近红外光敏多功能纳米载体的构建及药物靶向传递和成像研究

Near-infrared (NIR) light responsive nanomaterials take advantage of non-invasive mode, precisely controllable stimulus-responsibility at a specific time and location, which has great potential in the development of a new strategy for cancer therapy and diagnosis. This work proposes a novel strategy to fabricate near-infrared light-responsive multifunctional nanocarrier with core-shell structure, based upon upconversion nanoparticles (UCNP) and light sensitive amphiphilic copolymers (LSP) for improving targeted drug delivery and smart imaging. The self-assembly behavior of the upconversion nanocrystals having a variety of compositions and optical characteristics and UV-vis light sensitive amphiphilic copolymers will be investigated. The toxicity study in vitro and in vivo will used to evaluate the effect of the chemical compositions and structure on the biocompatibility of the nanocarriers. Based on the mechanism of two-stepped stimulus from external NIR light to internal UV-vis light, the work will establish the model of enabling the use of NIR light to triggered disrupt the nanocarriers and triggered release their "payloads", in which the NIR light is upconverted to UV-vis light by upconversion nanoparticles to degrade the copolymers. The in vitro and in vivo NIR light-triggered drug release profiles, tumor-targeting drug aggregation the nanocarriers will be studied. At the same time, the study will explore the transition from quenching of the upconversion luminescence by the light-sensitive groups in copolymers and/or the loading drugs to the recovery of the luminescence of UCNPs due to the luminescence resonance energy transfer (LRET) mechanism. The characteristic of the nanocarrier will be applied as an optical probe for the tumor-targeted imaging and enable the cancer therapeutics visible. This composite nanomaterial can combine the merits of light-sensitive polymers and upconversion nanomaterials, having great potential in biomedical applications.

近红外光刺激响应的纳米材料具有非损伤刺激响应模式，能够精确地控制纳米载体响应的时间和部位，成为癌症诊断治疗新的研究热点。拟以光敏感两亲性聚合物和上转换发光纳米材料为基础，融合两者特点构建新型多功能纳米载体用于提高药物传递的靶向性和可视化。研究不同组份和光学特性的上转换发光纳米材料和紫外可见光降解聚合物的组装过程，及组装体的化学组成和结构与生物相容性的关系。基于从外部近红外光到内部紫外可见光分两步完成的刺激机制，建立聚合物的亲疏水性变化导致纳米颗粒解离的作用模型，研究纳米药物在分子水平、细胞水平和动物体内的光刺激药物释放行为和肿瘤细胞靶向性。同时研究该纳米载体的荧光特性，基于荧光能量转移原理，由纳米载体荧光淬灭到荧光恢复的转变，为靶向肿瘤成像、肿瘤治疗可视化提供基础。此复合材料融合光敏聚合物和无机纳米材料两者优点，具有很好的生物医学应用潜力。

在本项目工作中，我们紧紧围绕近红外光响应性纳米材料的设计制备及其生物医学应用这一核心目标，探讨了这类新型材料在低能量高生物穿透性的近红外光介导下的肿瘤靶向行为和机理，并在此基础上开展了可视化的多模式肿瘤联合治疗。首先研究的是基于上转换纳米材料和光降解型高分子为主要成分的复合纳米材料，及其在肿瘤治疗和诊断中的初步应用。在光照作用下，在分子、细胞水平探讨了光响应聚合物的光学、降解行为，上转换纳米粒子的光学性质，纳米粒子的物理化学性质变化、纳米粒子与细胞的相互作用、光降解型细胞内外药物释放等。第二部分的工作同样紧紧围绕近红外光响应性纳米材料，采用碳纳米材料作为内部的光热转化器，实现了刺激光源从外部低能量光（近红外光）到内部高热量的转换，建立了分两步完成的刺激模式。将热敏感性纳米水凝胶作为结构上的壳和热响应部分，充分发挥水凝胶化学结构和功能基团的可控性，赋予了纳米材料良好的分散性、生物相容性、高载药率等优势。阐明了纳米药物尺寸上的变化增强纳米药物在肿瘤区域靶向富集以及肿瘤内部的穿透能力的内在机理，为提高化疗/光热疗的肿瘤联合治疗效果提供了实验基础。本项目的工作对时间、空间、剂量上通过光控制的靶向药物递送体系的研究，为后续的多重刺激响应性纳米药物递送体系的发展提供了坚实的前期基础和理论依据。