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

作为主要的临床成像方式之一，MRI可以无创地深入到完整的、不透明的物体中，以提供具有高分辨率的内部3D信息，这已经成为检测疾病的最强大的诊断工具之一。据估计，目前几乎50%的临床MRI扫描使用MRI造影剂（CA），这是一类新的药理学产品，可以增强MRI的对比度和灵敏度。大多数T1造影剂的固有低弛豫率（定义MRI CA有效性的术语）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。目前的建议主要旨在克服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，具有良好的生物医学应用兼容性。一系列的卟啉低聚物与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，将被设计，合成和表征。将研究这些变量对T1弛豫率的影响，以及它们的药代动力学特性和毒性，以评价它们在生物医学应用中的有效性和安全性。 此外，使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。在这个提议中，理论预测，化学合成，光谱表征和生物评价将战略性地结合起来。本研究所获得的系统构效关系将为今后更合理地设计磁共振造影剂提供指导。我们的长期目标是应用这种新一代的T1 CA，结合现代MRI技术和先进的分子靶向策略，选择性地和非侵入性地检测疾病，如癌症，在早期阶段。

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.