流动聚焦技术制备药物微载体研究

发布时间：2018-03-21 17:17

本文选题：微流体技术　切入点：流动聚焦　出处：《中国科学技术大学》2017年博士论文　论文类型：学位论文

【摘要】：传统药物微载体的制备方法存在包裹率低、颗粒分散性差以及包裹成分不可控等缺陷,流动聚焦(Flow Focusing,FF)技术作为微流体技术中一个非常重要的组成部分,以其易操作、技术稳定、包裹率高、材料适用性广以及环境条件的要求不苛刻等优势有望广泛应用于各类药物微载体的制备。本文利用流动聚焦技术制备了包裹全氟碳化合物(Perfluorocarbon,PFC)、吲哚菁绿(Indocyanine Green,ICG)、磁性纳米颗粒(Magnetic Nanoparticles,MNPs)等材料的多功能微载体,并研究其在超声影像、可控激发、荧光影像、药物传输、磁控分离、体外靶向等生物医学领域上的应用。具体内容如下:1.利用基于液滴的微流控芯片流动聚焦技术制备了刺激响应性微液滴(Stimuli-Responsive Microdroplets,SRMs)。SRMs 可以在外界刺激下进行快速的液-气相变以及体积膨胀,SRMs的内核为分散有纳米银粒子(Silver nanoparticles,SNPs)的PFC,SRMs的外壳为具有良好生物兼容性的磷脂。SRMs的粒径(4-50μm)可以通过调节内外相流体的流速来控制。在超声探头(1 MHz,1 W/cm2)的刺激下,SRMs被快速激发,并用超声影像进行记录,另外,用波长为445 nm,功率密度为35 W/cm2的激光照射SRMs,并在普通光学显微镜下观察SRMs的气化以及体积膨胀现象,实验证明了超声和激光激发SRMs的技术可行性。制备的SRMs可以在热消融、血管闭塞、局部给药等领域发挥重要的作用。2.利用液驱同轴流动聚焦技术(Liquid-Driven Coaxial Flow Focusing,LDCFF)制备了包裹高浓度荧光造影剂ICG的脂质体,其在定量荧光影像以及药物输送方面具有潜在的应用价值。制备过程包括首先产生均匀的水/油(W/O)微液滴,然后外层有机相逐渐挥发形成稳定的磷脂双分子层。研究得到了微液滴直径与聚焦小孔直径、内外相流量以及驱动相流量之间的关系。药物释放实验通过向分散有包裹ICG的脂质体的聚乙烯醇(PVA)溶液或是血浆中滴入酒精,酒精溶解磷脂膜后,1CG被释放至外部溶液,脂质体膜破碎后外部溶液的荧光强度增加十分明显,破碎后的荧光强度跟释放至外部溶液中的ICG的浓度呈线性相关。ICG是美国食品和药物管理局(The US Food and Drug Administration,FDA)批准的荧光造影剂,制备的包裹ICG的脂质体可以作为一个具有良好生物兼容性的传感器应用于定量临床影像以及影像导航药物输送等。LDCFF应用范围还可以进一步拓展,可以利用各种不同的壳材包裹其他各种高浓度的亲水性或疏水性的药物、DNA或蛋白质等。3.利用液驱复合流动聚焦技术(Liquid-Driven Compound-Fluidic Flow Focusing,LCFF)高产率制备了包裹单一成分或多成分的聚乳酸-羟基乙酸共聚物(Poly(lactic-co-glycolic acid),PLGA)微囊。装置组装过程包括首先将一个不锈钢同轴或复合针头插入一个腔体中,将针头端部对准腔体底部的聚焦小孔。制备了包裹MNPs的PLGA微囊,并研究了磁控聚集及分离现象,制备的PLGA微囊在磁控靶向药物输送等方面具有很大的应用价值;另外,我们利用LCFF技术制备了包裹两种相互反应材料的PLGA微液滴,并实现了这两种材料在PLGA微液滴中的可控微反应。制备的PLGA微囊的尺寸及形貌可以通过调节多相流体的流速进行控制,LCFF有望制备各种种类的多功能微载体并广泛用于生物医学等领域。
[Abstract]:Preparation method of traditional medicine micro carrier package exists low rate of particle dispersion and uncontrollable component package, flow focusing (Flow Focusing, FF) technology in microfluidic technology as a very important part, stable technology for its easy operation, high ratio of packaging materials, wide applicability and environmental conditions is not critical advantage is expected to be widely used in all kinds of drugs microcarrier preparation. This paper uses the flow focusing technique to prepare coated perfluorocarbon (Perfluorocarbon, PFC), indocyanine green (Indocyanine Green, ICG), magnetic nanoparticles (Magnetic Nanoparticles MNPs) multi functional materials such as micro carrier and, on the ultrasound image, controllable excitation, fluorescence imaging, magnetic separation, drug delivery, targeting applications such as biomedical field. The specific contents are as follows: 1. with the flow of the droplet based microfluidic chip Focusing on the preparation technology of stimulus responsive micro droplets (Stimuli-Responsive Microdroplets, SRMs).SRMs can be fast liquid gas phase transition under the external stimulation and volume expansion, SRMs kernel for silver nano particle dispersion (Silver nanoparticles, SNPs) PFC, SRMs shell has good biological compatibility of phospholipid.SRMs the particle size (4-50 m) can be adjusted by the internal fluid flow rate to control. In the ultrasonic probe (1 MHz, 1 W/cm2) under the stimulation of SRMs is