CAREER: Responsive Biomimetic Strategies in Drug Delivery: Molecular Brush Oligomers

技术摘要：本研究探索了使用两亲性刷状共聚物构建环境响应的丝状纳米结构，用于靶向药物递送应用。本提案的目的是通过形状依赖的环境可调机制，通过控制载体细胞相互作用来合成增强递送的结构。PI将设计分子刷的低聚物，其中包含沿主干和相邻刷之间的环境响应部分，以生产具有可控空间和/或时间三维结构、表面化学和机械性能的疏水溶质载体。这些结构的仿生方面依赖于这样一个事实，即它们是根据分泌粘蛋白的节段性设计的。可编程方面的目标是它们的环境触发的去寡聚化和构象转变。为了解决这一科学挑战，PI将利用明确的聚合物合成和共轭方法以及工程表面功能化技术。本课题的具体目标是：(1)设计、合成并表征具有ph敏感性的两亲性核壳分子刷，并对其进行寡聚化；(2)研究分子电刷低聚物的疏水塌缩、溶质加载及其引发的电刷细丝形状变化和去寡聚；(3)通过预组装构件的共聚，从分子刷合成表面图案颗粒。摘要：本研究将为设计受自然启发的新型聚合物提供有价值的信息。通过完成该项目获得的知识将使我们更好地了解这些构建块的结构/属性关系，并使我们能够在其他生物启发材料应用的背景下使用它们。如果成功，该项目将通过利用刺激响应高分子生物材料的化学柔韧性和独特的物理特性来控制载体-细胞在微到纳米尺度上的相互作用，从而推进药物载体的设计。拟议的CAREER项目的广泛影响将结合PI对“智能”聚合物生物材料发展的研究兴趣，以及旨在在整个本科预科教育阶段，特别是在代表性不足的学生群体中产生对该领域兴趣的教育项目。通过创造一个引人入胜和鼓舞人心的研究环境，PI将寻求在刺激反应聚合物系统和药物输送领域不断吸引本科生和研究生的兴趣。拟议研究的性质应该为学生提供跨学科的刺激挑战，从理论和实验角度对聚合物科学进行全面的教育，并提供具有创造性和批判性思维的解决问题的工具。

TECHNICAL ABSTRACT:This research explores the use of amphiphilic brush copolymers to build environmentally responsive filamentous nanostructures for targeted drug delivery applications. The objective of this proposal is to synthesize constructs that enhance delivery by controlling carrier-cell interactions through shape-dependent environmentally tunable mechanisms. The PI will design oligomers of molecular brushes containing environmentally responsive moieties along the backbone and between adjacent brushes to produce carriers of hydrophobic solutes with controllable spatial and/or temporal 3-D structure, surface chemistry, and mechanical properties. The biomimetic aspect of these constructs relies on the fact that they are designed after the segmental nature of secreted mucins. The programmable aspect targets their environmentally triggered de-oligomerization and conformational transitions. To address this scientific challenge the PI will utilize well-defined polymer synthesis and conjugation methods and engineer surface functionalization techniques. The specific objectives of this proposal are: (1) to design, synthesize, and characterize amphiphilic core-shell molecular brushes with pH-sensitivity and then carry out their oligomerization; (2) to study the hydrophobic collapse of molecular brush oligomers, solute loading, and the triggered shape change and de-oligomerization of brush filaments; and (3) to synthesize surface patterned particles from molecular brushes by the copolymerization of pre-assembled building blocks.NON-TECHNICAL ABSTRACT:The proposed research will provide valuable information regarding the design of new polymers inspired by nature. The knowledge gained through the completion of this project will provide us with a better understanding of the structure/property relationships of these building blocks and will allow us to use them in the context of other bioinspired materials applications. If successful, this project will advance drug-carrier design by harnessing the chemical flexibility and unique physical properties of stimuli-responsive polymeric biomaterials to control carrier-cell interactions across the micro-to-nano length scale. The broader impact of the proposed CAREER program will combine the PI's research interest in the development of 'intelligent' polymer-based biomaterials with an educational program targeted to generate interest in the field throughout the pre-undergraduate educational levels, particularly among under-represented student populations. By creating an engaging and inspiring research environment, the PI will seek to continually interest undergraduate and graduate students in the field of stimuli-responsive polymer systems and drug delivery. The nature of the proposed research should provide students with stimulating challenges across disciplines, a comprehensive education in polymer science from theoretical and experimental perspectives, and with the tools to address a problem with creativeness and a critical mindset.