Biodegradable macromolecular Blood pool contrast agents

描述(申请人提供)：本研究项目的目标是设计和开发新型的可生物降解的大分子Gd(111)配合物，作为安全、有效的磁共振成像(MRI)血池造影剂。动物模型显示，多二硫化物Gd(111)络合物无毒，具有延长血液循环时间，可降解并迅速从体内消除的特点。它们在进一步的临床前和临床开发方面很有希望。拟开展的研究将集中于优化多二硫化物的结构，以开发新一代非离子多二硫化物Gd(111)配合物，具有可控的体内降解率和药代动力学，并改善体内对比剂增强。新型非离子药物具有组织蓄积小、渗透压低等优点，在临床上具有广阔的应用前景。其具体目的是设计、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多硫化物Gd(111)配合物；研究其物理和化学性质，包括弛豫度、降解性、Gd(111)络合物的热力学稳定性和大分子制剂的化学稳定性；研究新制剂的血浆药代动力学、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量；通过常规和动态增强MRI研究可生物降解的大分子造影剂在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寻找一种降解率可控、有效的对比剂增强、最小的体内滞留和最佳的安全性特征的先导剂。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磁共振造影剂，用于临床癌症成像。本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危及生命的疾病的早期诊断的准确性。早期发现和诊断将使护理这些患者的医生能够寻求这些疾病的最早治疗，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.