed to develop more effective MRI contrast agents to improve accuracy for the earlier diagnosis of life-threatening diseases including cancer and diseases in the cardiovascular systems. Earlier detection and diagnosis will allow the physicians caring these patients to pursue the earliest treatment of these diseases, improve the quality of the patients' life and reduce the mortality rate.

描述（由申请人提供）：本研究项目的目的是设计和开发新型生物可降解大分子Gd（III）复合物作为安全、有效的磁共振成像（MRI）血池造影剂。聚二硫化物Gd（III）络合物是无毒的，具有延长的血液循环时间，可以降解并从体内快速消除，如动物模型中所示。它们有望用于进一步的临床前和临床开发。拟议的研究将重点关注聚二硫键结构的优化，以开发新一代非离子聚二硫键Gd（III）配合物，其体内降解速率和药代动力学可控，并改善体内对比度增强。新型非离子型药物具有最小的组织蓄积、低渗透压和广泛的临床应用。具体目标是设计、合成和表征具有可控降解速率和可控血浆药代动力学的新型非离子聚二硫化物Gd（III）络合物;研究它们的物理化学性质，包括Gd（III）螯合物的弛豫性、降解性和热力学稳定性以及大分子试剂的化学稳定性;研究新药的血浆药代动力学、消除和生物分布、血流动力学安全性、急性和亚急性耐受性以及最大耐受剂量;研究生物可降解大分子造影剂在动物模型中常规和动态增强MRI肿瘤成像的有效性;并鉴定具有可控降解速率、有效的对比增强最小的身体保留和最佳的安全性特征，用于进一步的临床前和临床开发。本项目的长期目标是开发一种安全、有效的生物可降解大分子血池MRI造影剂，用于临床肿瘤成像。该研究项目旨在开发更有效的MRI造影剂，以提高早期诊断危及生命的疾病（包括癌症和心血管系统疾病）的准确性。早期发现和诊断将使护理这些患者的医生能够对这些疾病进行早期治疗，改善患者的生活质量，降低死亡率。