聚多巴胺仿生交联AIE纳米诊疗体系构筑与应用研究

Facile preparation of multifunctional nanotheranostic systems is one of the frontier and hot research field in nanomedicine.Based on our research background in mussel inspired chemistry and aggregation induced emission (AIE) bioprobes, we proposed the ideas for fabrication of multifunctional polydopamine (PDA) cross linked AIE nanotheranostic systems via mussel inspired chemistry for the first time. Take advantage of the self polymerization of dopamine under alkaline solution, PDA cross linked AIE nanotheranostic systems can be easily prepared by design of AIE dyes and fabrication of AIE dyes and dopamine contained polymers. Photothermal treatment of cancer using PDA cross linked AIE nanotheranostic systems were further explored for the photothermal effects of PDA. On the other hand， many other moieties including functional polymers, therapeutics, targeting agents can be further introduced onto PDA cross linked AIE nanoparticles via Michael addition reaction due to the high reactivity of PDA, thus multifunctional nanotheranostic systems based on PDA cross linked AIE nanoparticles can be fabricated via mussel inspired chemistry. Then cell imaging, drug loading and controlled release as well as their targeting profiles of these multifunctional nanotheranostic systems will be investigated. Their pharmacokinetic behavior, biocompatibility as well as anti-tumor effects were also involved. The proposal developed a novel method for fabrication of PDA cross linked AIE based multifunctional theranostics. It will be not only of significance for deeply understanding the mussel inspired chemistry, but also provide novel ideas for development of other multifunctional nanotheranostic systems.

利用简单高效的方法，构建集成像和治疗为一体的多功能性纳米诊疗体系已成为当今纳米生物医学研究的重要方向和前沿领域。以贻贝仿生化学和聚集诱导发光(AIE)纳米探针构建领域的工作为基础，我们首次提出了利用贻贝仿生化学构筑聚多巴胺(PDA)交联的AIE荧光纳米诊疗体系的研究思路。通过AIE染料的设计，制备多种含有AIE染料和多巴胺的高分子；利用多巴胺的氧化自聚性质，实现AIE纳米颗粒的仿生交联。结合PDA的光热效应，探索PDA交联型AIE纳米诊疗体系在肿瘤热疗中的应用。另外，利用PDA的高化学反应活性，我们还可以将功能性高分子、治疗性成分、靶向基团通过Michael加成反应连接到AIE纳米颗粒表面上。再从细胞和动物层次研究其生物成像、药物载带和控制性释放及靶向性能；进而考察其代谢动力学行为、生物安全性和抗肿瘤效果。本项目不仅有利于深入理解贻贝仿生化学，也将为多功能纳米诊疗体系的构筑提供新的思路。

自2001年唐本忠院士首先提出聚集诱导发光现象以来，合成及构建聚集诱导发光性能的小分子以及功能材料成为化学研究的一个前言方向。本项目以聚集诱导发光分子合成为基础，通过聚集诱导发光分子的结构和官能团设计，发展了一系列的聚集诱导发光荧光材料的构建方法，探索了这些材料在生物荧光成像、多模成像以及诊疗一体化方面的应用。具体如下：1）发展了多种基于聚集诱导发光分子的发光材料的构建方法，包括多组分反应，可见光自催化聚集诱导发光分子可控聚合以及基于微波，超声辅助的聚集诱导发光材料的合成方法，2）通过聚集诱导发光材料的构建，将载药官能团、生物相容性高分子PEG以及聚集诱导发光分子集成到聚集诱导发光材料上，实现了这些聚集诱导发光材料在药物高效载带和可控释放以及诊疗一体化方面的应用；3）通过聚集诱导发光分子的设计，合成了本身具有聚集诱导发光性能以及质谱信号的荧光分子，探索了单一聚集诱导发光分子的双模成像应用；4）将聚集诱导发光分子和Gd3+集成到介孔硅上，实现了荧光和磁共振成像一体化应用。通过项目的实施，我们在聚集诱导发光生物应用材料进行了许多探索，发表了超过50篇的相关研究论文和综述。这些研究结果对于推动聚集诱导发光材料的发展，有利于中国在相关领域的引领作用。