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.

了解纳米颗粒特征如何介导其与体内血细胞的相互作用对于促进其安全性和有效性至关重要。传递到血液的纳米颗粒被红细胞，各种白细胞和血小板所包围。尽管血液的复杂性，但大多数开发用于成像应用的纳米颗粒的研究都集中在评估靶向纳米颗粒与称为巨噬细胞的白细胞亚型的纳米颗粒相互作用。巨噬细胞是人体针对异物的防御机制的一部分，众所周知可以隔离体内的纳米载体。尽管血小板和其他白细胞（例如中性粒细胞）丰富，但在纳米颗粒成像剂的设计中，这些血细胞通常被忽略。激活后，中性粒细胞和血小板可以粘在一起形成可以阻止血液流动的细胞聚集体，就像一团堵塞流水管一样。这个职业项目将产生有关金属氧化物纳米颗粒（其金属含量，表面涂料和大小）如何影响与中性粒细胞和血小板的相互作用的新知识。 Bennewitz博士将研究纳米颗粒设计如何介导细胞的摄取和运输，中性粒细胞和血小板的激活以及其在静态和动态系统中的下游细胞相互作用。该项目将通过更智能的设计策略来最大程度地减少脱离目标的效果，从而导致创建更安全，更有效的纳米颗粒对比剂，从而为磁共振成像进行磁共振成像。综合教育计划将针对西弗吉尼亚州的粗糙，低收入和第一代大学家庭的服务不足的学生，他们因不推进教育而处于危险中。总体而言，教育计划将引发对从学龄前到西弗吉尼亚州高中学生的所有年龄段的STEM的兴趣。通过结合动手研究，专家学习，艺术和科学的创造性整合，以及对纳米技术，成像和生物材料中现实世界应用的影响，这些宣传活动将激发年轻的科学家和工程师的下一代纳米颗粒对比对比的新型纳米粒子对比的测试依赖于与偏外型相互作用的相互作用，并依赖于偏见的含量和平原。活化的中性粒细胞和血小板可以形成嗜中性粒细胞 - 斑点骨料，从而触发下游损伤，包括释放名为中性粒细胞外陷阱的网络样DNA纤维。中性粒细胞外陷阱会促进内皮损伤，血小板激活和中性粒细胞募集，以促进血管阻塞。这是迫切需要阐明纳米颗粒对比剂如何与中性粒细胞和血小板相互作用以最大化安全性。 Bennewitz博士的小组表明，纳米颗粒对比剂涂层和金属含量通过中性粒细胞外陷阱，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在磁共振成像中使用的金属氧化物纳米颗粒的物理特征如何在完整系统中与中性粒细胞和血小板相互作用，包括静态体外测定，微流体芯片和原理小鼠模型。中心假设是纳米颗粒对比剂的物理特性调节中性粒细胞和血小板纳米颗粒的转运，细胞活化，中性粒细胞 - 骨骼骨料形成，中性粒细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测试：（1）研究金属氧化物纳米颗粒的摄取和中性粒细胞和血小板中的转运（2-3）评估金属氧化物氧化物纳米粒子介导的中性粒细胞和血小板激活，聚集，凝集中性粒细胞外粒细胞外胞外陷阱和动态流动条件下。该项目将具有变革性，因为Bennewitz博士将能够确定锰氧化物纳米颗粒，氧化铁纳米颗粒以及常规的cher樱桃樱桃对比剂如何影响嗜中性粒细胞骨膜串扰，中性粒细胞粒细胞外部陷阱，以及在体外和体内促进性对比度安全性。该职业项目的教育对象是：（1）通过向上界的计划将10个农村，低收入的西弗吉尼亚高中生进行夏季研究。学生将在静态和动态系统中与中性粒细胞和血小板进行纳米颗粒合成和孵育研究。 （2）通过西弗吉尼亚州科学公共外展团队向全州4,000名中学学生创建并传播一个生物医学工程模块。两项动手活动将集成到演讲中，以激发学生对荧光成像和聚合物刺激驱动传递的兴趣，这是该项目的两个关键研究概念。 （3）设计和领导一项互动科学遇到的艺术活动，专注于荧光绘画，在黑光下为10岁及以下儿童在火花的儿童下进行设计！想象力与科学中心。该教育计划将为服务不足的西弗吉尼亚州学生和公众提供对STEM教育和职业的兴趣。本科生和研究生将通过创建和传播宣传活动的组成部分来获得宝贵的心理和教学经验，从而增强他们对STEM的信心，领导和保留。该项目由CBET内的纳米级互动计划和启发竞争研究的既定计划共同资助。该奖项反映了NSF的法定任务，并通过使用该基金会的智力优点和更广泛的影响来评估NSF的法定任务。