CAREER: Impact of MRI contrast agent design on nanoscale interactions with neutrophils and platelets

职业：MRI 造影剂设计对中性粒细胞和血小板纳米级相互作用的影响

• 批准号: 2339015
• 负责人: Margaret Bennewitz
• 金额: $ 69.8万
• 依托单位: West Virginia University Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2029-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2339015&HistoricalAwards=false
• 关键词: CAREER; Impact; MRI; contrast; agent

Understanding how nanoparticle characteristics mediate their interactions with blood cells in the body is crucial to promoting their safety and effectiveness. Nanoparticles delivered to the bloodstream are surrounded by red blood cells, a variety of white blood cells, and platelets. Despite blood’s complexity, most studies developing nanoparticles for imaging applications have focused on assessing off-target nanoparticle interactions with a subtype of white blood cells called macrophages. Macrophages are part of the body’s defense mechanism against foreign objects and are known to sequester nanocarriers in the body. Despite the abundance of platelets and other white blood cells such as neutrophils, these blood cells are often ignored in the design of nanoparticle imaging agents. Upon activation, neutrophils and platelets can stick together to form cellular aggregates that can block blood flow, just as a clump of hair clogs a drainpipe. This CAREER project will generate new knowledge on how the physical characteristics of metal oxide nanoparticles (their metal content, surface coating, and size) impact interactions with neutrophils and platelets. Dr. Bennewitz will investigate how nanoparticle design mediates cell uptake and transport, activation of neutrophils and platelets, and their downstream cell-cell interactions in static and dynamic systems. This project will lead to the creation of safer and more effective nanoparticle contrast agents for magnetic resonance imaging by smarter design strategies to minimize off-target effects. The integrated education plan will target underserved students from rural, low-income, and first-generation college households in West Virginia, who are at-risk for not advancing their education. Collectively, the education plan will spark interest in STEM for all age groups from preschool to high school students in West Virginia. By combining hands-on research, experiential learning, creative integration of art and science, and exposure to real world applications in nanotechnology, imaging, and biomaterials, these outreach activities will inspire the next generation of young scientists and engineers.Conventional testing of novel nanoparticle contrast agents relies on evaluating off-target interactions with macrophages, disregarding neutrophils, and platelets. Activated neutrophils and platelets can form neutrophil-platelet aggregates that trigger downstream damage including release of web-like DNA fibers called neutrophil extracellular traps. Neutrophil extracellular traps provoke endothelial injury, platelet activation, and neutrophil recruitment to promote vessel blockage. Thus, there is a critical need to elucidate how nanoparticle contrast agents interact with neutrophils and platelets to maximize safety. Dr. Bennewitz’s group has shown that nanoparticle contrast agent coating and metal content modulates neutrophil function via differential release of neutrophil extracellular traps, reactive oxygen species, and cytokines. This CAREER project aims to determine how the physical characteristics of metal oxide nanoparticles used in magnetic resonance imaging mediate interactions with neutrophils and platelets in complementary systems including static in vitro assays, microfluidic chips, and a proof-of-principle mouse model. The central hypothesis is that the physical properties of nanoparticle contrast agents modulate neutrophil and platelet nanoparticle transport, cell activation, neutrophil-platelet aggregate formation, release of neutrophil extracellular traps, and thrombosis. The central hypothesis will be tested with the following research objectives: (1) Investigate metal oxide nanoparticle uptake and transport in neutrophils and platelets (2-3) Evaluate metal oxide nanoparticle-mediated neutrophil and platelet activation, aggregation, and release of neutrophil extracellular traps under static and dynamic flow conditions. This project will be transformative, as Dr. Bennewitz will be able to determine how manganese oxide nanoparticles, iron oxide nanoparticles, and conventional gadolinium chelate contrast agents impact neutrophil-platelet crosstalk, neutrophil extracellular traps, and thrombosis in vitro and in vivo to enhance contrast agent safety. The educational objectives of this CAREER project are to: (1) Host 10 rural, low-income West Virginia high school students in hands-on summer research through the Upward Bound Program. Students will be exposed to nanoparticle synthesis and incubation studies with neutrophils and platelets in static and dynamic systems. (2) Create and disseminate a Biomedical Engineering module to 4,000 middle and high school students state-wide via the West Virginia Science Public Outreach Team. Two hands-on activities will be integrated into the presentation to spark student interest in fluorescence imaging and polymer stimulus driven delivery, two key research concepts of this project. (3) Design and lead an interactive science meets art activity focused on fluorescent painting under blacklights for children aged 10 and under at the Spark! Imagination and Science Center. The education plan will cultivate interest in STEM education and careers for underserved West Virginia students and the public. Undergraduate and graduate students will gain valuable mentoring and teaching experience via their integral roles in creating and disseminating the outreach activities which will bolster their confidence, leadership, and retention in STEM. This project is jointly funded by the Nanoscale Interactions Program within CBET and the Established Program to Stimulate Competitive Research (EPSCoR).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.

