用于在分子水平监测癌细胞和纳米药物相互作用的超分辨光学成像方法研究

纳米药物以其特有的优势使其成为药物研究的热点，但其临床转化率极低，根本原因是缺乏在分子水平了解纳米药物与癌细胞相互作用的动力学机制。纳米药物的动力学特性与其疗效、毒副作用等密切相关，是评价其临床转化率的关键。因此，本项目提出并发展一种可在分子水平精确监测癌细胞和纳米药物相互作用过程的双色双光子STED超分辨成像方法，在该方法中拟采用双光子STED超分辨成像技术对深层样品成像，拟采用自适应光学技术校正STED系统和样品的像差提高成像深度和成像质量，拟采用高精度的光子数分离技术降低擦除光能量。建立集双光子STED超分辨成像、自适应光学像差校正技术和基于荧光寿命的光子数分离技术于一体的深层活细胞纳米分辨光学成像平台，对纳米药物的跨膜过程和癌细胞内纳米药物的释放过程进行精确监测，揭示纳米药物的动力学机制。该项目的研究将在疾病治疗、纳米药物开发和筛选等方面具有重要的研究意义和应用价值。

Nanodrugs have attracted much attention in drug research with unique advantages. However, the clinical translation efficiency of nanodrugs is extremely low, mainly due to the lack of understanding of the kinetics of interaction between nanodrugs and cancer cells at the molecular level. The pharmacokinetic characteristics of nanodrugs are strongly correlated with the therapeutic efficacy and side effects, which are critical to assess the possibility of clinical translation. Therefore, this proposal proposes and develops a two-color two-photon STED super resolution imaging method that can precisely monitor the interaction between cancer cells and nanodrugs at the molecular level. In this method, the two-photon STED super resolution imaging technology will be used to image deep sample, the adaptive optical technique will be used to correct the aberrations in STED system and samples, the phase plot based on fluorescence lifetime will be used to reduce STED light energy. In this proposal we will build a deep living cell nanoscale optical imaging platform encompassing two photons STED super resolution imaging, adaptive optical aberration correction technology and phase plots based on fluorescence lifetime to accurately monitor the transmembrane process of nanodrugs and the release process of nanodrugs within cancer cells, and to reveal the kinetic mechanism of nanodrugs. This research will have important research significance and application value in disease treatment, drug development and screening of nanodrugs.