酸响应的氧传感器门控的介孔纳米材料药物输送体系的研究

Ru (II) or Pt (II) complexes could be used as oxygen sensors, and also used for deep tissue imaging due to their properties of two-photon responses. Ru (II) or Pt (II) complexes could produce singlet oxygen under their excited states and play important roles in the area of photodynamic therapy. After loading anti-cancer chemodrug in the pores of aminated mesoporous silica nanoparticles (MCNs), Ru (II) or Pt (II) complexes owning active aldehyde groups could be linked onto the surface of MCNs by the reaction of amine and aldehyde. These two-photon absorbing oxygen sensors have similar comparable sizes with the pore diameters of MSNs and could be employed as gates in the drug delivery for blocking the release of DOX loaded in the pores of MSNs. Then, sensor capped, DOX loaded NH2-MSNs were encapsulated in the micelles formed by a biodegradable molecule of DSPE-PEG-OCH3. The micelle- and sensor-nanogates could be opened by the cleavage of Schiff-base bond upon pH lowering and the drug release from the pores. This drug delivery system integrates oxygen sensors and pH-responsive units for controlled drug release together. This is not only for tumor cell detecting and imaging by using the characteristics of the hypoxia and weak acidic environment of tumor cells, but also for treating tumor cells by chemotherapy and photodynamic therapy simultaneously.

Ru(II)或Pt(II)复合物可用作氧传感器，具有双光子响应性能，可对组织深层成像；并且在激发态下产生单线态氧，可对肿瘤部位进行光动力治疗。氨基功能化的介孔氧化硅纳米粒子（MSNs）装载抗癌药物后，Ru(II)或Pt(II)配合物的活性羰基与MSNs上的氨基发生反应后，生成的Schiff碱基团能将其连接到介孔材料上。由于双光子氧传感器配合物分子尺寸与MSNs孔道尺寸相当，能够封堵装载于孔道内的药物分子。利用生物可降解的DSPE-PEG-OCH3分子自组装形成胶束的能力，将双光子氧传感器门控的药物输送体系包裹进胶束。弱酸环境下，Schiff碱基团断开，双光子氧传感器和胶束分子从介孔材料表面脱离，装载的药物分子释放出来。由于肿瘤细胞的缺氧和弱酸性环境以及该纳米药物输送体系的氧传感和pH敏感刺激响应释放的功能，该体系不仅可以检测和成像肿瘤细胞，还可以对肿瘤细胞进行化疗和光动力联合治疗。

氧传感器在海洋、气象、环境科学、生物学和生命科学等方面都有非常重要的应用价值。基于压力、电化学和荧光淬灭等机理研制出的氧传感器仅部分能够实现高精度、定量检测氧气。基于氧气的重要意义我们主要开展了以下五个方面的研究工作。.1）以钙钛矿量子点为参比层来制备对氧气响应的比率型双层聚合物膜，该膜能够实现对不同氧气浓度响应的颜色变化。进一步考察微纳加工后对氧气传感性能的影响，实验表明微纳加工后的氧气传感器均可提高对氧气响应的灵敏度。.2）通过氧化还原反应在多孔板中制备氧/pH双传感凝胶薄膜，用来同时监测不同细菌浓度下耗氧及pH变化。该双传感凝胶薄膜能够为研究抗生素对细菌新陈代谢的影响以及评估抗生素的活性提供重要参考依据；为原位和高通量监测细菌新陈代谢过程中氧消耗以及pH变化提供新的研究方法。.3）设计一种新型生物相容的含有氧探针的水凝胶薄膜材料，利用光刻技术进行微纳加工后，考察对氧气传感性能的影响，并探究材料形成光栅的线宽对细胞生长形态的影响，结果表明氧传感器不仅可以用来监控细胞生长过程中氧含量的变化，而且对细胞的伸长程度以及细胞的排列均有一定程度影响， .4）采用多臂聚乙二醇作为引发剂来引发“-己内酯”的聚合反应后，获得多臂嵌段共聚物，使用其形成的胶束包裹具有较高氧气传感效率的疏水性PtTFPP氧探针，并将其应用于细胞呼吸的原位监测。.5）将吸收双光子的（2PA）红色发射基团化学偶联到两亲性共聚物上，进一步接枝cRGD后形成的胶束用于富含αvβ3整合素的肿瘤细胞的靶向生物成像，并将其应用于细胞呼吸的原位监测。