Development of Metalloporphyrin for Diversified Applications: from Contrast Agent for Magnetic Resonance Imaging to Electrocatalyst for Carbon Dioxide Reduction

开发金属卟啉的多元化应用：从磁共振成像造影剂到二氧化碳还原电催化剂

• 批准号: RGPIN-2022-04860
• 负责人: Zhang, Xiaoan
• 金额: $ 1.75万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762184
• 关键词: Development; Metalloporphyrin; Diversified; Applications; Contrast

Our program explores the structural and functional diversity of metalloporphyrin for the development of 1) next generation contrast agent (CA) for magnetic resonance imaging (MRI), and 2) novel electrocatalyst for CO2 reduction. Part 1 focuses on the design, synthesis and evaluation of new Mn3+-porphyrin (MnP) as Gd-Free MRI CA. MRI is based on spatially encoded NMR signals mainly from H2O protons. The image contrast of MRI can be enhanced by paramagnetic agent via shortening the NMR relaxation time of local 1H nuclei, thus enabling the detection of otherwise invisible disease. Gadolinium based CA (GBCA) has dominated clinic market for >30 years. Recently, however, GBCAs have been linked to severe side effects due to the low kinetic stability, causing the release and deposition of toxic Gd3+ ion in vivo. The low sensitivity, thus high dose of GBCA escalates the toxicity risk. To overcome these intrinsic limitations of GBCAs, we've been dedicated to developing Gd-free alternatives based on MnP. Through rational design, we've shown that new MnPs with higher sensitivity, stability and biocompatibility can be synthesized. This allowed us to further design different classes of MnPs specific for extracellular, liver-targeted, intravascular or intracellular applications, demonstrating the potential of MnP not only to replace the existing GBCAs, but also to enable new functions that classic GBCAs are unable to reach. This proposal explores the following directions: 1) study how metal-ligand interaction influences the MRI sensitivity and stability of MnPs; 2) optimize the key properties of MnPs by rational ligand modification; 3) design new strategy for MRI based reporter-gene system, allowing monitoring of protein-expression in live animals, 4) develop general approach for labeling antibody with MnPs-oligomer for targeted disease imaging; 5) explore new chemical reactions for MnP bioconjugation. Our long-term goal is to develop MRI probes for detecting diseases and visualizing biological activities in living objects with optimal safety, sensitivity, and specificity. Part 2 of the proposal will expand the functions of MP for electrochemical CO2 reduction. Based on the initial success, we will tackle the following key challenges in the field: 1) study mechanism of CO2 electrochemical reduction, focused on the order and energy barrier of electron and proton transfer; 2) design novel porphyrins with improved coupled efficiency between electron and proton transfer; 3) study the structure-activity relationship, in particular on how different metal ions and/or spin states influence the rate-determining step; and 4) develop new strategy for efficient immobilization of porphyrin catalyst on electrode surface. Rooted in the common ground of porphyrin chemistry, both parts of the program span the interface of organic, inorganic, biological, analytical, and physical chemistry, engaging and cultivating multidisciplinary collaborations, thus ideal for HQP training.

我们的项目探索金属卟啉的结构和功能多样性，以开发1）用于磁共振成像（MRI）的下一代造影剂（CA），和2）用于CO2还原的新型电催化剂。第一部分着重于新的Mn 3 +-卟啉（MnP）作为无Gd MRI CA的设计、合成和评价。MRI基于主要来自H2O质子的空间编码NMR信号。磁共振成像的图像对比度可以通过顺磁剂通过缩短局部1H核的NMR弛豫时间来增强，从而使得能够检测到否则不可见的疾病。钆基CA（GBCA）已主导临床市场超过30年。然而，最近，由于动力学稳定性低，GBCA与严重的副作用有关，导致有毒Gd 3+离子在体内的释放和沉积。低敏感性，因此高剂量的GBCA增加了毒性风险。为了克服GBCA的这些固有局限性，我们一直致力于开发基于MnP的无Gd替代品。通过合理的设计，我们已经证明可以合成具有更高灵敏度、稳定性和生物相容性的新型MNP。这使我们能够进一步设计出不同种类的MNP，这些MNP特异性地用于细胞外、肝脏靶向、血管内或细胞内应用，证明了MNP不仅可以取代现有的GBCA，而且还可以实现经典GBCA无法实现的新功能。本论文的主要研究方向是：1）研究金属-配体相互作用对MNP的MRI敏感性和稳定性的影响; 2）通过合理的配体修饰优化MNP的关键特性; 3）设计基于MRI的MNP-基因系统的新策略，实现活体动物蛋白质表达的监测; 4）开发MNP-寡聚体标记抗体用于靶向疾病成像的通用方法; 5）探索新的化学反应用于MNP生物缀合。我们的长期目标是开发MRI探针，以最佳的安全性，灵敏度和特异性检测疾病和可视化活体生物活动。该提案的第2部分将扩展MP用于电化学CO2还原的功能。在此基础上，我们将在以下几个方面展开研究：1）研究CO2电化学还原机理，重点研究电子和质子转移的有序性和能垒; 2）设计新型卟啉化合物，提高电子和质子转移的耦合效率; 3）研究结构-活性关系，特别是不同的金属离子和/或自旋状态如何影响速率决定步骤;（4）探索卟啉催化剂在电极表面高效固定化的新方法。植根于卟啉化学的共同点，该计划的两个部分跨越有机，无机，生物，分析和物理化学的界面，参与和培养多学科合作，因此非常适合HQP培训。