近红外二区（NIR-II, 1000-1700 nm）荧光成像因生物体对NIR-II光吸收及散射作用相对较弱，同时受组织自发荧光干扰较小，使得NIR-II荧光成像具有组织穿透性好，信噪比高等优点，近年来成为生物成像领域的研究热点。有机小分子荧光染料因其生物相容性好，光物理性质易调控等优点而受到广泛关注。然而，目前设计NIR-II荧光染料的构效关系规律仍不明确。此外，当前已报道的NIR-II荧光染料的荧光量子产率普遍较低，而且在水溶液中由于溶剂极性增加和聚集诱导猝灭等因素，发光量子产率进一步降低。因此，开发具有高荧光量子产率的NIR-II荧光染料仍面临巨大挑战。
本文基于氮杂-氟硼二吡咯（Aza-BODIPY）荧光团，通过合理的分子修饰和组装策略，制备了一系列性能优异的NIR-II荧光染料，具体包括以下两部分研究内容：
一、通过在Aza-BODIPY荧光团母核结构上引入咔唑基团，制备NIR-Ⅱ 荧光分子。咔唑基团的引入不仅可以增大染料分子的共轭结构，并且可以促进分子内电子转移，使Aza-BODIPY荧光团的吸收和发射光谱发生显著红移。通过设计、合成具有不同推拉电子结构的咔唑基Aza-BODIPY荧光染料，系统研究它们的光物理性质和轨道能级，总结了Aza-BODIPY荧光分子构效关系的设计规律。根据该规律最终设计得到，两个最大荧光发射峰位于1000 nm以上的新型Aza-BODIPY分子。
二、通过调控Aza-BODIPY类分子的分子间作用力和亲疏水性质，筛选得到高度有序J-聚集的NIR-II荧光染料。单晶衍射分析和光谱研究结果表明，3,5-位引入二苯并噻吩基团，1,7-位引入对烷氧基苯基团有利于促进其形成J-聚集体。通过进一步在1,7-位进行亲水基团和亲脂基团的修饰，得到了高亮度的两亲性衍生物ABDOG-2。相比单体，其J-聚集体的吸收峰发生180 nm左右的红移，摩尔消光系数达到1.6×105 cm-1M-1，绝对荧光量子产率达到10.11%。光热性能研究表明，其具有优异的光热稳定性和好的光热转换能力，为其进一步用于活体小鼠肿瘤的光热诊疗一体化奠定了基础。
 

The near-infrared region two (1000-1700 nm) fluorescence imaging has attracted much attention in the field of biological imaging due to the relatively weak absorption and scattering effect of the organism on NIR-II light and the small interference of tissue spontaneous fluorescence, which makes the fluorescence imaging of NIR-II have the advantages of good tissue penetration and high signal-to-noise ratio. Organic small molecule fluorescent dyes have been widely concerned because of their good biocompatibility and easy control of photophysical properties. However, the structure-activity relationship of the design of NIR-II fluorescent dyes is still unclear. In addition, the fluorescence quantum yield of the reported NIR-II fluorescent dyes is generally low, and the luminescence quantum yield is further reduced in aqueous solution due to the increase of solvent polarity and aggregation induced quenching. Therefore, the development of NIR-II fluorescent dyes with high fluorescence quantum yield still faces great challenges.
Herein, based on Aza-BODIPY fluorophores, a series of excellent NIR-II fluorescent dyes were prepared through molecular modification and assembly strategies, including the following two research contents:
First, the NIR-II fluorescent molecule was prepared by introducing carbazole group in the parent nucleus structure of Aza-BODIPY fluorophore. The introduction of carbazole group can not only increase the conjugate structure of dye molecules, but also promote the intramolecular electron transfer, so that the absorption and emission spectra of Aza-BODIPY fluorophore can be significantly redshifted. By designing and synthesizing carbazyl Aza-BODIPY fluorescent dyes with different push-pull electronic structures, their photophysical properties and orbital energy levels were systematically studied, and the design law of structure-activity relationship of Aza-BODIPY fluorescent molecules was summarized. According to this law, two new Aza-BODIPY molecules with maximum fluorescence emission peaks above 1000 nm were finally designed.
Second, by regulating the intermolecular force and hydrophilic and hydrophobic properties of Aza-BODIPY molecules, the highly ordered J-aggregation of NIR-II fluorescent dyes were screened. The results of single crystal diffraction and spectral analysis show that the introduction of dibenzothiophene groups at position 3,5 and p-alkoxy phenyl groups at position 1,7 can promote the formation of J-aggregates. By further modification of hydrophilic groups and lipophilic groups at position 1,7, a high-brightness amphiphilic derivative ABDOG-2 was obtained. Compared with the monomer, the absorption peak of J-aggregates showed a redshift of about 180 nm, the molar extinction coefficient reached 1.6×105 cm-1M-1, and the absolute fluorescence quantum yield reached 10.11%. The photothermal properties showed that it had excellent photothermal stability and good photothermal conversion ability, which laid the fousndation for further application of it in the integrated photothermal diagnosis and treatment of living mouse tumors.