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

West Virginia University Research Corporation, Morgantown WV

Investigators

Abstract

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.