具有聚集诱导发光性质的树状大分子的组装及其在癌症多模态诊疗方面的研究

The current theranostic platform largely relies on the integration of multiple materials with different functionalities. The all-in-one approach has the risk of high complicity with reduced reproducibility. Smart design of simple molecules born with multifunction should represent one of the future directions in theranostics. Comparing with conventional theranostic materials, fluorogens with aggregation-induced emission (AIEgens) characteristics have been demonstrated to possess intrinsic advantages in terms of various imaging and therapeutic modalities, representing one type of such smart materials. However, currently developed theranostic AIEgens are all single modal imaging-guided monotherapy. Considering the practical clinical applications, the development of multimodalities of diagnostic imaging and therapy is attracting increasing interest, because different modalities are able to compensate for each other and provide enhanced imaging quality and therapeutic efficacy. . This project will synthesize multifunctional AIEgens with multimodal imaging (FLI/PAI/PTI) and synergistic therapy (PDT/PTT). Covalently conjugating AIEgens with hydrophilic dendrimers generates amphiphilic AIE macromolecules, which readily self-assemble into AIE nanoparticles for study on their multimodal theranostic applications in cancer. For mimicking the arginine-rich domains in natural transduction peptides, dendritic arginine-rich architecture is designed to bring inherent multivalent effects to enhance the tumor cell-and-tissue dual penetrating abilities, Meanwhile, the introduction of guanidinium-rich groups of arginine into the supramolecular assembly can offer a very efficient strategy to generate dual mitochondrial and nuclear targeting, which facilitates the phototherapy (PDT/PTT). On the other hand, endowing the AIE-active nanoparticles with tumor-activatable dual-penetration and dual-targeting must be an extremely important consideration to enhance tumor-specific invasion and minimize disturbance to normal tissue. This project will provide useful insights into the design of multimodal theranostic materials with AIE features, and open up a novel avenue on ingenious combination of AIEgens and dendrimers for defeating theranostic dilemmas on cancer.

当前诊疗一体化体系的构建主要依赖于将不同功能材料结合在一起而形成多功能纳米粒子。然而，各种材料之间存在难以预测的相互作用导致其极为复杂的制备过程和较低的重复性。因此，设计集多种功能于一体的智能分子用以构建诊疗一体化系统用于临床癌症治疗意义重大。与传统的诊疗分子相比，聚集诱导发光分子在多种成像与治疗方面都具有显著优势，但是当前开发的诊疗一体的聚集诱导发光分子均为单一成像引导的单一治疗，而实际临床中则需要不同成像方式以及不同治疗模式间进行结合，才能达到精准、高效的癌症诊疗效果。. 本项目拟合成具多模态诊疗的聚集诱导发光分子，通过共价结合树状大分子组装成纳米粒子，用于癌症多模态诊疗的研究。充分利用树状大分子特定分子构筑，开发的多模态诊疗体系还具有以下优势：血液长循环；肿瘤激活的“细胞-组织”双重渗透；线粒体和细胞核双重靶向。该体系有望为癌症的干预提供新的解决方案和思路。

开发集多种诊疗模态于一体的多功能有机分子用于癌症诊疗一体化对于提高癌症治疗效果意义重大。与传统的有机诊疗分子相比，聚集诱导发光分子在多种成像与治疗中都具有显著优势，非常适宜于开发成为多功能诊疗分子。然而当前开发的诊疗一体的聚集诱导发光分子均为单一成像引导的单一治疗，而实际临床中则需要不同成像方式以及不同治疗模式间进行结合，才能达到精准、高效的癌症诊疗效果。基于此，本项目通过多种策略调控聚集诱导发光分子在聚集态下的分子运动，在保留辐射跃迁与系间窜越耗散途径的前提下，使部分激发态能量以非辐射热耗散的形式衰减，巧妙实现其激发态能量的辐射跃迁与非辐射跃迁之间的平衡，以此构建了一系列集荧光成像、光声成像、光动力治疗和光热治疗等多种诊疗功能于一体的聚集诱导发光分子，无需其他诊疗试剂协助，仅仅基于单种多功能的聚集诱导发光分子，即可实现荷瘤小鼠模型的荧光−光声双模态成像指导的肿瘤光动力−光热协同治疗。此外，本项目负责人还从荧光成像指导的光动力治疗、光声成像指导的光热治疗和多模态诊疗三个方面系统全面总结了不同功能的聚集诱导发光诊疗分子的常用设计策略及其在光学诊疗领域的广泛应用，概括了聚集诱导发光分子在生物医学领域特别是疾病诊疗领域的突出优势并提炼出了“聚集增强诊疗（aggregation-enhanced theranostics, AET）”概念。本项目的研究成果将为高性能聚集诱导发光诊疗材料的开发提供分子设计原则，并为癌症多模态光学诊疗研究提供新材料和新方法。在基金的支持下，项目负责人在Chemical Society Reviews, Advanced Materials, ACS Nano, Biomaterials等国际重要学术期刊上发表标注受本项目资助的论文共8篇，包括“ESI高被引论文”2篇，2篇论文获得“最佳论文奖”。申请相关专利2项。协助培养研究生2名。