Collaborative Research: Elucidating the Nanoscale Interaction between Invertible Micellar Assemblies (IMAs) and Biopolymer Cargos under Varied Environments

合作研究：阐明不同环境下可逆胶束组件（IMA）和生物聚合物货物之间的纳米级相互作用

• 批准号: 2217474
• 负责人: Zhongyu Yang
• 金额: $ 60.92万
• 依托单位: North Dakota State University Fargo
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2217474&HistoricalAwards=false
• 关键词: Collaborative; Research; Elucidating; Nanoscale; Interaction

Research in drug delivery by polymeric carriers is still in its infancy. The demanding challenge in this field is to find the right carrier architecture and the optimum polymer chemistry that can facilitate controlled delivery and release of therapeutic agents (drugs) to their targets. A unique carrier is invertible polymer micellar assemblies, which are formed by the rapid self-organization/assembly of polymers with alternated and repeated hydrophobic (water-hating) and hydrophilic (water-loving) segments in a rod-like shape (tens of nanometers long). Drugs and polypeptides/nucleic acids which can treat various diseases but cannot be directly introduced to human body can be incorporated into invertible micellar assemblies. Once the environmental conditions are changed (i.e., when the assemblies from water “arrive” to the cellular membrane), the invertible micellar assemblies reverse their dimensions and geometry (shape) in a smart way to effectively deliver and release cargo molecules to the targets (biological membranes) and, thus, treat relevant diseases. Although the structure and dynamics of invertible micellar assemblies have been understood to a certain level, the key questions that still need to be answered are (i) what properties of cargo-loaded invertible micellar assemblies make them efficient in treating diseases (ii) how significant is a fact of unique change of shape (called “inversion” in this project) for efficient delivery performance. Answering these questions require an in-depth understanding on the interactions between drug cargos and invertible micellar assemblies under varied environments at the molecular level, which is a challenging task because most commonly seen techniques do not have a sufficiently high resolution to “penetrate” the assemblies and probe biopolymer cargos therein. In this project, researchers from the North Dakota State University bridge this knowledge gap by labelling biopolymers and studying the behavior of the labeled sites using a unique technique known as Electron Paramagnetic Resonance spectroscopy. The obtained data will provide details on how invertible micellar assemblies interact with the solvent environment and the biopolymer cargos as well as how the cargos move and/or aggregate within the interior of invertible micellar assemblies. This information not only answers aforementioned questions but also assists in the rational design of new delivery vehicles that better adapt/deliver biopolymers and/or drugs, broadening the application of invertible micellar assemblies as general drug carriers to treat various diseases. The research team will provide training to underrepresented students including Native American students and local undergraduate and high school students on nanotechnology and chemistry. The team will also offer scientific educational opportunities for youths whose parents are deployed as soldiers through the Operation Military Kids program in the state of North Dakota.This project aims to understand the interactions among the invertible micellar assemblies, cargo, and environment (solvent) at the nanoscale, in order to reveal the mechanistic details in the interior of invertible micellar assemblies when biopolymer cargos are loaded and released due to environment polarity changes. This goal will be achieved via three steps: (i) revealing the changes in the morphology, crowding, and polarity of invertible micellar assemblies under varied solvent conditions, (ii) depicting the impact of biopolymer cargo loading on the morphology, crowding, and polarity of invertible micellar assemblies in water, and (iii) elucidating the movement and aggregation state (if any) of the biopolymer within invertible micellar assemblies upon environment polarity change. The key to acquiring this knowledge is to covalently place an Electron Paramagnetic Resonance spin probe/tag at specific locations/positions within the invertible micellar assemblies and on biopolymers, followed by Electron Paramagnetic Resonance spectroscopy study of (bio)polymer structure and dynamics. This research will provide maps of the local crowding and polarity within the invertible micellar assemblies under various solvent conditions and locate various segments of biopolymer cargos (connecting which lead to cargo conformation) in the invertible micellar assemblies based on the local crowding and polarity of the cargo. The obtained knowledge offers a direct connection between the microenvironment of invertible micellar assemblies and cargo structure/hydrophobicity/polarity to assess and rationalize the relative strength of the interactions between invertible micellar assemblies and cargos. This work will also use the information of cargo location and cargo movement to depict the relative position of cargos upon interacting with the invertible micellar assemblies. Lastly, this research will elucidate the possible structural changes of cargos, if any, caused by the interactions between invertible micellar assemblies and cargos. All of these efforts will result in an in-depth understanding of the cargo uptake/release performance and the interactions between invertible micellar assemblies and cargos. This project will also provide training to students at various educational levels (high school, undergraduate) from diverse backgrounds by offering hands-on research experience in cutting-edge nanotechnology, biopolymer engineering, and spectroscopy. The obtained knowledge and experimental approaches from research activities will be disseminated through scientific peer-review journal publications, national/international conferences, and local science fairs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

