基于金属增强荧光机制的"可视化"光动力治疗纳米递送系统的构建及功能研究

Photodynamic therapy (PDT) is a promising therapeutic approach for various cancers and other diseases. PDT combines a photosensitizer (PS) and light of an appropriate wavelength to impart cytotoxicity via the generation of reactive molecular species. The light-induced electronic excitation of a PS can result not only in a cytotoxic effect but also in the emission of fluorescence due to relaxation of the excited-singlet-state PS back to the ground state. Gold nanorods (AuNRs) have drawn more attention owing to their well-defined optical features, especially surface plasmon resonance (SPR), which makes them ideal enhancement agents, such as metal-enhanced fluorescence (MEF). By utilizing a chemical approach, the structure and the optical properties of AuNRs as well as the distance between AuNRs and PS can be easily tuned. After tuned to achieve satisfactory fluorescence intensities, we will synthesis a core-shell structured multifunctional hybrid nanocomplex, in which PEG-PEI hydrogel, which could be formed by chemically cross-linked networks of the branched PEI and poly(ethylene glycol) (PEG), might be chemically grafted onto a single prefabricated AuNRs-based nanoparticles. In addition, the shell of PEG-PEI hydrogel are very promising as PS -delivery carriers because of its high loading capacity, high stability, and responsiveness to environmental factors, such as ionic strength, pH, and temperature that are unprecedented for common pharmaceutical nanocarriers. It is reasonable to speculate that the branched PEI is not only able to facilitate the current PS-delivery systems to move across cell membranes through rapid endocytosis but also able to disrupt intracellular organelles through a "proton sponge effect", while PEG may allow passive tumor accumulation of PS-delivery systems. To maximize specificity to tumor, PS-delivery systems will be finally functionalized by tumor-targeting molecules, such as folate, and transferring, and aptamer. In this project, the functional assembly of the PS-delivery systems will be studied, and the effects of structure of PS-delivery systems on the optical properties and photo-induced singlet oxygen generation, photo-cytotoxicity, PDT effect of PS will be studied in vitro and in vivo. By this work, we try find out the efficient route to adjust the structure to achieve satisfactory fluorescence intensities and PDT effects. The result of this project will provide information for the development and application of the efficient PS-delivery systems, which might be beneficial for guiding the design for diagnostic and imaging during PDT treatment for tumor.

在光动力反应体系中，光敏剂的荧光量子效率和单态氧产出效率成竞争性关系。因此，通过调控光敏剂与其载体之间的相互作用，以期同步实现肿瘤的光敏剂荧光诊断和光动力治疗，将为推动肿瘤的治疗向可视化、有效化、个性化、多样化发展提供重要保障。本项目旨在基于金属增强荧光原理，通过调控纳米金棒的结构、光学性质及其与光敏剂（酞菁）之间的距离等，实现酞菁的荧光增强效应。在此基础上，本项目还将结合纳米水凝胶对光敏剂药物的高负载能力，进行纳米光敏剂递送系统的组装，以协调发挥肿瘤靶向、荧光成像和光动力治疗等多功能性。本项目将通过调控纳米光敏剂递送系统的结构与理化性质，考察酞菁和单态氧的释放效率及其影响因素、抗肿瘤效果及其机制、荧光增强效果及其机制，阐明酞菁与其载体材料之间的"结构-相互作用-功能性" 的关系，并探讨纳米光敏剂递送系统与肿瘤细胞的相互作用机制，从而为肿瘤的"精确定位、精确治疗"提供理论基础和实验数据。

在光动力反应体系中，光敏剂的荧光量子效率和单态氧产出效率成竞争性关系。在本项目中，基于贵金属荧光增强及表面拉曼增强原理，我们开展了以下研究工作：1.探究了金纳米棒装载的近红外光敏剂的结构与荧光增强及单态氧产率之间的关系。2. 结合纳米水凝胶的环境响应性及金纳米棒的自组装效应，构建金纳米棒水凝胶用于近红外光介导的肿瘤光热/光动力协同治疗研究。3.基于贵金属荧光增强原理，利用金纳米颗粒实现了对亚硝酸根离子的高灵敏度检测应用。4.将金纳米颗粒与磁性氧化铁进行核壳包覆，实现了前列腺素的检测及磁共振成像应用。5.充分发挥了金纳米棒的自组装及表面拉曼增强效应，构筑了应用于体外的前列腺素的高效检测探针。6.开发了基于近红外光敏剂的多模式生物成像应用。本项目充分阐明了光敏剂与其载体材料之间的"结构-相互作用-功能性" 的关系，并探讨了纳米光敏剂递送系统与肿瘤细胞的相互作用机制，从而为肿瘤的"精确定位、精确治疗"提供理论基础和实验数据支持。

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