Porphyrin-based high relaxivity MRI T1 contrast agents for biomedical imaging

用于生物医学成像的基于卟啉的高弛豫 MRI T1 造影剂

• 批准号: 387704-2010
• 负责人: Zhang, XiaoAn
• 金额: $ 2.33万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=507147
• 关键词: Porphyrin; based; relaxivity; MRI; T1

As one of the major clinical imaging modalities, MRI can noninvasively penetrate deep into an intact, opaque object to provide interior 3D information with a high resolution, which has become one of the most powerful diagnostic tools for detecting diseases. It was estimated that almost 50% of clinical MRI scans nowadays used a MRI contrast agent (CA), a new class of pharmacological product which can enhance the contrast and sensitivity of MRI. The intrinsic low relaxivity (a term that defines the efficacy of MRI CA) for most T1 contrast agents has become a critical technical bottle-neck, limiting its broader application and potential in clinical medicine and biomedical research. The current proposal mainly aims to overcome the relaxivity limitation of T1 CA, using a systematic chemical approach based on a well-established Solomon-Bloembergen -Morgan theory, and to develop porphyrin-based high relaxivity T1 CAs with well-suited compatibility for biomedical applications. A series of porphyrin oligomers with systematically programmed chemical and physical parameters, including molecular size, molecular geometry and conformational rigidity, will be designed, synthesized and characterized. The influence of these variables on the T1 relaxivity, together with their pharmacokinetic properties and toxicity, will be investigated, to evaluate their efficacy and safety for biomedical application. In addition, the potential of using the diamagnetic version of these new porphyrin-oligomers for fluorescence imaging and photodynamic therapy (PDT) will also be examined. In this proposal, theoretical prediction, chemical synthesis, spectroscopic characterization, and biological evaluation will be strategically combined. The systematic structural-activity relationship obtained from current study will provide a guidance towards more rational design of MRI CAs in the future. Our long-term goal is to apply this new generation of T1 CAs, in combination with modern MRI technique and advanced molecular targeting strategy, to selectively and noninvasively detect disease, such as cancer, at early stage.

作为主要的临床成像方式之一，MRI可以无创地深入到完整、不透明的物体内部，提供高分辨率的内部3D信息，已成为检测疾病最有力的诊断工具之一。据估计，当今临床 MRI 扫描中近 50% 使用 MRI 造影剂 (CA)，这是一类新型药物产品，可以增强 MRI 的对比度和灵敏度。大多数T1造影剂固有的低弛豫率（定义MRI CA功效的术语）已成为关键的技术瓶颈，限制了其在临床医学和生物医学研究中的更广泛应用和潜力。目前的提案主要旨在克服T1 CA的弛豫限制，使用基于完善的Solomon-Bloembergen-Morgan理论的系统化学方法，并开发基于卟啉的高弛豫T1 CA，具有非常适合生物医学应用的兼容性。将设计、合成和表征一系列具有系统编程的化学和物理参数（包括分子大小、分子几何形状和构象刚性）的卟啉低聚物。将研究这些变量对 T1 弛豫度的影响及其药代动力学特性和毒性，以评估其生物医学应用的功效和安全性。 此外，还将研究使用这些新型卟啉低聚物的抗磁性版本用于荧光成像和光动力疗法（PDT）的潜力。在该提案中，理论预测、化学合成、光谱表征和生物学评估将被战略性地结合起来。当前研究获得的系统结构-活性关系将为未来更合理的MRI CA设计提供指导。我们的长期目标是应用新一代 T1 CA 结合现代 MRI 技术和先进的分子靶向策略，在早期选择性、无创地检测疾病，例如癌症。