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

职业：药物输送中的响应仿生策略：分子刷低聚物

• 批准号: 1151535
• 负责人: Margarita Herrera-Alonso
• 金额: $ 51.38万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1151535&HistoricalAwards=false
• 关键词: CAREER; Responsive; Biomimetic; Strategies; Drug

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.

技术摘要：本研究探索了使用两亲刷状共聚物构建环境响应性丝状纳米结构用于靶向药物递送应用。本提案的目的是合成通过形状依赖性环境可调机制控制载体-细胞相互作用来增强递送的结构。 PI将设计分子刷的低聚物，该分子刷含有沿着主链和相邻刷之间的环境响应部分，以产生具有可控空间和/或时间3-D结构、表面化学和机械性能的疏水溶质载体。这些构建体的仿生方面依赖于它们是在分泌粘蛋白的节段性质之后设计的事实。 可编程方面靶向其环境触发的去低聚和构象转变。为了解决这一科学挑战，PI将利用明确的聚合物合成和缀合方法以及工程表面官能化技术。本课题的具体目标是：（1）设计、合成和表征具有pH敏感性的两亲性核壳分子刷，并进行其齐聚反应;（2）研究分子刷齐聚物的疏水性塌陷、溶质负载以及引发刷丝的形变和去齐聚反应;（3）通过预组装结构单元的共聚反应，由分子刷合成表面图案化的颗粒。非技术摘要：这项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/性能关系，并使我们能够在其他生物启发材料应用中使用它们。 如果成功，该项目将通过利用刺激响应性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纳米长度尺度上的载体-细胞相互作用，从而推进药物载体设计。 拟议的CAREER计划的更广泛的影响将结合联合收割机PI的研究兴趣，在“智能”聚合物基生物材料的发展与教育计划，有针对性地在整个本科前教育水平，特别是在代表性不足的学生群体中产生兴趣的领域。通过创造一个引人入胜和鼓舞人心的研究环境，PI将寻求在刺激响应聚合物系统和药物输送领域不断吸引本科生和研究生。拟议研究的性质应该为学生提供跨学科的刺激性挑战，从理论和实验角度对聚合物科学进行全面的教育，并提供以创造性和批判性思维解决问题的工具。