层层组装膜负载缓释抗生素和抗肿瘤双药物的研究

发布时间：2018-01-05 19:23

本文关键词：层层组装膜负载缓释抗生素和抗肿瘤双药物的研究　出处：《太原理工大学》2017年硕士论文　论文类型：学位论文

【摘要】：近年来,随着纳米技术的快速发展,纳米尺度药物传送载体因在医学领域具有很高的应用价值而成为了载药纳米材料方面的研究热点之一,其中单药物载体的研究已经相对成熟,关于双药物及多药物传送体系的研究便受到了研究工作者广泛的关注。层层组装聚合物膜是运用层层组装技术,让带异种电荷的聚电解质利用双方间非共价弱作用力而交替沉积的一种纳米多层膜。它制备条件温和、操作简易,而且可以把不同性质、不同种类的药物分子以不同的方式实现在膜上的负载,基于以上所述,本文旨在通过层层组装技术,以无毒、生物相容并可降解的聚电解质作为膜的基元,制备出了两组可以共同负载抗生素与抗肿瘤药物的双药物缓释层层组装膜,本研究为新的双药物传送体系提供了实验依据。首先,制备了可以负载缓释两种正电荷药物盐酸万古霉素(VAN)和盐酸柔红霉素的(DNR)的多层膜。以复合物聚天冬氨酸-盐酸万古霉素(PASP-VAN)与壳聚糖季铵盐(HTCC)作为构筑基元,运用层层组装技术,制备了聚合物复合物膜(PASP-VAN/HTCC)*10,完成了VAN的层层组装负载,并通过改变PASP-VAN和HTCC的p H值,研究了构膜基元的p H值对VAN负载量的影响,得到成膜最佳p H条件为(PASP-VAN_(4.0)/HTCC_(8.0))*10,缓释实验表明,层层组装负载的VAN缓释时间为1650min。然后以最佳p H条件的聚合物复合物膜(PASP-VAN_(4.0)/HTCC_(8.0))*10为基础,让第二种药物DNR以扩散的方式完成后负载,实现两种正电荷药物在同一层层组装聚合物膜的共同负载,记作DNR-(PASP-VAN_(4.0)/HTCC_(8.0))*10。双药物体系体外释放结果显示:DNR与VAN的释放时间分别为540min与720min;运用原子力显微镜(AFM)得知:未组装膜的基底、单药物的膜(PASP-VAN_(4.0)/HTCC_(8.0))*10、双药物的膜DNR-(PASP-VAN4.0/HTCC_(8.0))*10三者的膜表面粗糙度依次增加。其次,研究了阻隔层对药物缓释效果的影响。为了延缓抗肿瘤药物DNR的释放速率,将双药物体系与阻隔层相结合。先制备聚合物膜(PASP_(4.0)/HTCC_(8.0))*20,让DNR以扩散的方式先进行负载,再分别采用喷涂层层组装法与浸泡层层组装法在该聚合物膜表面组装阻隔层(PASP/PAH)*n(n表示周期数),最后让VAN以复合物PASP-VAN的形式与HTCC层层组装到膜中,从而实现DNR与VAN的共同负载。实验比较分析了喷涂层层组装与浸泡层层组装两种方式下,10T阻隔层的组装效果,并进一步探讨了喷涂层层组装方式下阻隔层的周期数对DNR释放效果的影响,结果表明:阻隔层可以延缓DNR的释放速率,两种方式下制备的10T阻隔层,阻隔效果相差不大,但喷涂组装比浸泡层层组装效率高;喷涂层层组装方式下20T阻隔层与10T阻隔层分别使DNR的释放时间延长2310min和420min;双药物释放显示:VAN与DNR的释放时间分别持续1680min和2700min,通过调节阻隔层的周期数可以实现对药物的控释。最后,制备了可以负载异种电荷药物头孢曲松钠(CTX)和DNR的膜双药物缓释体系。先将阳离子型复合物(PAH-CTX)与透明质酸钠(HA)作为膜材料,利用两者间的静电作用层层组装制备膜(HA_(4.0)/PAH-CTX7.5)*6,再在此膜的表面继续层层组装空白膜(PASP_(4.0)/PDDA)*20,将药物DNR以浸泡的方式后负载于空白膜上,并喷涂20T阻隔层来减缓DNR的释放速率。释放实验表明,CTX释放时间为9h,DNR的释放时间持续81h,抗生素CTX的快速释放有助于及时杀灭细菌以防感染,DNR长效释放有助于减少抗肿瘤药物的服用次数,进而减弱DNR的毒副作用。
[Abstract]:In recent years, with the rapid development of nanotechnology, nano scale drug delivery carrier because it has a high application value in the medical field and has become one of the hot research of drug loaded nano materials, the study of single drug carrier has been relatively mature, research on double drug and drug delivery system has been studied extensively attention is the use of the polymer film layer by layer by layer by layer technique, let the oppositely charged polyelectrolyte by non covalent weak interactions between the two sides of a nano multilayer film and deposition. It is mild preparation conditions, simple operation, and can have different properties, different types of drug molecules in different ways to achieve load at the film, based on the above, this paper aims to self-assembly technology, with non-toxic, biocompatible and biodegradable polymer electrolyte membrane as basic element, prepared Two groups of double drug release of antibiotics and anticancer drugs common load LbL assembly films, this study provides experimental basis for the dual drug delivery system. Firstly, the preparation can load two positive charge drug release of vancomycin hydrochloride (VAN) and daunorubicin hydrochloride (DNR) with composite multilayer film. Poly aspartic acid (PASP-VAN) and vancomycin hydrochloride chitosan quaternary ammonium salt (HTCC) used as building blocks, using layers of assembly technology, polymer composite membrane was prepared (PASP-VAN/HTCC) *10, completed the LBL VAN load, and by changing the PASP-VAN