Lanthanide Metallacrowns as Near-Infrared Fluorescent Probes for Optical Imaging

描述（由申请人提供）：早期发现癌症对提高患者生存率和生活质量至关重要。利用近红外荧光造影剂进行近红外光学成像是一种相对不成熟的肿瘤检测方式，其潜力尚未得到充分发挥。镧系离子（Ln3+）具有非常适合用作近红外造反差剂的发光特性，而一类被称为金属冠（MC）的超分子结构是Ln3+离子致敏近红外荧光的一个有前途的平台。本课题的重点是合成和开发用于肿瘤成像的Ln3+[MC]配合物。具体来说，我们将1)合成一系列Ln3+[MC]结构并表征它们的光物理性质以确定能量传递机制，2)设计新的MC配体在附着肽易位载体时在可见光区域吸收，3)评估对一系列肿瘤细胞系的体外生物相容性。利用目前已合成的Ln3+[MC]系列结构，研究了发射波长(？F)，荧光量子产率(？f)，荧光寿命（¿f）和水合值(q)将被制表，为进一步合成精制和优化近红外荧光提供必要的信息。将探索氘化配体，以确定分子的哪些部分参与了向Ln3+离子的能量转移。基于氟酮染料的新配体也将被制成，以进一步将吸收转移到可见光中。这些新的配体将允许引入官能团以偶联肿瘤靶向肽，这些肽将被重新合成。最后，具有最有前途的光学性质的Ln3+[MC]s和与肿瘤靶向肽结合的Ln3+[MC]s将推进到体外生物相容性研究，包括检查溶液稳定性、细胞活力、细胞摄取和细胞内荧光。总的来说，这种合成策略之后的初步生物学评估将为进一步的合成改进提供信息。这些研究的完成将有助于更好地了解Ln3+[MC]s的荧光特性，并确定有希望作为近红外荧光肿瘤造影剂实际应用的候选物质。

DESCRIPTION (provided by applicant): Early detection of cancer is essential to improve patient's survival rates and quality of life. Near-infrared (NIR) optical imaging using a NIR fluorescent contrast agent is one relatively undeveloped modality for tumor detection whose potential has not yet been fully realized. Lanthanide ions (Ln3+) have luminescent properties well suited for application as NIR contrast agents and one promising platform for sensitization of Ln3+ ions for NIR fluorescence is a class of supramolecular structures called metallacrowns (MC). The focus of this proposal will be to synthesize and develop Ln3+[MC] complexes for tumor imaging applications. Specifically we will 1) synthesize a series of Ln3+[MC] structures and characterize their photophysical properties in order to determine the energy transfer mechanism, 2) design new MC ligands to absorb in the visible region while attaching peptide translocation vectors, and 3) assess in vitro biocompatibility against a range of tumor cell lines. Using the series of Ln3+[MC] structures that have been synthesized to date, key photophysical parameters, such as emission wavelength (?f), fluorescence quantum yield (?f), fluorescence lifetime (¿f), and hydration number (q), will be tabulated providing the necessary information for further synthetic refinement and optimization of NIR fluorescence. Deuterated ligands will be explored to determine which parts of the molecule participate in energy transfer to the Ln3+ ion. New ligands based on fluorone dyes will also be made to further shift the absorption into the visible. These new ligands will allow introduction of functional groups for conjugation to tumor targeting peptides which will be synthesized de novo. Finally, Ln3+[MC]s with the most promising optical properties and those conjugated to tumor targeting peptides will be advanced to in vitro studies of biocompatibility that will include examination of solution stability, cell viability, celular uptake, and intracellular fluorescence. Overall, this synthetic strategy followed by preliminary biological assessment will inform further synthetic refinement. Completion of these studies will provide a better understanding of the fluorescent properties of Ln3+[MC]s and identify promising candidates for practical application as NIR fluorescent tumor contrast agents.