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首页> 外文学位 >Interactions of synthetic polymers with cell membranes: Cell penetration of polycationic polymers and multivalent effects of targeted nanodevices.
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Interactions of synthetic polymers with cell membranes: Cell penetration of polycationic polymers and multivalent effects of targeted nanodevices.

机译：合成聚合物与细胞膜的相互作用：聚阳离子聚合物的细胞渗透和靶向纳米器件的多价作用。

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摘要

This dissertation describes biological interactions of synthetic polymers relevant to two major biomedical applications, gene delivery and targeted drug delivery. The first part describes biological interactions of polycationic polymers that have been commonly used as gene delivery/cell transfection agents. This study reveals that polycationic polymers such as amine terminated poly(amidoamine) (PAMAM) dendrimers, poly-L-lysine, polyethylenimine, diethylaminoethyl-dextran induce membrane permeabilization in living cells. Exposure of cells to the polycationic polymers caused enzyme leakage out of the cells, polymer internalization into the cells, and diffusion of small molecular probes in and out of the cells. In contrast, charge neutral acetamide and negatively charged carboxylate terminated PAMAM dendrimers, as well as polyethyleneglycol and poly(vinyl alcohol) do not enter the cells or cause permeability of the cell membranes. By combining our previous AFM observation and a variety of in vitro tests presented here, we conclude that a nanoscale hole formation mechanism is an important pathway for polycationic polymer-cell interactions.; The second part of this study deals with multivalent interaction of cancer cell targeting dendritic nanodevices with a receptor protein target. Dendrimer-based anti-cancer nanotherapeutics containing ∼5 folate molecules have shown in vitro and in vivo efficacy in cancer cell targeting. Multivalent interactions have been inferred from observed targeting efficacy but have not been experimentally proven. This study provides quantitative and systematic evidence for multivalent interactions between these nanodevices and folate binding protein (FBP). A series of the nanodevices were synthesized by conjugation with different amounts of folate. Dissociation constants ( KD) between the nanodevices and FBP measured by SPR are dramatically enhanced through multivalency (∼2,500-170,000 fold). Qualitative evidence is also provided for a multivalent targeting effect to KB cells using flow cytometry. These data support the hypothesis that multivalent enhancement of KD, not an enhanced rate of endocytosis, is the key factor resulting in the improved biological targeting by these drug delivery platforms, providing a design guide for future receptor targeting agents.
机译：本论文描述了与两种主要生物医学应用相关的合成聚合物的生物相互作用，即基因传递和靶向药物传递。第一部分描述了聚阳离子聚合物的生物相互作用，该聚阳离子聚合物通常用作基因传递/细胞转染剂。这项研究揭示了聚阳离子聚合物，例如胺端基的聚（酰胺基胺）（PAMAM）树状大分子，聚-L-赖氨酸，聚乙烯亚胺，二乙基氨基乙基-葡聚糖可诱导活细胞中的膜通透性。细胞暴露于聚阳离子聚合物中会导致酶从细胞中漏出，聚合物内化到细胞中以及小分子探针在细胞内外扩散。相反，带电荷的中性乙酰胺和带负电荷的羧酸酯封端的PAMAM树状聚合物，以及聚乙二醇和聚乙烯醇不会进入细胞或引起细胞膜通透性。通过结合我们先前的AFM观察结果和此处介绍的各种体外测试，我们得出结论，纳米级孔形成机制是聚阳离子聚合物与细胞相互作用的重要途径。这项研究的第二部分涉及癌细胞靶向树突状纳米器件与受体蛋白靶标的多价相互作用。含有约5个叶酸分子的基于树状聚合物的抗癌纳米疗法在癌细胞靶向中已显示出体外和体内功效。从观察到的靶向功效可以推断出多价相互作用，但尚未得到实验证明。这项研究为这些纳米器件与叶酸结合蛋白（FBP）之间的多价相互作用提供了定量和系统的证据。通过与不同量的叶酸共轭合成了一系列纳米器件。纳米器件和通过SPR测量的FBP之间的解离常数（KD）通过多价（〜2,500-170,000倍）得到显着提高。还提供了使用流式细胞仪对KB细胞的多价靶向作用的定性证据。这些数据支持以下假设：KD的多价增强而不是内吞率的提高是导致这些药物递送平台改善生物靶向性的关键因素，从而为未来的受体靶向剂提供了设计指南。

著录项

  • 作者

    Hong, Seungpyo.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Chemistry Polymer.; Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 149 p.
  • 总页数 149
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 高分子化学（高聚物）;生物医学工程;
  • 关键词

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