基于萘酰亚胺类分子J聚集组装构筑智能响应型光热治疗

Photothermal therapy takes merit of photothermal conversion materials to kill cancer cell by generating local high temperature. This method possesses advantages including minimal invasiveness and good biosafety. It is of great significant to promote the clinical application of photothermal therapy. However, few types of organic photothermal agents were reported, along with the limited functions. And worst of all, the positive effect of photothermal therapy is hardly to observe in deep tissue area. Based on the controllable molecular self-assembly strategy, the research project is aiming to synthesize a series of naphthalimide derivatives and further prepare the J-aggregating nanoparticles. The absorbance wavelength and fluorescence intensity of J-aggregating nanoparticles could be easily regulated owing to its temperature-sensitive aggregation/disaggregation behavior. On one hand, the red shift of absorbance wavelength and enhancement of fluorescence intensity could achieve the long-wavelength fluorescence imaging-guided photothermal therapy without changing molecular structure and energy gap feature. Furthermore, the light transmissivity would be enhanced due to the disaggregation of J-aggregating nanoparticles at high temperature. As a result, the effective and extensive cancer cell killing in deep tissue could be finally realized through the deep and homogeneous heating. This work develops an innovate method to design stimuli-responsive organic photothermal agents via the molecular self-assembly strategy. It could not only enrich the types of organic photothermal agents, but also provide a simple and effective concept to construct a smart photothermal therapy system.

近红外光热治疗借助光热试剂产生局部高温杀伤癌细胞，具有微创和生物安全性高等优点，如何推动其进一步临床应用意义重大。然而，目前已报道的有机光热试剂种类较少且功能单一。此外，大多数光热试剂对深层组织的光热治疗效果不理想。本项目拟从分子可控自组装的角度出发，合成一系列新型萘酰亚胺类染料分子，基于染料分子温度响应的J聚集/解聚集行为，获得温敏性吸收波长和荧光强度可调的J聚集纳米粒子。一方面，J聚集纳米粒子吸收光谱红移且荧光增强，可以在不改变分子结构和能级的基础上实现长波长荧光成像辅助的光热治疗。同时，J聚集纳米粒子光热转换产生的高温可以使纳米粒子发生解聚集，提高入射光的透过率，提升深层加热和均匀加热性能，最终实现肿瘤组织的深层次、大面积损伤。该工作创新性地借助分子自组装策略设计刺激响应型有机近红外光热材料，不仅丰富了有机光热材料的种类，更为智能深层组织光热治疗体系的构筑提供了简单有效的设计思路。

近红外光热治疗主要是借助于光热转换材料将吸收的近红外光能转换成热能，提高肿瘤部位的温度，进而达到杀伤肿瘤细胞的目的。在此过程中，近红外光热转换材料的选择以及近红外光强度的检测是重中之重。然而，目前已报道的有机光热试剂种类较少且功能单一，而近红外光强度的检测多依赖于固体传感材料，缺乏一定的柔性和可掺杂性。本项目通过筛选母核结构和侧基类型设计合成一系列不同吸收波长的氮杂并苯四酰亚胺染料分子，并通过改变溶液浓度或溶剂种类来调节氮杂并苯四酰亚胺染料分子的J-聚集或H-聚集行为，在增强其水分散性，延长其近红吸收波长和提高其光热转换效率几个方面进行了深入研究。除此之外，在调控低共熔溶剂热力学性质构建高性能近红外光热传感器用于检测近红外光强度方面也开展了初步探索。项目具体研究内容和研究成果包括：（1）通过优化芳核结构以及侧基取代类型，将氮杂并苯四酰亚胺分子吸收波长调节至近红外区。（2）引入β支化的亲水性低聚乙二醇侧链，合成两亲性的氮杂并苯四酰亚胺分子，在水溶液中形成稳定的H-聚集纳米粒子，并在细胞水平和动物水平评估H-聚集纳米粒子的光热治疗效果。（3）侧链支化位点由β支化优化为δ支化，合成的侧链δ支化的两亲性氮杂并苯四酰亚胺分子能够在水溶液中形成规整的J-聚集体，吸收波长红移的同时大大提高了光热转换效率。（4）利用超热敏低共熔溶剂做液体温敏介质，并与光热转换材料复合，构建高效的近红外光热传感器用于监测近红外光强度。以上研究工作的展开不仅为借助调控分子的J-聚集或H-聚集行为设计新型有机近红外光热材料提供了创新性实例，也为基于低共熔溶剂构建高效近红外光热传感器提供了简单有效的设计思路。