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.
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