了解纳米颗粒的特性如何介导其与体内血细胞的相互作用对于提高其安全性和有效性至关重要 尽管血液很复杂，但输送到血液中的纳米颗粒周围都是红细胞、各种白细胞和血小板。开发用于成像应用的纳米粒子的重点是评估纳米粒子与一种称为巨噬细胞的白细胞亚型的脱靶相互作用，巨噬细胞是人体抵御异物的防御机制的一部分，并且已知可以隔离。尽管体内存在大量血小板和其他白细胞（例如中性粒细胞），但在纳米颗粒成像剂的设计中，这些血细胞经常被忽略，一旦激活，中性粒细胞和血小板就会粘在一起形成细胞聚集体，从而阻塞血液。就像一丛头发堵塞排水管一样，这个职业项目将产生关于金属氧化物纳米颗粒的物理特性（它们的金属含量、表面涂层和尺寸）如何影响相互作用的新知识。 Bennewitz 博士将研究纳米颗粒设计如何介导细胞摄取和运输、中性粒细胞和血小板的激活以及它们在静态和动态系统中的下游细胞间相互作用。该综合教育计划将针对来自西弗吉尼亚州农村、低收入和第一代大学家庭的服务不足的学生，他们处于危险之中。总的来说，该教育计划将通过结合实践研究、体验式学习、艺术与科学的创造性整合以及接触，激发西弗吉尼亚州从学前班到高中生的所有年龄段对 STEM 的兴趣。这些推广活动将激励下一代年轻科学家和工程师。新型纳米颗粒造影剂的常规测试依赖于评估与巨噬细胞的脱靶相互作用，而忽略中性粒细胞和血小板。活化的中性粒细胞和血小板可以形成中性粒细胞-血小板聚集体，引发下游损伤，包括释放称为中性粒细胞胞外陷阱的网状DNA纤维，中性粒细胞胞外陷阱引起内皮损伤、血小板活化和中性粒细胞募集，从而促进血管阻塞。 Bennewitz 博士的研究小组表明，迫切需要阐明纳米颗粒造影剂如何与中性粒细胞和血小板相互作用，以最大限度地提高安全性。纳米粒子造影剂涂层和金属含量通过中性粒细胞胞外陷阱、活性氧和细胞因子的差异释放来调节中性粒细胞功能。该职业项目旨在确定磁共振成像中使用的金属氧化物纳米粒子的物理特性如何介导与中性粒细胞和血小板的相互作用。在补充系统中，包括静态体外测定、微流控芯片和原理验证小鼠模型，中心假设是纳米颗粒造影剂的物理特性。调节中性粒细胞和血小板纳米颗粒的运输、细胞活化、中性粒细胞-血小板聚集体的形成、中性粒细胞胞外陷阱的释放和血栓形成中心假设将通过以下研究目标进行检验：（1）研究中性粒细胞和血小板纳米颗粒的摄取和运输。血小板 (2-3) 评估金属氧化物纳米颗粒介导的中性粒细胞和血小板活化、聚集和中性粒细胞胞外释放该项目将具有变革性，因为 Bennewitz 博士将能够确定氧化锰纳米粒子、氧化铁纳米粒子和传统钆螯合物造影剂如何影响中性粒细胞-血小板串扰、中性粒细胞胞外陷阱和血栓形成。体外和体内增强造影剂安全性 该职业项目的教育目标是： (1) 接待 10 名西弗吉尼亚州农村低收入高中。学生将通过 Upward Bound 项目进行暑期实践研究。学生将在静态和动态系统中接触中性粒细胞和血小板的纳米粒子合成和孵化研究。 (2) 创建并向 4,000 所初中和高中传播生物医学工程模块。通过西弗吉尼亚州科学公共外展团队在全州范围内的学生将在演示中融入两项实践活动，以激发学生对荧光成像和聚合物刺激驱动的交付（该项目的两个关键研究概念）的兴趣。 (3) 在 Spark! 想象力与科学中心设计并领导一项以黑光下荧光绘画为主题的互动科学与艺术活动！本科生和研究生将通过他们在创建和传播外展活动中的重要作用获得宝贵的指导和教学经验，这将增强他们对 STEM 的信心、领导力和保留力。该项目由纳米尺度互动计划共同资助。 CBET 和刺激竞争研究既定计划 (EPSCoR)。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。