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它们与体内血细胞的相互作用，对于提高它们的安全性和有效性至关重要。被输送到血液中的纳米颗粒被红细胞、各种白细胞和血小板所包围。尽管血液很复杂，但大多数用于成像应用的纳米颗粒研究都集中在评估脱靶纳米颗粒与一种称为巨噬细胞的白细胞的相互作用上。巨噬细胞是人体抵御外来物的防御机制的一部分，并被认为可以隔离体内的纳米载体。尽管血小板和其他白细胞（如中性粒细胞）丰富，但这些血细胞在纳米颗粒显像剂的设计中经常被忽略。一旦被激活，中性粒细胞和血小板就会粘在一起形成细胞聚集体，阻碍血液流动，就像一丛头发堵塞排水管一样。这个CAREER项目将产生新的知识，研究金属氧化物纳米颗粒的物理特性（金属含量、表面涂层和尺寸）如何影响与中性粒细胞和血小板的相互作用。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-细胞相互作用。该项目将通过更智能的设计策略，最大限度地减少脱靶效应，为磁共振成像创造更安全、更有效的纳米颗粒造影剂。这项综合教育计划将针对西弗吉尼亚州农村、低收入家庭和第一代大学生家庭中得不到充分教育的学生，他们有可能无法继续接受教育。总的来说，该教育计划将激发西弗吉尼亚州从学龄前到高中生的所有年龄组对STEM的兴趣。通过结合动手研究、体验式学习、艺术与科学的创造性结合，以及在纳米技术、成像和生物材料方面的实际应用，这些拓展活动将激励下一代年轻的科学家和工程师。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，而忽略了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，包括释放被称为中性粒细胞胞外陷阱的网状DNA纤维。中性粒细胞胞外诱捕引起内皮损伤、血小板活化和中性粒细胞募集，促进血管阻塞。因此，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。Bennewitz博士的研究小组表明，纳米颗粒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不同释放来调节中性粒细胞的功能。该CAREER项目旨在确定用于磁共振成像的金属氧化物纳米颗粒的物理特性如何介导与中性粒细胞和血小板在互补系统中的相互作用，包括静态体外试验、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运输、细胞活化、中性粒细胞-血小板聚集形成、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验证：(1)研究金属氧化物纳米颗粒在中性粒细胞和血小板中的摄取和运输（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激活、聚集和中性粒细胞胞外陷阱在静态和动态流动条件下的释放。这个项目将是革命性的，因为Bennewitz博士将能够确定氧化锰纳米颗粒、氧化铁纳米颗粒和传统的钆螯合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，从而提高造影剂的体外和体内安全性。这个CAREER项目的教育目标是：(1)通过“向上发展计划”，邀请10名来自西弗吉尼亚州农村的低收入高中学生参加暑期实践研究。学生将接触到纳米粒子的合成和培养研究与中性粒细胞和血小板在静态和动态系统。(2)通过西弗吉尼亚科学公共推广团队，创建并向全州4000名中学生和高中生传播生物医学工程模块。两个实践活动将整合到演示中，以激发学生对荧光成像和聚合物刺激驱动传递的兴趣，这是本项目的两个关键研究概念。(3)在Spark为10岁及以下儿童设计并领导一场以黑灯下荧光绘画为主题的互动科学与艺术活动！想象与科学中心。该教育计划将培养西弗吉尼亚州学生和公众对STEM教育和职业的兴趣。本科生和研究生将通过他们在创建和传播外展活动中的不可或缺的角色获得宝贵的指导和教学经验，这将增强他们对STEM的信心、领导力和保留率。该项目由CBET内的纳米级相互作用项目和促进竞争性研究的既定项目（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并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，被认为值得支持。