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

技术摘要：这项研究探索使用两亲性刷状共聚物来构建环境友好的丝状纳米结构，用于靶向药物输送应用。这项提议的目标是合成通过形状依赖的环境可调机制控制载体-细胞相互作用来增强递送的构建体。PI将设计分子刷的低聚物，分子刷沿主干和相邻刷子之间含有环境响应部分，以产生具有可控空间和/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在环境中引发的去寡聚和构象转变。为了应对这一科学挑战，PI将利用明确定义的聚合物合成和共轭方法，并设计表面功能化技术。这项建议的具体目标是：(1)设计、合成和表征具有pH敏感性的两亲性核壳分子刷，然后进行其齐聚；(2)研究分子刷低聚物的疏水坍塌、溶质负载以及刷丝的形状变化和解聚；以及(3)通过预组装构建块的共聚从分子刷合成表面图案粒子。非技术摘要：该研究将为受自然启发的新型聚合物的设计提供有价值的信息。通过这个项目的完成所获得的知识将使我们更好地了解这些构件的结构/性质关系，并使我们能够将它们用于其他生物启发材料的应用。如果成功，该项目将通过利用刺激响应型聚合物生物材料的化学灵活性和独特的物理特性来控制微米到纳米尺度上的载体与细胞之间的相互作用，从而推动药物载体的设计。拟议中的职业计划的更广泛影响将把PI对开发基于聚合物的“智能”生物材料的研究兴趣与一个旨在激发整个本科预科教育水平对该领域的兴趣的教育计划结合起来，特别是在代表性不足的学生群体中。通过创造一个引人入胜和鼓舞人心的研究环境，PI将寻求继续吸引本科生和研究生对刺激响应性聚合物系统和药物输送领域的兴趣。拟议研究的性质应该为学生提供跨学科的激励性挑战，从理论和实验角度对聚合物科学进行全面教育，并提供工具来解决具有创造性和批判性思维的问题。

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.