肿瘤微环境多重响应的近红外二区荧光纳米探针用于肿瘤特异性成像及其引导光热-化学动力学协同治疗

尽管近红外二区荧光成像相较于近红外一区荧光成像具备更深的组织穿透深度和更高的信噪比，但目前报道的近红外二区荧光探针仍存在肿瘤成像特异性差的难题。本项目拟利用肿瘤组织微酸、乏氧以及肿瘤细胞内高表达GSH的特性，构建肿瘤微环境多重响应的近红外二区荧光纳米探针，以实现对肿瘤的特异性精准成像及其引导的光热-化学动力学协同治疗。首先利用二硫键连接的IR820-青蒿琥酯与Fe3+自组装合成病毒状纳米探针；继而在其周围引入微酸/乏氧响应性PEG，构建病毒状内核-球形外壳纳米探针。该探针可高效蓄积于肿瘤组织，并经微酸/乏氧连续刺激触发外壳分离，形貌反转为病毒状而特异性增强肿瘤细胞摄取；脱壳后的内核可被GSH分解，释放IR820而特异性激活近红外二区荧光信号并引导光热治疗；同时释放的Fe3+可被GSH还原为Fe2+，催化青蒿琥酯裂解产生碳中心自由基以发挥化学动力学治疗作用。本项目将为肿瘤精准诊疗提供新思路。

NIR-II fluorescence imaging possesses deeper tissue penetration and higher imaging signal-to-noise ratio than NIR-I fluorescence imaging. However, the currently reported NIR-II fluorescence probes still encounter the low imaging specificity for tumors. This project aims to takes advantages of both tumoral acidic/hypoxic and tumoral intracellular reductive characteristics to construct a tumor microenvironment multi-responsive NIR-II fluorescence nanoprobe, which can realize the specific precise imaging for tumors to guide photothermal-chemodynamic synergistic therapy. First, we chose disulfide-bridged IR820-artesunate and Fe(III) ions to synthesize virus-inspired nanoprobes by assembly. We further introduce weak acidity/hypoxia-responsive PEG onto the surface of virus-like nanoprobes to construct virus-like core-spherical shell nanoprobes. Our nanoprobes can efficiently reach tumor sites in which the weakly acidic and hypoxic microenvironment can successively trigger the shell detachment for shape reversal to virus-like surface, significantly enhancing the uptake by tumor cells. Afterwards, the shell-detached core can be degraded by the high level of GSH inside tumor cells, to release IR820 to activate the NIR-II fluorescence signals for guidance of photothermal therapy. Meanwhile, the released Fe(III) can be reduced to Fe(II) by intracellular GSH to catalyze AS to generate carbon-centered free radicals for chemodynamic therapy. Therefore, this project will provide significant new insights for precise theranostics.