Thermosensitive display of ligand molecules on microgel scaffolds to facilitate switchable bioadhe-sion

微凝胶支架上配体分子的热敏展示以促进可切换的生物粘附

• 批准号: 397673471
• 负责人: Professor Dr. Stephan Schmidt
• 金额: --
• 依托单位: Institut für Makromolekulare Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397673471?language=en
• 关键词: Thermosensitive; display; ligand; molecules; microgel

Stimuli-responsive polymer coatings with switchable interaction to cells or pathogens are becoming increasingly important in the context of biosensing, tissue engineering, drug delivery and other areas. However, the great majority of reports in the literature describe materials that change their affinity to biological systems by switching non-specific interactions, i.e. hydrophobicity or steric repulsion upon stimuli like temperature or pH. Therefore, it is the broad aim of this project to establish "smart" microgel systems with thermosensitive display of ligand moieties to switch the specific interaction to protein receptors. Recently, we have established non-responsive hydrogel-based microgels conjugated with various ligands exhibiting highly specific interactions to protein receptors. The receptor binding affinity of such hydrogel scaffolds could be tuned by varying the multivalent display of conjugated ligands, e.g. by changing their density, linker chemistry or polymer backbone. Within this project, we now extend this approach towards microgels with poly(N-isopropylacryalamide) (PNIPAM) as responsive polymer matrix that allow changing surface area of gel particles and their ligand display by means of temperature stimulus. Furthermore, we intend to utilize the shift in hydrophobicity of PNIPAM upon temperature change to control ligand display. Therefore, case studies on biotin, mannose and hyaluronic acid as highly relevant ligand systems with varying degree of hydrophobicity will be coupled to PNIPAM microgels and their temperature dependent presentation will be tested by calorimetric receptor binding studies. In addition, the radial distribution of ligands within the microgel will be varied to form microgels with a functionalized shell and a thermosensitive core in order to improve the specificity of their interaction. Taking the temperature dependence of the microgels’ network structure into consideration, we envision surface coatings of ligand-functionalized microgels with the ability to catch and release pathogens. Therefore, the temperature dependent ligand display, microgel mechanics and bio-adhesion of the microgels will be studied via fluorescence, light scattering and force spectroscopy measurements. Finally, their ability to accumulate and release pathogens will be tested by studying the adhesion of E. coli on mannose functionalized microgel films.Overall, the microgel conjugates to be established in this proposal may represent a new way to control the activity of ligands in a polymer scaffolds by temperature stimulus. This proposal mainly focuses on fundamental questions, i.e. the overall feasibility, performance and mechanistic aspects of ligand display in responsive gels. As a first proof-of-concept application, the last part of the project will concentrate on material science aspects and application of ligand conjugated PNIPAM microgels as bioactive coating.

与细胞或病原体具有可切换相互作用的刺激响应聚合物涂层在生物传感、组织工程、药物递送和其他领域的背景下变得越来越重要。然而，文献中的绝大多数报告描述了通过切换非特异性相互作用来改变其对生物系统的亲和力的材料，即在温度或pH等刺激下的疏水性或空间排斥。因此，该项目的广泛目标是建立具有配体部分的热敏显示的“智能”微凝胶系统，以切换与蛋白质受体的特异性相互作用。最近，我们已经建立了非响应性的水凝胶为基础的微凝胶与各种配体的共轭表现出高度特异性的相互作用，蛋白质受体。这种水凝胶支架的受体结合亲和力可以通过改变缀合配体的多价展示来调节，例如通过改变它们的密度、接头化学或聚合物骨架。在这个项目中，我们现在将这种方法扩展到微凝胶与聚（N-异丙基丙烯酰胺）（PNIPAM）作为响应性聚合物基质，允许通过温度刺激改变凝胶颗粒的表面积及其配体显示。此外，我们打算利用温度变化时PNIPAM疏水性的变化来控制配体展示。因此，生物素，甘露糖和透明质酸作为具有不同程度的疏水性的高度相关的配体系统的案例研究将被耦合到PNIPAM微凝胶和它们的温度依赖性介绍将通过量热受体结合研究进行测试。此外，配体在微凝胶内的径向分布将变化以形成具有官能化壳和热敏核的微凝胶，以改善它们相互作用的特异性。考虑到微凝胶网络结构的温度依赖性，我们设想配体功能化微凝胶的表面涂层具有捕获和释放病原体的能力。因此，温度依赖的配体显示，微凝胶力学和微凝胶的生物粘附将通过荧光，光散射和力谱测量进行研究。最后，通过研究E.总的来说，在该提议中建立的微凝胶缀合物可能代表了一种通过温度刺激来控制聚合物支架中配体活性的新方法。该建议主要集中在基本问题，即在响应凝胶中的配体展示的整体可行性，性能和机理方面。作为第一个概念验证应用，该项目的最后一部分将集中在材料科学方面和配体共轭PNIPAM微凝胶作为生物活性涂层的应用。

项目成果

Thermosensitive display of carbohydrate ligands on microgels for switchable binding of proteins and bacteria.

• DOI: 10.1021/acsami.9b08537
• 发表时间: 2019-07
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: T. Paul;Sophie Rübel;Marco Hildebrandt;A. K. Strzelczyk;Carina Spormann;T. Lindhorst;Stephan Schmidt

Temperature switchable glycopolymers and their conformation-dependent binding to receptor targets.

温度可切换的糖聚合物及其与受体靶标的构象依赖性结合

• DOI: 10.1021/acs.biomac.0c00676
• 发表时间: 2020
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Strzelczyk;Feldhof;Schmidt
• 通讯作者: Schmidt

Quantifying Thermoswitchable Carbohydrate-Mediated Interactions via Soft Colloidal Probe Adhesion Studies.

• DOI: 10.1002/mabi.202000186
• 发表时间: 2020-08
• 期刊: Macromolecular bioscience
• 影响因子: 4.6
• 作者: A. K. Strzelczyk;T. Paul;Stephan Schmidt

Selective Adhesion and Switchable Release of Breast Cancer Cells via Hyaluronic Acid Functionalized Dual Stimuli-Responsive Microgel Films.

• DOI: 10.1021/acsabm.1c00586
• 发表时间: 2021-07
• 期刊: ACS applied bio materials
• 影响因子: 4.7
• 作者: Melanie Schmidt;A. Franken;Dimitri Wilms;T. Fehm;H. Neubauer;Stephan Schmidt

Switchable adhesion of E. coli to thermosensitive carbohydrate presenting microgel layers: a single cell force spectroscopy study.

• DOI: 10.1021/acs.langmuir.0c02040
• 发表时间: 2020-09
• 期刊: Langmuir : the ACS journal of surfaces and colloids
• 作者: Dimitri Wilms;Fabian Schröer;T. Paul;Stephan Schmidt