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首页> 外文学位 >Therapeutic self -assembled monolayers for coronary stent based drug delivery systems.
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Therapeutic self -assembled monolayers for coronary stent based drug delivery systems.

机译：用于冠状动脉支架的药物输送系统的自组装治疗性单层。

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摘要

This dissertation investigates the use of self-assembled monolayers (SAMs) as a novel technique for attaching and releasing therapeutic drugs directly from metal implants. The two metal/SAMs systems used in this study were titanium/phosphonic acid and gold/thiol systems. In this study, we mainly investigated the following: (a) stability of SAMs, (b) chemical attachment of therapeutics to SAMs, (c) drug release kinetics of therapeutic SAMs and (d) biocompatibility of SAMs and therapeutic SAMs.;First, a hydroxyl-terminated phosphonic acid (PA) SAM was coated on Ti. The stability of the SAM was investigated in tris-buffered saline (TBS) at 37°C, double distilled water (dd-H2O), ambient air, and ultra-violet (UV) light. For comparison purposes, a hydroxyl-terminated thiol SAM was coated on Au and its stability was also investigated under similar conditions. The specimens were primarily characterized using X-ray photoelectron spectroscopy (XPS) and contact angle measurements were also taken. In TBS or dd-H 2O, a portion of PA SAM molecules were desorbed from the Ti surface over a period of 14 days, while the thiol SAM on Au was stable up to 21 days under similar conditions. In ambient air, the PA SAM on Ti was stable up to 14 days, while the thiol SAM on Au was not stable for even one day. Under UV-radiation exposure, the alkyl chains of the PA SAM were decomposed leaving only the phosphonate groups on the Ti surface after 12 hours. Under similar conditions, decomposition of alkyl chains of the thiol SAM was observed on the Au surface accompanied with oxidation of thiolates.;Second, therapeutic SAMs (TSAMs) were prepared by chemically attaching flufenamic acid, a model drug, to --OH terminated SAMs coated Ti and Au surfaces. Three different methods of esterification (acid chloride esterification, dry heat esterification, and direct esterification) were explored to attach flufenamic acid to SAMs coated metal surfaces. TSAMs coated metal surfaces were characterized using XPS, fluorescent microscopy and atomic force microscopy (AFM). XPS confirmed the formation of ester bonds between flufenamic acid and SAMs. The distribution of drug molecules on SAMs coated metal specimens was studied using fluorescent microscopy. AFM images showed the change in surface morphology before and after drug attachment.;Third, in vitro drug release kinetics of TSAMs was investigated using high performance liquid chromatography (HPLC). TSAMs coated metal specimens prepared via acid chloride, dry heat esterification, and direct esterification were immersed in TBS at 37°C for 28 days. TBS was analyzed at 1, 3, 7, 14, 21, and 28 days to determine the amount of drug released. The cumulative drug release profiles of TSAMs prepared via different esterification techniques have different types of drug release profiles. Large scatters were observed in the data for the release profiles of both Ti and Au prepared through acid chloride