多功能介孔SiO2/水凝胶纳米复合纤维双重载药体系的研制

It is well known that mesoporous SiO2-coated NaYF4:Yb3+, Er3+ nanocomposites (NaYF4:Yb3+, Ecr3+@mSiO2 NPs) have been investigated as drug carriers because of their stable porous structure, nontoxic nature, good biocompatibility, and up-conversion fluorescence emission. The hydrophilicity of thermo-responsive multiblock poly(ester urethane)s, which comprises poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG) and poly(ε-caprolactone) (PCL) segments, could be controlled by changing the temperature of the environment. The changes are reversible. These thermo-responsive copolymer films formed highly swollen hydrogel-like materials when soaked in cold water and shrank when soaked in warm water. In this project, we intent to design and prepare NaYF4:Yb3+, Er3+@mSiO2 NPs contained thermo-responsive poly(ester urethane)s hydrogel nanocomposite fibers as double-container drug loading system (DCDLS) via electrospinning. The system could load two kinds of drugs at the same time and show different release behaviors due to their different distribution in the nanocomposite fibers. The rate of drugs release could be controlled by changing the temperature of the nanocomposite fiber environment. The near-infrared (NIR) active materials, which can convert the absorbed photo energy to heat with high efficiency, are encapsulated in the NaYF4:Yb3+, Er3+@mSiO2/hydrogel nanocomposite fibers. Upon exposure to a NIR laser beam, the release of drugs can be controlled by the conversion of absorbed NIR radiation into localized heat, and NaYF4:Yb3+, Er3+@mSiO2 NPs inside the DCDLS exhibit up-conversion fluorescent emission. Both doxorubicin hydrochloride and pacilitaxel are loaded in the DCDLS, the biocompatibility of drug carrier materials, the in vitro and in vivo NIR-responsive drug release properties of DCDLS, and the effect of dual drug combination on inhibition propagation of the cancer cells will be examined and investigated in detail. We aim at developing a multifunctional drug delivery system (DDS) combining the properties of double-container drug loading, NIR-responsive drug release and up-conversion fluorescent label.

介孔SiO2包覆NaYF4:Yb3+, Er3+纳米复合材料，具有稳定的孔道结构、良好的生物相容性和上转换发光性质，可作为药物缓释载体。包含聚乙二醇、聚丙二醇和聚己内酯的聚酯型聚氨酯是一种温敏性的多嵌段共聚物，其亲水性随环境温度的变化而发生可逆的转变。本项目拟利用静电纺丝将两种材料整合在一起制备水凝胶纳米复合纤维，复合纤维具有双重载药功能可担载两种药物并通过调控装载位置和环境温度来实现药物的控制释放。近红外活性材料具有光热转换能力，将其引入到载药体系中，近红外光照射下体系温度升高使温敏性水凝胶复合纤维收缩并将担载的药物释放出来，而且体系具有上转换荧光发射。载药体系担载盐酸阿霉素和紫杉醇两种抗癌药物，检测材料在体外及体内的生物相容性，研究体系在体外及体内的近红外响应药物释放行为，探讨协同给药对于肿瘤细胞的抑制效果，建立一种具有双重载药、近红外响应释药及上转换荧光标记多种功能的药物传递系统。

本项目主要围绕稀土发光材料的性能改善、基于稀土发光材料的药物载体的合成、基于电纺复合纤维的双重载药体系的构建及载药应用等方面的工作展开，具体的包括：(1) 在稀土发光材料合成方面，采用水热法合成了稀土离子掺杂的GdOF上转换发光材料，通过调节Yb3+/Ln3+ (Ln = Er, Ho, Tm)的掺杂比例实现多种发光颜色的调控；采用高温溶剂法合成单分散、尺寸均一、形貌规则的稀土上转换纳米晶(UCNPs)，通过对结构与掺杂方式的调整、核-壳结构的设计，实现对材料光学性质的调控，如β-NaYF4:Yb3+, Er3+、β-NaYF4:Yb3+, Er3+@β-NaGdF4:Yb3+、NaYF4:Yb/Nd/Er@NaYF4:Nd、NaYF4:Yb3+, Er3+@NaYF4:Yb3+@NaNdF4:Yb3+@ NaYF4:Yb3+胶体纳米晶等；(2) 设计合成了具有多种功能（发光、磁性、多孔）的稀土纳米复合材料，如均匀、单分散的介孔SiO2直接包覆上转换纳米粒子的β-NaYF4:Yb3+/Er3+@ mSiO2和β-NaYF4:Yb3+, Er3+@β-NaGdF4:Yb3+@mSiO2纳米颗粒、NaYF4:Yb/Gd/Er上转换磁性纳米粒子修饰的SiO2纳米管和多孔羟基磷灰石(HAp)纳米纤维、聚丙烯酸(PAA)包覆上转换纳米粒子的NaYF4:Yb3+, Er3+@NaYF4:Yb3+@NaNdF4:Yb3+@NaYF4:Yb3+@PAA纳米颗粒；(3) 在电纺水凝胶纤维中引入另外一种药物载体或光热材料，得到多功能的双重载药体系，达到协同增效的目的，如NaYF4:Yb3+/Er3+@mSiO2、NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2、Gu9S5@mSiO2、聚苯胺纳米颗粒修饰的聚己内酯-明胶(PG)复合纤维等；(4) 在材料的应用方面，将得到的多孔复合材料和电纺复合纤维材料作为药物载体，以抗炎药物布洛芬(IBU)和吲哚美辛(IMC)或抗癌药物阿霉素(DOX)作为模型药物，初步研究了材料的药物吸附与释放、细胞毒性，通过激光共聚焦显微镜成像(LSCM)、流式细胞术、上转换荧光成像等技术考察了肿瘤细胞对载药纳米颗粒的吞噬效果,以及载药体系对肿瘤细胞的体外/体内抑制效率等性能。项目执行期间共计在Adv. Funct. Mater.、Small、Nanosca