Lanthanide Metallacrowns as Near-Infrared Fluorescent Probes for Optical Imaging

描述(申请人提供)：早期发现癌症对提高患者存活率和生活质量至关重要。使用近红外荧光造影剂的近红外光学成像是一种相对不发达的肿瘤检测方法，其潜力尚未完全实现。稀土离子(Ln3+)具有非常适合作为近红外对比剂的发光性质，而一种被称为金属冠醚(MC)的超分子结构是一种很有前途的敏化Ln3+离子近红外荧光的平台。这项提议的重点将是合成和开发用于肿瘤成像应用的Ln3+[MC]络合物。具体地说，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，使其在可见区域吸收，同时连接多肽转位载体；3)评估对一系列肿瘤细胞的体外生物相容性。利用迄今已合成的一系列Ln3+[MC]结构，将列出关键的光物理参数，如发射波长(？F)、荧光量子产率(？F)、荧光寿命(？f)和水化数(Q)，为进一步合成精制和优化近红外荧光提供必要的信息。为了确定分子的哪些部分参与了向Ln3+离子的能量转移，我们将探索氢化配体。基于荧光酮染料的新配体也将被制造出来，以进一步将吸收转移到可见光。这些新的配体将允许引入官能团，用于偶联到将从头合成的肿瘤靶向多肽。最后，具有最有前途的光学性质和那些与肿瘤靶向多肽结合的Ln3+[MC]S将被推进到体外生物相容性研究，包括溶液稳定性、细胞存活率、细胞摄取和细胞内荧光的检查。总体而言，这一综合战略之后是初步的生物评估，将为进一步的综合改进提供信息。这些研究的完成将使人们更好地了解Ln3+[MC]S的荧光性质，并确定作为近红外荧光肿瘤造影剂的潜在候选者。

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.