and HTCC P H, of the P configuration H membrane element values of the load effect on the VAN film P H, get the best conditions for (PASP-VAN_ (4) /HTCC_ (8)) *10 release experiment showed that the release time of layer by layer VAN load for 1650min. and then to the polymer composite film the best conditions (PA P H SP-VAN_ (4) /HTCC_ (8)) *10, completed second drugs DNR the way to spread after the load, two kinds of positive charge drugs loads at the same layer by layer of polymer film, denoted as DNR- (PASP-VAN_ (4) /HTCC_ (8)) *10. double drug release system objects the results showed that the release time DNR and VAN were 540min and 720min; the use of atomic force microscope (AFM) that the unassembled membrane substrate, single drug membrane (PASP-VAN_ (4) /HTCC_ (8)) *10, DNR- double membrane drugs (PASP-VAN4.0/HTCC_ (8)) *10 three film rough surface the degree of increase in turn. Secondly, study the influence of barrier layer drug release effect. In order to delay the release rate of antitumor drug DNR, the dual drug system and the combination of the first barrier layer. The preparation of polymer film (PASP_ (4) /HTCC_ (8)) *20, let DNR the way to spread the first load. Then use the spraying layer group Charging method and immersion method to assemble the barrier layer by layer assembly layer on the surface of the polymer membrane (PASP/PAH) *n (N cycle number), finally let VAN and HTCC in the form of complex PASP-VAN self-assembly into the membrane, so as to realize the common load of DNR and VAN. The comparative analysis of a spray assembly and soaking the assembly layers in two ways, assembling effect of 10T barrier layer, and further discusses the influence of spraying layer by layer, number of cycles of barrier layer under the release effect of DNR results showed that the release rate of barrier layer can delay DNR, two kinds of methods for preparation of 10T barrier layer, the barrier effect is similar, but the spray assembly the assembly of high efficiency than soaking; spraying layer by layer mode 20T barrier layer and 10T layer respectively. The release time of DNR prolonged 2310min and 420min; double drug release showed that the release time of VAN and DNR respectively for 1680min and 2700min, The number of cycles regulating barrier layer can be achieved on the drug release control. Finally, the preparation can load different charges of ceftriaxone sodium drug (CTX) and DNR double membrane drug delivery system. The cationic complexes (PAH-CTX) and sodium hyaluronate (HA) as a membrane material, layer by layer assembly system the film prepared by the electrostatic interaction between the two (HA_ (4) /PAH-CTX7.5) *6, then the surface of this film to the assembly of blank membrane (PASP_ (4) /PDDA) *20, the drug DNR to soak after loaded on the blank film, release rate and spraying 20T barrier to slow release experiment of DNR. CTX showed that the release time was 9h, the release time DNR 81h sustained, rapid release of antibiotic CTX helps to kill bacteria to prevent infection, have helped to reduce the frequency of use of antitumor drugs DNR and DNR long-acting release, reduced toxicity.

【学位授予单位】：太原理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1

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