Biodegradable macromolecular Blood pool contrast agents

描述（由申请人提供）：本研究项目的目标是设计和开发新型可生物降解的大分子Gd（ll）复合物，作为安全，有效的磁共振成像（MRI）血池造影剂。动物模型显示，聚二硫Gd（ll）配合物无毒，血液循环时间长，可降解并迅速从体内消除。它们有望进一步进行临床前和临床开发。本研究将重点对聚二硫化物的结构进行优化，开发出体内降解率和药代动力学可控、体内增强效果更好的新一代非离子型聚二硫化物Gd（ll）配合物。这种新型的非离子型药物具有最小的组织积累、低渗透压和广泛的临床应用前景。具体目的是设计、合成和表征具有可控制降解率和可控制血浆药代动力学的新型非离子多二硫化物Gd（ll）配合物；研究Gd（ll）螯合物的弛豫性、可降解性、热力学稳定性和大分子试剂的化学稳定性等理化性质；研究新型药物的血浆药代动力学、消除和生物分布、血流动力学安全性、急性和亚急性耐受性及最大耐受剂量；探讨生物可降解大分子造影剂在常规和动态MRI增强动物模型肿瘤成像中的效果；并为进一步的临床前和临床开发确定一种降解率可控、有效增强造影剂、最小体潴留和最佳安全性的先导剂。该项目的长期目标是开发一种安全、有效的可生物降解的大分子血池MRI造影剂，用于临床癌症成像。该研究项目旨在开发更有效的MRI造影剂，以提高对包括癌症和心血管系统疾病在内的威胁生命疾病的早期诊断的准确性。早期发现和诊断将使照顾这些患者的医生能够尽早治疗这些疾病，提高患者的生活质量，降低死亡率。

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.