多重刺激响应性纳米药物的光热治疗与化疗的协同抗肿瘤研究

Multiple stimuli-responsive nanocarrier is utilized to circumvent a series of physiological barriers in tumor-targeting drug delivery for chemotherapy, in which the rational design for programmed stimuli-response and the interaction of its responsive behavior with physiological barrier is key to the therapeutic effectiveness. This work proposes preparation of a multifunctional nanocarrier with near-infrared light, temperature, and pH stimuli-responsive change in size, surface charge and functional groups in attempt to programmed overcome those obstacles. 1）The nanomedicine's capability change of extravasation and penetration in tumor dependent on the size change of the nanocarrier under the near-infrared light induced photothermal effect will be studied. 2）tumor acidic stimulus responsive surface charge and functional groups change is designed to simultaneously fulfill the requirement of prolonged blood circulation and high-efficient cell uptake. 3）In the meantime, the physiological properties of tumor impacted by the photothermal effect of nanocarrier, for example the penetrability of blood vessels in tumor and permeability of tumor interstitial matrix will be studied. Based on these studies, the mechanism of drug nanocarrier homogeneous accumulation and penetration in tumor, especially in deep regions of tumor will be explored. As such, we anticipate explaining the mechanism of photo-thermotherapy and chemotherapy synergistic antitumor effect and optimizing this strategy to improve the tumor therapy outcome.

多重刺激响应性纳米载体，能突破化疗药物靶向肿瘤输送中的多种生理屏障，而其多重刺激响应机制的合理性、程序化设计及其响应行为对生理屏障的相互作用是决定其功效的关键。本项目拟制备近红外光、温度、pH刺激下，尺寸和表面性质响应性转变的多功能纳米药物载体，程序性的应对各种生理屏障。a）研究纳米载体在近红外光热作用下尺寸变化对其血管穿透、肿瘤内部渗透能力的作用；b）表面电荷、表面基团在肿瘤酸度下的变化解决其血循环与细胞摄取双重屏障的要求；c）初步研究肿瘤生理性质在纳米载体产生的近红外光热效应下的改变，如血管通透性能、肿瘤间基质渗透性能。在此基础上，探讨纳米药物载体在肿瘤组织内部扩散与均匀性富集的最优化方案，初步阐明该纳米药物载体的光热疗与化疗的协同抗肿瘤治疗的机制，为光热疗法与化疗的协同治疗提供新的思路。

多重刺激响应性纳米药物载体，能突破靶向肿瘤递送中的多种生理病理屏障。而其多重刺激响应机制的合理化、程序化设计及其与多重屏障的相互作用是决定其功效的关键。本项目制备了若干系列在近红外光、温度、pH刺激下，尺寸和表面性质响应性转变的多功能纳米药物载体，程序性的应对各种生理屏障。a）制备了基于碳纳米管的纳米药物复合载体，研究了在近红外光热作用下，其尺寸变化对其血管穿透、肿瘤内部渗透能力的作用；发现了其尺寸重复变化下的肿瘤细胞间递送现象，解释了该纳米载体增强肿瘤内部渗透的原理。b）构建了基于荧光上转换纳米晶体的纳米药物复合载体，有效地将NIR转化为UV-Vis，实现载体的去PEG化转变，解决其血循环与细胞摄取双重屏障的要求，同时增强了肿瘤内部的渗透能力；c）线粒体靶向新策略的探索，制备了若干系列响应红外光、温度等表面性质、尺寸变化型纳米药物载体，通过其结构调控，无需表面修饰线粒体靶向基团，实现线粒体靶向药物递送；d）初步研究肿瘤生理性质，例如如血管通透性能、肿瘤免疫反应在纳米载体产生的治疗下的改变。在此基础上，探讨纳米药物载体在肿瘤组织内部扩散与均匀化富集的最优化方案，初步阐明基于纳米药物复合载体的多种疗法的协同抗肿瘤治疗的机制，为肿瘤协同治疗提供新的思路。