Biodegradable Macromolecular MRI Contrast Agents

可生物降解高分子MRI造影剂

• 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
• 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

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）： 本研究的主要目的是开发可生物降解的高分子钆 (III) 复合物作为用于癌症成像的安全、有效的 MRI 造影剂。由于恶性肿瘤的血管丰富以及肿瘤血管的通透性高，大分子药物具有较长的血浆和组织保留时间，并且可以优先在实体瘤中积聚。近十年来已经证明，大分子造影剂在癌症检测和分期以及肿瘤血管生成成像方面优于临床使用的低分子量MRI造影剂，并且可能具有利用MRI对癌症治疗反应进行无创成像的潜力。然而，缓慢的金属清除和随之而来的毒性作用限制了大分子Gd(III)配合物的临床开发。需要创新的方法来解决这个问题。我们打算开发一类新型可生物降解的大分子Gd(III)复合物，它可以被体内的生物分子降解成更小的分子，在MRI检查后很容易从体内清除。将设计可生物降解的结构并将其纳入大分子顺磁复合物的聚合物主链中。这些结构可以被血浆中的生物分子裂解，导致大分子断裂成更小的复合物，这些复合物可以通过肾小球滤过去除。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。初步评价药物的弛豫性、降解性、急性毒性、体内清除率和对比度增强等理化和生物学特性。在R33阶段，药物的结构将得到优化。将使用体外和体内方法详细评估它们的 NMRD 概况、安全性、体内清除率和癌症成像对比度增强。将选择具有低毒性、适当的体内保留时间、可接受的体内清除率和对癌症MR成像有效的对比增强的先导药物进行进一步的临床前和临床开发。