通过聚合物载体进行药物递送的研究仍处于起步阶段。该领域的严峻挑战是找到合适的载体结构和最佳的聚合物化学，以促进治疗剂（药物）向其靶点的受控递送和释放。一种独特的载体是可逆的聚合物胶束组装体，其通过具有交替和重复的疏水（憎水）和亲水（喜水）链段的聚合物以棒状形状（数十纳米长）的快速自组织/组装形成。可以将治疗各种疾病但不能直接引入人体的药物和多肽/核酸掺入可逆胶束组装体中。一旦环境条件改变（即，当来自水的组装体“到达”细胞膜时），可逆胶束组装体以巧妙的方式反转它们的尺寸和几何形状（形状），以有效地将货物分子递送和释放到靶（生物膜），从而治疗相关疾病。虽然可逆胶束组装体的结构和动力学已经被理解到一定水平，但仍然需要回答的关键问题是（i）负载货物的可逆胶束组装体的什么性质使它们在治疗疾病中有效（ii）形状的独特变化（在该项目中称为“反转”）对于有效递送性能的事实有多重要。解决这些问题需要在分子水平上深入了解药物货物和可逆胶束组装体在不同环境下的相互作用，这是一项具有挑战性的任务，因为大多数常见的技术不具有足够高的分辨率来“穿透”组装体并探测其中的生物聚合物货物。在这个项目中，来自北达科他州州立大学的研究人员通过标记生物聚合物并使用称为电子顺磁共振光谱的独特技术研究标记位点的行为来弥合这一知识差距。所获得的数据将提供关于可逆胶束组装体如何与溶剂环境和生物聚合物货物相互作用以及货物如何在可逆胶束组装体内部移动和/或聚集的细节。这些信息不仅回答了上述问题，而且还有助于合理设计新的递送载体，更好地适应/递送生物聚合物和/或药物，拓宽可逆胶束组装体作为一般药物载体治疗各种疾病的应用。该研究小组将为代表性不足的学生提供纳米技术和化学方面的培训，包括美洲原住民学生和当地本科生和高中生。该团队还将通过北达科他州的军事儿童行动计划为父母被部署为士兵的年轻人提供科学教育机会。该项目旨在了解纳米尺度下可逆胶束组装体、货物和环境（溶剂）之间的相互作用，以揭示生物聚合物货物因环境极性变化而装载和释放时可逆胶束组装体内部的机理细节。这一目标将通过三个步骤实现：（i）揭示在不同溶剂条件下可逆胶束组装体的形态、拥挤和极性的变化，（ii）描绘生物聚合物货物负载对水中可逆胶束组装体的形态、拥挤和极性的影响，和（iii）阐明环境极性改变时生物聚合物在可逆胶束组装体内的运动和聚集状态（如果有的话）。获得这些知识的关键是将电子顺磁共振自旋探针/标签共价地放置在可逆胶束组装体内和生物聚合物上的特定位置/位置处，然后进行（生物）聚合物结构和动力学的电子顺磁共振光谱研究。这项研究将提供地图的局部拥挤和极性内的可逆胶束组件在各种溶剂条件下，并定位各种片段的生物聚合物货物（连接导致货物构象）在可逆胶束组件的基础上的局部拥挤和极性的货物。所获得的知识提供了可逆胶束组装体的微环境和货物结构/疏水性/极性之间的直接联系，以评估和合理化可逆胶束组装体和货物之间的相互作用的相对强度。这项工作也将使用货物的位置和货物的运动信息来描绘货物与可逆胶束组装体相互作用时的相对位置。最后，本研究将阐明可逆胶束组装体与货物之间的相互作用可能引起的货物结构变化。所有这些努力将导致在货物摄取/释放性能和可逆胶束组装体和货物之间的相互作用的深入了解。该项目还将通过提供尖端纳米技术，生物聚合物工程和光谱学方面的实践研究经验，为来自不同背景的各种教育水平（高中，本科）的学生提供培训。从研究活动中获得的知识和实验方法将通过科学同行评审期刊出版物、国家/国际会议和当地科学博览会传播。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

项目成果

Application of High-Pressure Electron Paramagnetic Resonance (EPR) Spectroscopy in Protein Science

高压电子顺磁共振（EPR）波谱在蛋白质科学中的应用

• DOI: 10.1007/s00723-023-01573-4
• 发表时间: 2023
• 期刊: Applied Magnetic Resonance
• 影响因子: 1
• 作者: MacRae, Austin;Armstrong, Zoe;Lenertz, Mary;Li, Qiaobin;Forge, Aiden;Wang, Max;Feng, Li;Sun, Wenfang;Yang, Zhongyu
• 通讯作者: Yang, Zhongyu