环境响应性"开-关"智能纳米容器的构建及对槐定碱靶向触发释放研究

Sophoridine has stronger activities for varous tumor, such as lung cancer, choriocarcinoa and digestive tract cancer. Because of its disadvantages of wide distribution, rapid elimination, low biological half-life and bioavailability in vivo, the clinic efficiency and application of sophoridine were limited. In this study, environmental-responsive and "opening-closing" nanocontainer was fabricated using reductive deposition method, core-shell and RAFT synthesis technology. Meanwhile, the characterization of nanocontainer was investigated by modern analysis techniques. Sophoridine, as the model drug, was loaded by the nanocontainer, and the release properties in vitro was studied by changing temperature and magnetic field. The delivery and targeted mechanism of nanocontainer in vivo was investigated by MRI and pharmacokinetics methods. For realizing trigger-released of sophoridine from the nanocontainer,the relationship between temperature changes of tumor tissue and sophoridine release was studied according to the magnetocaloric effect, and mathematical model was established. In this study, hyperthermia and chemotherapy was used to treat tumor at the same time. The new concepts of superparaagnetic, environmental-responsive and inorganic nanoparticle were introduced into the drug delivery system,which would be improve the develepment and research for drug delivery system. The design of this project is novel and has good originality.

槐定碱对肺癌、绒癌和消化道癌等具有较强的治疗作用。前期研究表明，槐定碱采用传统方式给药，在体内分布广，半衰期短，代谢快，生物利用度低，达不到良好的治疗效果，且具有一定的神经毒副作用。本项目利用部分还原沉淀法，核-壳和可逆加成断裂链转移（RAFT）合成技术构建环境响应性"开-关"靶向触发释放智能纳米容器，借助现代分析技术对其性能进行研究。以槐定碱为装载对象，采用体外释放方法探讨温度与交变磁场对释放度的影响。利用磁共振成像扫描技术和药物动力学手段研究纳米容器在动物体内输送行为和靶向机理。根据外加磁场与纳米容器的磁热效应，研究肿瘤组织温度变化与纳米容器释放槐定碱的关系，建立数学模型，实现纳米容器对槐定碱的触发释放。本项目将超顺磁性、环境敏感性及无机纳米材料等概念引入到新型的药物传输载体中，以促进新型药物传输载体的研究和开发。本项目设计思路新颖，与国内外相关工作相比，具有很好的原创性。

项目背景：槐定碱等药物具有很好的抗肿瘤作用，但是他们生物半衰期短，代谢快，生物利用度底。因此，需要新型的载药体系对这些药物进行输送。环境响应性“开-关”智能纳米容器具有靶向触发释放功能，可以克服这些药物自身的缺点；主要研究内容：我们设计了一系列环境响应性纳米容器（温度磁响应多孔硅，pH响应纳米介孔硅，温度响应性纳米囊，pH响应壳聚糖纳米粒，壳聚糖自组装纳米粒，壳聚糖微球纳米微球和壳聚糖纳米脂质体），利用现代分析手段（SEM，TEM，FI-IR，TG和N2吸附解吸附，HPLC等）并对他们的工艺，理化性质，环境响应性，载药量和包埋率，体外释放和体内实验进行了详细研究；重要结果及关键数据：结果表明成功构建的一系类环境响应性纳米容器，形貌复合要求，粒径均匀，通过调节环境可控制对槐定碱等模型药物的有效装载和释放，模型药物被纳米容器包埋后提高了其稳定性，生物利用度和生物半衰期。以温度响应性纳米容器为例进行说明：温度磁响应纳米容器具有核(介孔硅)-壳温(度响应性高分子材料)结构，介孔硅具有大量空洞结构，比表面积大，负载率高，温度响应性材料在不同温度下出现“开-关”状态，实现对模型药物的控制吸附和释放；在25°C和42°C时装载率分别为46.54%和18.69%，25 °C时前10 h槐定碱的累积释放率为25.01%，50 h后的累积释放率达64.45%，而在42 °C时50 h后累积释放率仅为25.95%；生物半衰期（t1/2）从标准液的2.13h增加到11.46h，生物利用度（AUC0-t）从10.56提高到167.24，模型药物的稳定性极大提高。科学意义：纳米“容器”载体可避免模型药物与体内外不良环境(氧气，pH和酶等)接触，提高其稳定性，降低毒副作用，提高生物半衰期和生物利用度。本课题为开发新型的药物载体提供一定参考。