rapidly stimulated, and records, using ultrasound imaging in addition, with the wavelength of 445 nm, the power density is 35 W/cm2 SRMs laser irradiation, and observe the in ordinary optical microscope SRMs gasification and volume expansion phenomenon, the experiment proves the technical feasibility of SRMs ultrasonic and laser. The preparation of SRMs in thermal ablation, vascular occlusion, local administration and other fields play important roles in.2. Drive coaxial flow focusing technique using liquid (Liquid-Driven Coaxial Flow Focusing, LDCFF) liposome with high concentration of fluorescent contrast agent ICG was prepared and has potential application value in the delivery of quantitative fluorescence imaging and drug. The preparation process includes the first uniform water / oil (W/O) micro droplet, then the outer layer the organic phase gradually evaporated to form a stable bilayer. Of micro droplet diameter and pore diameter of internal flow focusing, and drive the relationship between the phase flow. Drug release experiment to dispersed liposome ICG polyvinyl alcohol (PVA) solution or plasma drops of alcohol, alcohol soluble phospholipids after the film, 1CG was released to the external solution, liposome membrane after breaking the fluorescence intensity of the external solution increased obviously after the break of the fluorescence intensity to release to the external solution in the concentration of ICG was linear .ICG is the United States Food and Drug Administration (The US Food and Drug Administration, FDA) approved fluorescent contrast agent liposome prepared by ICG can be used as a good biological compatibility of the sensor in the application of quantitative clinical imaging and image-guided drug delivery.LDCFF application can also further expand, can use the various drugs shell material covered various other high concentration of hydrophilic or hydrophobic, DNA or protein.3. by liquid displacement composite flow focusing technique (Liquid-Driven Compound-Fluidic Flow Focusing, LCFF) package of single or multiple component poly lactic acid glycolic acid copolymer was prepared for high yield (Poly (lactic-co-glycolic, acid) PLGA) microcapsules. Device assembly process including a first coaxial stainless steel or composite needle into a cavity, the needle tip at the bottom. Focus hole department. MNPs coated PLGA microcapsules were prepared and studied by magnetron aggregation and separation, preparation of PLGA microcapsules has great application value in the aspects of drug delivery to the magnetron target; in addition, we use LCFF technology to prepare two kinds of mutual reaction materials coated PLGA micro droplets, and to achieve the two kinds of materials in PLGA micro controlled droplet micro reaction. To control the size and morphology of prepared PLGA microcapsules can be adjusted by the multiphase fluid flow, LCFF is expected to be multifunctional preparation of various types of micro carrier and is widely used in biomedical fields.

【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ460.4

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