esterification. Burst release profiles with smaller scatters were observed for both Ti and Au prepared through dry heat esterification. Direct esterification produced a controlled drug release profile for Au specimens; however, burst release profiles were observed for Ti specimens. These findings demonstrated that the techniques used to attach drug molecules may significantly affect the drug release profiles.;Fourth, the biocompatibility of SAMs and therapeutic SAMs was investigated. Human aortic endothelial cells (HAECs) were seeded on seven different surfaces, which included control glass, control-Ti, control-Au, SAMs coated Ti, SAMs coated Au, TSAMs coated Ti, and TSAMs coated Au. The viability and proliferation of HAECs were investigated by using the MTT colorimetric assay. The cell adhesion on SAMs and TSAMs coated metal surfaces is comparable to control metal surfaces and better than plain glass surfaces. The highest number of viable cells was observed on SAMs coated metal surfaces and control-Ti surfaces. Cell proliferation was observed on SAMs and TSAMs coated metal surfaces even though the rate of proliferation was slower than control surfaces. The phase contrast microscopic images of HAECs showed spreading cells with typical polygonal shape on SAMs and TSAMs coated surfaces similar to control surfaces. The expression of surface adhesion protein, platelet endothelial cell adhesion molecule-1 (PECAM-1), showed that the phenotype of endothelial cells was preserved on SAMs and TSAMs coated surfaces similar to control surfaces. (Abstract shortened by UMI.).
机译：本文研究了自组装单分子膜（SAMs）作为一种直接从金属植入物上附着和释放治疗药物的新技术的应用。本研究中使用的两种金属/ SAMs系统是钛/膦酸和金/硫醇系统。在这项研究中，我们主要研究以下内容：（a）SAM的稳定性，（b）治疗剂与SAM的化学结合，（c）治疗SAM的药物释放动力学以及（d）SAM与治疗性SAM的生物相容性。将羟基封端的膦酸（PA）SAM涂覆在Ti上。在37°C的Tris缓冲盐水（TBS），双蒸馏水（dd-H2O），环境空气和紫外（UV）光中研究了SAM的稳定性。为了比较，将羟基封端的硫醇SAM涂覆在Au上，并在相似条件下研究其稳定性。使用X射线光电子能谱（XPS）对样品进行主要表征，并进行接触角测量。在TBS或dd-H 2O中，PA SAM分子的一部分在14天的时间内从Ti表面脱附，而Au上的硫醇SAM在相似条件下最多可稳定21天。在环境空气中，Ti上的PA SAM可以稳定长达14天，而Au上的硫醇SAM甚至可以稳定一天。在紫外线辐射下，PA SAM的烷基链分解了12小时后仅在Ti表面留下了膦酸酯基。在相似的条件下，在金表面观察到硫醇SAM的烷基链分解并伴随着硫醇盐的氧化。第二，通过将模型药物氟苯那酸化学连接到--OH端接的SAM制备治疗性SAM（TSAM）。涂层的Ti和Au表面。探索了三种不同的酯化方法（酰氯酯化，干热酯化和直接酯化），以将氟虫酰胺酸附着到SAMs涂覆的金属表面上。使用XPS，荧光显微镜和原子力显微镜（AFM）对TSAM涂层的金属表面进行了表征。 XPS证实了氟芬那酸和SAM之间形成酯键。使用荧光显微镜研究了药物分子在SAMs涂层金属标本上的分布。原子力显微镜图像显示了药物附着前后的表面形态变化。第三，采用高效液相色谱法（HPLC）研究了TSAMs的体外释药动力学。将通过酰氯，干热酯化和直接酯化制备的涂有TSAM的金属样品浸入37°C的TBS中28天。在第1、3、7、14、21和28天对TBS进行分析，以确定释放的药物量。通过不同的酯化技术制备的TSAM的累积药物释放曲线具有不同类型的药物释放曲线。在数据中观察到较大的散射，表明通过酰氯酯化制备的Ti和Au的释放曲线。通过干热酯化制备的Ti和Au均观察到具有较小散射的爆发释放曲线。直接酯化产生了金样品的可控药物释放曲线。然而，观察到钛试样的爆裂释放曲线。这些发现表明，用于附着药物分子的技术可能会显着影响药物释放曲线。第四，研究了SAM与治疗性SAM的生物相容性。将人主动脉内皮细胞（HAEC）接种在七个不同的表面上，这些表面包括对照玻璃，对照Ti，对照Au，SAMs涂覆的Ti，SAMs涂覆的Au，TSAMs涂覆的Ti和TSAMs涂覆的Au。使用MTT比色测定法研究了HAEC的活力和增殖。电池在SAM和TSAM涂层金属表面上的附着力与对照金属表面相当，并且比普通玻璃表面更好。在涂有SAM的金属表面和对照Ti表面上观察到活细胞数量最多。尽管增殖速率比对照表面慢，但在SAMs和TSAMs涂覆的金属表面上观察到细胞增殖。 HAEC的相差显微镜图像显示，在与对照表面相似的SAM和TSAM涂层表面上，散布有典型多边形形状的细胞。表面粘附蛋白，血小板内皮细胞粘附分子-1（PECAM-1）的表达表明，在与对照表面相似的SAMs和TSAMs涂层表面上，内皮细胞的表型得以保留。 （摘要由UMI缩短。）。

著录项

  • 作者

    Mani, Gopinath.;

  • 作者单位

    The University of Texas at San Antonio.;

  • 授予单位 The University of Texas at San Antonio.;
  • 学科 Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 161 p.
  • 总页数 161
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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