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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=529097
• 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.

MRI作为主要的临床成像方式之一，可以无创深入到完整、不透明的物体内部，提供高分辨率的内部三维信息，已成为最强大的疾病诊断工具之一。据估计，目前近50%的临床MRI扫描使用MRI造影剂（CA），这是一种新型的药物产品，可以增强MRI的造影剂和敏感性。大多数T1造影剂固有的低弛豫度（一个定义MRI CA疗效的术语）已经成为一个关键的技术瓶颈，限制了其在临床医学和生物医学研究中的广泛应用和潜力。目前的建议主要是为了克服T1 CA的弛豫限制，利用基于完善的Solomon-Bloembergen -Morgan理论的系统化学方法，开发基于卟啉的高弛豫T1 CA，并具有良好的生物医学应用兼容性。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的卟啉低聚物，包括分子大小、分子几何形状和构象刚性。将研究这些变量对T1弛豫度的影响，以及它们的药代动力学特性和毒性，以评估它们在生物医学应用中的有效性和安全性。此外，利用这些新的卟啉低聚物的抗磁性版本的荧光成像和光动力治疗（PDT）的潜力也将被检查。在本提案中，理论预测，化学合成，光谱表征和生物学评价将战略性地结合起来。本研究获得的系统的构效关系将为今后更合理地设计MRI ca提供指导。我们的长期目标是应用这种新一代T1 CAs，结合现代MRI技术和先进的分子靶向策略，在早期有选择性和无创地检测疾病，如癌症。