红光TADF型光敏剂的合成及其光动力肿瘤治疗性能

Malignant tumor (cancer) is one of the major diseases that threatens human health, and has become a major concern for researchers. The traditional treatments of cancer mainly are surgery, chemotherapy and radiotherapy. However, these treatments can cause serious systematic damage and side effects. Due to minimally invasive, good controllability and low systemic damage, the emerging photodynamic therapy has received widespread attention in oncotherapy. Photosensitizers as the core part of photodynamic therapy still exist some imperfections, such as weak absorption in red region, low yield of singlet oxygen and selectivity. In this project, the applicant designs different types of large conjugated units with multiple electron-withdrawing groups as acceptor units via the molecular engineering, then synthesizes a series of water-soluble red light-absorbing thermally-activated delayed fluorescence (TADF) materials, and further investigates the effect of the types of acceptor units and substituted sites on photophysical properties. As a result, we propose a principle for controllably prepare red TADF emitters with different energy gap between singlet state and triplet state (ΔEST). Moreover, the red TADF emitters can be served as photosensitizers, so we study the influence of ΔEST on the yield of singlet state oxygen and fluorescence imaging, and then further apply the photosensitizers to tumor-imaging and targeting photodynamic therapy, and aim to exploit high singlet oxygen yield, low dark cytotoxicity and biocompatible red TADF-type photosensitizers.

光动力治疗作为一种微创、可控性好和低系统性损坏的肿瘤治疗方法，受到科研人员的广泛关注。光敏剂作为光动力肿瘤治疗的核心与关键，仍然存在红光吸收能力弱和单线态氧产率低的问题。在本项目中，申请人提出，通过分子工程手段设计不同类型的具有多个吸电子基团的大共轭单元作为受体单元，来合成系列具有水溶性的红光吸收的热活化延迟荧光（TADF）材料，研究受体单元类型及其取代位置对TADF性质的影响，揭示红光TADF材料的设计原理，有望可控地制备具有不同单线态-三线态能隙差的TADF材料。在此基础上，以红光TADF材料作为光敏剂，研究能隙差对单线态氧产率和荧光成像的影响，进一步将其应用于肿瘤成像介导的光动力治疗，开发出高的单线态氧产率、低暗毒性和良好生物相容性的红光TADF型肿瘤治疗光敏剂。

近红外光，尤其是二区近红外光，由于具有弱的组织散射作用和高的最大允许曝光剂量，使其具有深的组织穿透深度，在肿瘤光诊疗领域备受关注。本项目围绕近红外光吸收有机光热材料的设计合成、及其微环境响应、光热效应和抗肿瘤性能方面开展一系列科学研究，并取得了一些研究成果，具体成果为：（1）提出了利用给受体分子间π-π作用来制备电荷转移复合物纳米粒子，表现出高NIR-II吸收能力，且光热转换效率高于42%，发现了电荷转移复合物纳米粒子可以选择性地与半胱氨酸发生加成反应，从而抑制胞内GSH的生物合成，造成氧化还原失衡和GPX4蛋白活性抑制，诱导细胞铁死亡，并通过NIR-II光治疗和铁死亡协同作用可以有效地改善肿瘤治疗效率。（2）利用Fe3+与多酚的配位络合作用，构建了具有3D结构的配位聚合物的纳米粒子。由于多酚配体与Fe3+之间发生配体到金属的电荷转移作用, BDP-Fe NPs展现出高的光热转换效率（49%）和良好的NIR-II光声成像造影剂。由于Fe3+ 的化学动力作用，通过化学动力/光热协同效应，可以有效地杀死肿瘤细胞。（3）以卟啉锌衍生物（ZnP）为核，并在ZnP纳米粒子表面包裹聚多巴胺，得到具有核壳结构的纳米粒子（ZnP@PDA NPs），ZnP@PDA NPs不仅保持着优异的光动力性能，还具有高的光热转换能力，其光热转换效率可达46.8%。在细胞和活体层面的实验证明ZnP@PDA NPs能够有效地靶向肿瘤部位，以及高的光毒性和肿瘤光治疗效率。在基金支持下，申请人以第一作者或通讯作者分别在Angew. Chem. Int. Ed., Chem. Commun., J. Mater. Chem. B等专业杂志上发表研究论文8篇，申请发明专利2件，培养研究生3名，圆满地完成了基金申请时的预期目标。