【作者】 郭瑞；

【导师】 徐章润；

【作者基本信息】 东北大学 ， 分析化学， 2015， 硕士

【摘要】 药物微球是一种新的药物剂型,在药物递送和释放过程中,微球制剂因能以更好的效果灵活传递药物,对医疗技术有着巨大的影响。微球的尺寸对药物释放程度、生物分布、及给药途径影响很大,可利用尺寸依赖性特征达到理想的释放效果。近年来,不同活性成分的共传输引起了越来越多人的关注。微流控技术可用于制备尺寸可控、单分散性良好的微球,并能精确地封装多种特定剂量的药物,实现不同活性成分在特定位点的可控释放;还可在微球中同时负载药物和靶向识别物质,实现药物的靶向释放。本文设计了一种多通道阵列化液滴形成芯片,可以形成不同物质的多种浓度梯度组合,基于此制备了一系列包含不同浓度的两种抗癌药物的聚合物微球,用于筛选两种药物的最佳协同浓度。论文第一章中,首先综述了用于制备多功能微粒的微流控方法,包括光刻法、微模塑法和微液滴模板法;其次介绍了药物微球的常用材料及制备方法;然后介绍了微流控浓度梯度形成技术在药物筛选及控释方面的应用;最后提出了本文的工作目的及设计思想。论文第二章中,加工了一种多层硅橡胶浓度梯度液滴芯片,以聚乙二醇二丙烯酸酯(Poly(ethylene glycol)diacrylate,PEGDA)为载体材料,以盐酸阿霉素和紫杉醇为模型药物,制备了多种不同浓度组合的药物微球。实验中设计和优化了芯片构型;考察了通道形状、深度和流速对液滴形成的影响。单个通道中液滴直径的变异系数在2.6%-5.4%之间(n=50),8个通道间液滴直径的变异系数为5.0%(n=400);芯片中形成的浓度梯度变化趋势与理论计算结果基本一致。制备了带有荧光标记的微球,证明PEGDA微球能够同时负载两种亲疏水性不同的物质;最后制备了含有8种不同浓度组合药物的微球,用于诱导HeLa细胞凋亡,筛选出其最佳协同浓度。论文第三章中,对本文建立的微流控液滴芯片用于浓度梯度PEGDA药物微球的制备方法进行了总结,并对其应用前景进行了展望。更多还原

【Abstract】 Drug microsphere is a novel pharmaceutical dosage form.Microspheres have an enormous impact on medical technology since they enable flexible delivery of drugs with improved performance during the drug delivery and release process.The size of microspheres strongly affects their drug release profile,biodistribution and administration route,and the desired release effect can be achieved by utilizing their size-dependent feature.Recently,co-delivery of different actives has attracted increasing interest.With microfluidic techniques,monodisperse microparticles with controlled size can be generated,and drugs with desired dose can be precisely encapsulated in the microparticles.Thus,actives can be released at desired sites with controllable rate.While drugs and target substances are loaded in the microspheres simultaneously,targeted release of the drug can be achieved.In this paper,a multi-channel chip for generating droplet array was designed,and a variety of concentration gradient combinations of different substances could be formed.Based on the chip,polymer microspheres containing different concentrations of two anticancer drugs were prepared for screening the optimum synergistic concentration of the drugs.In chapter 1,microfluidic methods for preparing multi-functional particles were reviewed,including photolithographic techniques,micromolding methods and droplet template methods.Then the materials and methods for preparing drug microspheres were introduced.The microfluidic concentration-gradient generation techniques used in drug screening and controlled release were also summarized.Finally,the purpose and design of this work were proposed.In chapter 2,a multilayered PDMS chip for generating concentration-gradient droplets was manufactured.With Poly(ethylene glycol)diacrylate(PEGDA)as a carrier material,doxorubicin hydrochloride and paclitaxel as model drugs,multiple microspheres containing different concentration combinations of drugs were prepared.The configuration of chip was designd and optimized in the experiment.The effects of channel shape,depth and flow-rate on droplet formation were investigated.The coefficients of variation of the droplet size in each channel were 2.6%-5.4%(n=50),while the coefficient of variation in 8 channels was 5.0%(n=400).The trend of concentration gradient in the chip was almost the same as theoretically calculated values.By preparing the two-fluorescence-labeled microspheres,it was demonstrated that two materials with different hydrophilicity could be simultaneously loaded in PEGDA microspheres.Finally,microspheres containing eight different concentration combinations of drugs were prepared for inducing apoptosis of HeLa,and the optimum synergistic activity of two drugs was screened.In chapter 3,the method established in this work for preparation of PEGDA microspheres containing concentration gradient drugs was summarized,and their application prospects in the future were predicted as well.更多还原