• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Self-Assembling Peptide Amphiphiles for Therapeutic Delivery of Proteins, Drugs, and Stem Cells.
【24h】

Self-Assembling Peptide Amphiphiles for Therapeutic Delivery of Proteins, Drugs, and Stem Cells.

机译：自组装肽两亲物，用于蛋白质，药物和干细胞的治疗性输送。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Biomaterials are used to help regenerate or replace the structure and function of damaged tissues. In order to elicit desired therapeutic responses in vivo, biomaterials are often functionalized with bioactive agents, such as growth factors, small molecule drugs, or even stem cells. Therefore, the strategies used to incorporate these bioactive agents in the microstructures and nanostructures of biomaterials can strongly influence the their therapeutic efficacy. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures with improved interaction with three types of therapeutic agents: bone morphogenetic protein 2 (BMP-2) which promotes osteogenic differentiation and bone growth, anti-inflammatory drug naproxen which is used to treat osteo- and rheumatoid arthritis, and neural stem cells that could differentiate into neurons to treat neurodegenerative diseases. For BMP-2 delivery, two specific systems were investigated with affinity for BMP-2: 1) heparin-binding nanofibers that display the natural ligand of the osteogenic protein, and 2) nanofibers that display a synthetic peptide ligand discovered in our laboratory through phage display to directly bind BMP-2. Both systems promoted enhanced osteoblast differentiation of pluripotent C2C12 cells and augmented bone regeneration in two in vivo models, a rat critical-size femur defect model and spinal arthrodesis model. The thesis also describes the use of PA nanofibers to improve the delivery of the anti-inflammatory drug naproxen. To promote a controlled release, naproxen was chemically conjugated to the nanofiber surface via an ester bond that would only be cleaved by esterases, which are enzymes found naturally in the body. In the absence of esterases, the naproxen remained conjugated to the nanofibers and was non-bioactive. On the other hand, in the presence of esterases, naproxen was slowly released and inhibited cyclooxygenase-2 (COX-2) activity, an enzyme responsible for inflammation. Finally, PA nanofibers were utilized as synthetic extracellular matrices (ECM) to encapsulate neural stem cells and promote neuron differentiation. Here, the influence of ECM nanostructures on neuron differentiation was assessed by comparing wide and narrow nanoribbons that were crafted from identical PA molecules. The PAs self-assembled into wide nanoribbons at pH 6.6, but raising the pH to 7.2 promoted increased side-chain ionization and electrostatic repulsion, thus resulting in a structural transformation into thin nanoribbons. In contrast, introducing divalent Ca2+ counterions at pH 6.6 stabilized the intermolecular cohesion of the PA molecules and the wide nanoribbon shape was preserved upon increasing pH. Interestingly, the wide nanoribbon gel exhibited a higher stiffness than the narrow nanoribbon gel. When neural stem cells were encapsulated, the wide nanoribbon matrix was able to promote neuron differentiation, while the thin nanoribbon matrix contracted and prevented neuron differentiation. Mechanistically, the collapse of the thin ribbons likely increased the local density and cell-cell contact of the stem cells, which has been found previously to prevent differentiation into neuronal lineage. Taken together, these findings demonstrate the significance of protein-material or cell-material interactions in achieving optimal therapeutic effects and provide future strategies for developing functional supramolecular biomaterials.
机译：生物材料用于帮助再生或替换受损组织的结构和功能。为了在体内引起期望的治疗反应，通常用生物活性剂例如生长因子，小分子药物或什至干细胞对生物材料进行功能化。因此，用于将这些生物活性剂掺入生物材料的微结构和纳米结构中的策略可强烈影响其治疗功效。使用自组装肽两亲物（PAs），这项工作研究了与三种类型的治疗剂相互作用改善的超分子纳米结构：促进骨形成和骨生长的骨形态发生蛋白2（BMP-2），消炎药萘普生用于治疗骨关节炎和类风湿关节炎，以及可以分化为神经元以治疗神经退行性疾病的神经干细胞。对于BMP-2的递送，研究了两个对BMP-2有亲和力的特定系统：1）肝素结合纳米纤维显示出成骨蛋白的天然配体，以及2）纳米纤维显示了通过实验室通过噬菌体发现的合成肽配体。显示直接绑定BMP-2。两种系统都促进了多能性C2C12细胞的成骨细胞分化增强，并在两个体内模型（大鼠临界大小的股骨缺损模型和脊柱关节固定术模型）中增强了骨再生。本文还描述了使用PA纳米纤维改善抗炎药萘普生的传递。为了促进控制释放，萘普生通过酯键化学结合到纳米纤维表面，该酯键只能被酯酶裂解，酯酶是体内天然存在的酶。在没有酯酶的情况下，萘普生仍然与纳米纤维缀合，并且没有生物活性。另一方面，在存在酯酶的情况下，萘普生会缓慢释放并抑制环氧合酶2（COX-2）活性（一种引起炎症的酶）。最后，PA纳米纤维被用作合成细胞外基质（ECM）来封装神经干细胞并促进神经元分化。在这里，通过比较由相同PA分子制成的宽和窄纳米带，评估了ECM纳米结构对神经元分化的影响。 PA在pH 6.6时自组装成宽的纳米带，但将pH升高到7.2则促进了侧链电离和静电排斥的增加，从而导致结构转变为薄的纳米带。相反，在pH 6.6处引入二价Ca2 +抗衡离子可稳定PA分子的分子间内聚力，并在pH升高时保留宽的纳米带形状。有趣的是，宽的纳米带凝胶比窄的纳米带凝胶具有更高的刚度。当封装神经干细胞时，宽的纳米带基质能够促进神经元分化，而薄的纳米带基质收缩并阻止神经元分化。从机理上讲，薄带的塌陷可能会增加干细胞的局部密度和细胞间接触，这先前已被发现可以防止分化为神经元谱系。综上所述，这些发现证明了蛋白质-材料或细胞-材料相互作用在实现最佳治疗效果方面的重要性，并为开发功能性超分子生物材料提供了未来的策略。

著录项

  • 作者

    Lee, Sungsoo Seth.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Materials science.;Biochemistry.;Biomedical engineering.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 178 p.
  • 总页数 178
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号