Lanthanide Metallacrowns as Near-Infrared Fluorescent Probes for Optical Imaging

描述（由申请人提供）：癌症的早期检测对于提高患者的生存率和生活质量至关重要。使用近红外荧光造影剂的近红外（NIR）光学成像是一种相对不发达的肿瘤检测方式，其潜力尚未完全实现。镧系离子（Ln 3+）具有非常适合用作NIR造影剂的发光性质，并且用于敏化Ln 3+离子以用于NIR荧光的一种有前景的平台是一类被称为金属冠（MC）的超分子结构。 本提案的重点将是合成和开发用于肿瘤成像应用的Ln 3 +[MC]配合物。具体而言，我们将1）合成一系列Ln 3 +[MC]结构并表征其生物物理性质，以确定能量转移机制，2）设计新的MC配体以在可见光区吸收，同时连接肽易位载体，3）评估对一系列肿瘤细胞系的体外生物相容性。使用一系列的Ln 3 +[MC]结构，已合成的日期，关键的光物理参数，如发射波长（？f）、荧光量子产率（？f）、荧光寿命（<$f）和水合数（q）将被制成表格，为进一步合成改进和优化NIR荧光提供必要的信息。氘代配体将被探索，以确定哪些部分的分子参与能量转移到Ln 3+离子。基于荧光酮染料的新配体也将进一步将吸收转移到可见光。这些新的配体将允许引入用于缀合至将从头合成的肿瘤靶向肽的官能团。最后，具有最有前途的光学性质的Ln 3 +[MC]s和与肿瘤靶向肽缀合的那些将被推进到生物相容性的体外研究，其将包括溶液稳定性、细胞活力、细胞摄取和细胞内荧光的检查。 总的来说，这种合成策略，然后进行初步的生物学评估，将为进一步的合成改进提供信息。这些研究的完成将提供更好地理解的荧光特性的Ln 3 +[MC]的，并确定有前途的候选人作为近红外荧光肿瘤造影剂的实际应用。

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.