肽调控自组装酞菁光热纳米药物的制备、应用与组装机理研究

Photothermal therapy is a new developing anti-cancer technology, where the photo-sensitizers play a crucial role of determining the therapeutic effects. In terms of organic molecular sensitizers which exhibit high bioavailability and low toxicity, that how to design their structure and loading pattern, and optimize their photothermal therapeutic efficiency has become an important researching topic. While by utilizing natural peptide with self-assembly property, functional molecules can be well-tuned to self-assemble into controllable nanosystem and improve their stability as well as delivery efficiency. For the photothermal sensitizers, generally they were combined with peptides by intermolecular weak interactions and then co-assembled to nanosystem. In contrast, assembly of peptides and sensitizers that are connected by covalent bonds was rarely researched thus far. In this project, we plan to synthesize novel phthalocyanine-peptide conjugates as assembly units to fabricate monodispersed and stable nanoparticles, to investigate the effects of hydrophobicity and electricity from different peptides, and to study the assembly mechanism by molecular simulation. Further, by researching the in vitro and in vivo performance and toxicity of the prepared nanosystems, it is perspective to obtain a novel peptide-based photothermal therapeutic nanodrug system integrated with high conversion efficiency, high stability, and efficient drug delivery.

光热治疗是一种新兴的抗肿瘤技术，其中光敏剂的设计与选择是影响光热治疗效果的关键因素。对于具有良好生物相容性和低毒性的有机光敏剂小分子，如何设计其自身结构和负载方式并优化其光热治疗效果一直是研究中的难点。利用天然肽分子的自组装性质可以调控功能分子自组装形成纳米体系，提升稳定性和药物递送效率。对于光热治疗的光敏剂，通常将肽与光敏剂通过分子间弱作用结合，共组装形成纳米体系。而将肽与光敏剂以共价键结合形成肽缀合物进行自组装的方式目前罕见相关研究。本项目将合成新型酞菁—肽缀合物作为组装分子单元，通过自组装形成均一、稳定的纳米颗粒，通过选择不同的寡肽分子研究亲疏水性和电性对自组装过程的影响，并利用分子模拟手段揭示其自组装机理。进一步研究该自组装体系与细胞或活体作用，从而制备集高光热转换效率、高度稳定和有效递送于一体的新型肽基纳米光热药物体系。

本项目以制备新型肽基光热药物为目标，设计并合成了一系列酞菁—肽缀合物作为组装分子单元。其中酞菁—苯丙氨酸二肽缀合物通过自组装，可形成均一稳定的纳米颗粒，其光热转化效率在680 nm光照下达到43.6%，在体内表现出良好的光热治疗效果。同时，该化合物可通过动力学控制的自组装过程形成全新的纳米纤维结构，形成强烈的近红外吸收。产生这一特殊现象的原因为超分子结构中酞菁基团的间距非常小，导致分子间电荷转移，从而显著影响了前线轨道能级。基于这些研究，进一步总结了光热转化的基本机理并提出超分子光热效应，阐释了在光热治疗中超分子体系调节自身的光热转化能力更加简单灵活的物理化学机制。本项目的实施为设计新型光热纳米药物提供了新方法和理论指导，将推动光热药物向高效、精准、多功能化发展，同时也为推动光热治疗领域发展贡献了有益思路。