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Principal Investigator: Nicholas Oliver Fischer
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2023
Award: $272,874
Funding agency: National Institute of Biomedical Imaging and Bioengineering
19F MRI, has shown promising success in clinical trials for monitoring cell therapy, where small groups of
cells, showing poor contrast in 1H-MRI (Magnetic Resonance Imaging), are easily tracked using 19F-MRI.1
Contrast is provided by nanoemulsions of perfluorocarbon (PFC) oils pre-loaded into cells. A major advantage
of 19F-MRI is that lack of natural fluorine in the body allows for very high contrast-to-noise for 19F-MRI
compared to 1H-MRI.2 Use of 19F-MRI in molecular imaging, by targeting specific biomarkers, is of great
interest, but the development of probes for these applications has been an elusive goal. Typical synthetic
methods produce relatively large particles, > 150 nm, which induce nonspecific uptake by phagocytic cells.
While avid nonspecific uptake is advantageous for labeling T cells and other immune cells ex vivo, it is a
decided limitation for imaging of biomarkers as it can create high background signal in the inflamed tissues
characteristic in many diseases. 19F MRI should be an excellent platform for biomarker detection but there is a
critical unmet need for suitable 19F MRI contrast agents that avoid nonspecific immune cell surveillance.
Ideally, contrast agents need to be<100 nm to avoid nonspecific uptake. We propose exploratory studies to
develop innovative new 19F MRI contrast agents based on nanodiscs. Nanodiscs are < 50 nm in size, avoid
liver clearance, and escape immune surveillance. We hypothesize that nanodiscs, which are structurally similar
to high density lipoproteins that carry cholesterol in a hydrophobic core, may be ideal for carrying hydrophobic
perfluorocarbons. Our aims are to explore synthetic parameters in benchtop (Aim 1) and microfluidic (Aim 2)
approaches to optimize loading of perfluorocarbons into nanodiscs. In each aim we will systematically
investigate variables that influence nanodisc size and perfluorocarbon loading. New nanodiscs will be
characterized for physical properties such composition and dimensions, and the top 3 products from each Aim
will be evaluated for lack of toxicity and biodistribution in a mouse model. The leading nanodiscs will be
modified for targeting CD204, a biomarker for tumor associated macrophages, and tested in a mouse breast
cancer model. We are team composed of contrast agent (UCD) and nanodisc (LLNL) experts who are ideally
positioned and well-equipped to carry out the proposed aims. The success of this project would add novel
nanodiscs materials with the potential not only for targeted 19F MR molecular imaging, but for applications in
photoacoustic, and radiotherapy, and tracking drug delivery.
Terms: <Affect><Animals><Apolipoproteins><Area><Biodistribution><Biological><Biological Markers><Biopsy><Body Tissues><Breast Cancer Model><Breast tumor model><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell Therapy><Cells><Characteristics><Charge><Cholesterol><Circulation><Clinical><Complex><Contrast Agent><Contrast Drugs><Contrast Media><Detection><Development><Diameter><Dimensions><Disease><Disease Marker><Disorder><Drug Delivery><Drug Delivery Systems><Environment><F element><Fluorine><Fluorocarbons><Formulation><Foundations><Gadolinium><Gd element><Goals><H+ element><HDL><HDL Lipoproteins><Heavy Lipoproteins><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><High Density Lipoproteins><High density lipoprotein><Histology><Hydrogen Ions><Hydrogen Oxide><Hydrophobicity><Image><Immune><Immune Surveillance><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Intracellular Communication and Signaling><Investigation><Label><Lipid Bilayers><Lipids><Liquid substance><Liver><Liver Cells><Longitudinal Studies><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Membrane><Methods><Mice><Mice Mammals><Microfluidics><Modality><Modeling><Monitoring Clinical Trials><Murine><Mus><Mφ><NMR Imaging><NMR Tomography><Noise><Nuclear Magnetic Resonance Imaging><Oils><Perfluorocarbons><Phagocytes><Phagocytic Cell><Phagocytosis><Position><Positioning Attribute><Precision therapeutics><Production><Protons><Radiation therapy><Radioactive Isotopes><Radioisotopes><Radionuclides><Radiopaque Media><Radiotherapeutics><Radiotherapy><Reagent><Reticuloendothelial System><Risk><Sampling><Scaffolding Protein><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Structure><Surface><System><T-Cells><T-Lymphocyte><TM-MKR><Techniques><Technology><Testing><Therapeutic><Thick><Thickness><Tissues><Toxic effect><Toxicities><Toxicity Testing><Toxicity Tests><Tumor Markers><Tumor-associated macrophages><Vaccines><Validation><Water><Work><Zeugmatography><alpha-Lipoproteins><amebocyte><aqueous><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><cell culture><cell cultures><cell imaging><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular imaging><cellular therapeutic><cellular therapy><chelation><clinical imaging><commercial scale manufacturing><detection sensitivity><developmental><disease diagnosis><fluid><fluorophore><hepatic body system><hepatic organ system><imaging><imaging agent><imaging biomarker><imaging marker><imaging probe><imaging study><imaging-based biological marker><imaging-based biomarker><imaging-based marker><improved><innovate><innovation><innovative><interest><lipid bilayer membrane><liquid><long-term study><longitudinal outcome studies><longterm study><mammary cancer model><mammary tumor model><manufacturing ramp-up><manufacturing scale-up><membrane structure><mimetics><molecular imaging><molecule imaging><mouse model><murine model><nano emulsion><nano materials><nano particle><nano systems><nano-sized particle><nanodisc technology><nanodisk><nanoemulsion><nanomaterials><nanoparticle><nanosized particle><nanosystems><new technology><novel><novel technologies><nuclear imaging><particle><physical property><pilot test><precision therapies><precision treatment><radiation treatment><scale up><scale up batch><scale up production><specific biomarkers><stoichiometry><success><surfactant><targeted biomarker><thymus derived lymphocyte><treatment with radiation><tumor biomarker><tumor specific biomarker><ultrasound><upscale manufacturing><uptake><validations><µfluidic>