Biodegradable Macromolecular MRI Contrast Agents

可生物降解高分子MRI造影剂

基本信息

批准号：
6924683
负责人：
ZHENG-RONG LU
金额：
$ 28.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2007-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6924683
关键词：
biodegradable product bioimaging /biomedical imaging contrast media cysteine diethylenetriaminepentaacetate early diagnosis gadolinium genetically modified animals histology imaging /visualization /scanning laboratory mouse laboratory rat macromolecule magnetic resonance imaging neoplasm /cancer blood supply neoplasm /cancer diagnosis pharmacokinetics plasma polymers technology /technique development

biodegradable product bioimaging /biomedical imaging contrast media cysteine diethylenetriaminepentaacetate early diagnosis gadolinium genetically modified animals histology imaging /visualization /scanning laboratory mouse laboratory rat macromolecule magnetic resonance imaging neoplasm /cancer blood supply neoplasm /cancer diagnosis pharmacokinetics plasma polymers technology /technique development

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项目摘要

DESCRIPTION (provided by applicant): The main aim of this research is to develop biodegradable macromolecular gadolinium (III) complexes as safe, effective MRI contrast agents for cancer imaging. Macromolecular agents have a prolonged plasma and tissue retention time and can preferentially accumulate in solid tumors because of the vascularity of malignant tumors and the hyperpermeability of tumor blood vessels. It has been demonstrated in the last decade that macromolecular contrast agents are superior in cancer detection and staging and neoplastic angiogenesis imaging to the low molecular weight MRI contrast agents used in clinics, and may have a potential for noninvasive imaging of cancer treatment response with MRI. However, the slow metal clearance and consequent toxic effects have limited the clinical development of macromolecular Gd(III) complexes. Innovative approaches are required to solve this problem. We intend to develop a new class of biodegradable macromolecular Gd(III) complexes, which can be degraded into smaller molecules by the biomolecules in the body, which can be readily cleared from the body after the MRI exams. Biodegradable structures will be designed and incorporated into the polymer backbones of macromolecular paramagnetic complexes. The structures can be cleaved by the biomolecules in the plasma, resulting in breakage of the macromolecules into smaller complexes that can be removed through renal glomerular filtration. This project includes feasibility (R21) and development (R33) phases. In the R21 phase, biodegradable macromolecular Gd(III) complexes will be designed and synthesized to demonstrate the feasibility of the novel agents. The physicochemical and biological properties including relaxivity, degradability, acute toxicity, in vivo clearance and contrast enhancement of the agents will be preliminarily evaluated. In the R33 phase, the structures of the agents will be optimized. Their NMRD profile, safety, in vivo clearance and contrast enhancement in cancer imaging will be evaluated in detail using in vitro and in vivo methods. A lead agent with low toxicity, appropriate in vivo retention time, acceptable in vivo clearance rate and effective contrast enhancement on cancer MR imaging will be selected for further preclinical and clinical development.

描述（由申请人提供）：这项研究的主要目的是开发可生物降解的大分子gadolinium（III）复合物作为癌症成像的安全，有效的MRI对比剂。大分子剂具有延长的血浆和组织保留时间，并且由于恶性肿瘤的血管性和肿瘤血管的过度过敏性，因此可以优先积聚在实体瘤中。在过去的十年中，大分子对比剂在癌症检测和分期和肿瘤血管生成成像中的表现优于临床中使用的低分子量MRI对比剂，并且可能具有对MRI癌症治疗反应的非侵袭性成像的潜力。然而，慢金属清除率和随之而来的有毒作用限制了大分子GD（III）配合物的临床发展。需要创新的方法来解决此问题。我们打算开发一类新的可生物降解的大分子GD（III）配合物，可以通过体内的生物分子降解为较小的分子，在MRI检查后可以很容易地从体内清除。可生物降解的结构将被设计并掺入大分子顺磁复合物的聚合物骨架中。可以通过血浆中的生物分子裂解结构，从而导致大分子破裂成较小的络合物，这些复合物可以通过肾肾小球过滤去除。该项目包括可行性（R21）和开发（R33）阶段。在R21阶段，将设计和合成可生物降解的大分子GD（III）配合物，以证明新型药物的可行性。将初步评估物理化学和生物学特性，包括松弛性，降解性，急性毒性，体内清除和对比度增强。在R33阶段，将优化代理的结构。他们的NMRD曲线，安全性，体内清除率和癌症成像中的对比度增强将使用体外和体内方法进行详细评估。毒性低，合适的体内保留时间，可接受的体内清除率和对癌症MR成像的有效对比度增强的铅剂，以进一步的临床前和临床发育。