Document text
Principal Investigator: JAMES K TSURUTA
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2019
Award: $76,258
Funding agency: National Institute of Biomedical Imaging and Bioengineering
ABSTRACT
Lipid shelled perfluorocarbon (PFC) microbubbles ranging from 0.5 to 8 microns in diameter have been
approved by the FDA to enhance the contrast of blood for diagnostic ultrasound imaging. The micro scale of
ultrasound contrast agents limits them to the bloodstream, eliminating the enhanced permeability and retention
(EPR) observed in many tumors. The ability to create nanoparticles from existing lipid-shelled microbubble
contrast agents lets us leverage the non-toxic formulations of these agents, and lets us create novel targeted
nanoparticles using any of the established strategies for formulating targeted microbubbles. Microbubbles
targeted to Secreted Frizzled Related Protein 2 (SFRP2) showed significant discrimination between tumor and
normal vasculature, and SFRP2 is highly expressed in a variety of breast cancers. We and our colleagues
found that cold and increased pressure caused conventional gas-phase ultrasound contrast to condense into
lipid-shelled nanodroplets of liquid PFC. With sufficient energy, these non-echogenic agents revert back to
conventional ultrasound contrast agents. Nanodroplets share the advantages inherent to nanoparticle
strategies for cancer therapy: passive accumulation in tumors enhanced by the EPR effect, targeted
accumulation within tumors aided by targeting moieties, and reduced systemic dosing. Activating nanodroplets
with ultrasound provides a high degree of spatial selectivity, preventing re-entry of the micro scale bubbles into
the vasculature, thus maintaining a high local concentration of contrast agent. Molecular imaging that
interrogates the interstitial space within tumors widens the physical scope of imaging with the payoff of a higher
density of bound contrast throughout the tumor volume, and additional opportunities to target tumor molecules
that are not found in the vascular endothelium. We propose that extravascular molecular imaging with SFRP2-
targeted nanodroplets will increase the sensitivity of detecting breast cancer compared to microbubble
molecular imaging while maintaining the molecular specificity needed to decrease false diagnoses. A critical
barrier to leveraging molecularly targeted, lipid shelled perfluorocarbon nanodroplets is a fundamental lack of
knowledge about their biodistribution in normal and tumor tissue. We propose to combine existing, established
techniques to create SFRP2-targeted, and non-targeted nanodroplet formulations carrying a biotin and DNA
label, determine their circulating half-lives, and use immunohistochemical detection of biotin or quantitative
polymerase chain reaction assays of our unique DNA payload to characterize the biodistribution of these liquid
perfluorocarbon droplets in normal and tumor tissues. Establishing the ability of targeted nanodroplets to cross
the endothelial cell layer leverages existing microbubble contrast agents, promotes development of novel nano
agents, and increases the impact of ultrasound for detecting breast cancer by developing a novel, highly
sensitive ultrasound method that leverages the discriminatory power of targeted molecular imaging in the
vascular and extravascular space of breast lesions.
Terms: <Acoustic><Acoustics><Assay><Back><Benign><Bioassay><Biodistribution><Biologic Assays><Biological Assay><Biotin><Blood><Blood Circulation><Blood Reticuloendothelial System><Blood Vessels><Bloodstream><Body Temperature><Body Tissues><Breast Cancer><Caliber><Cancer Treatment><Carrying Capacities><Cell Communication and Signaling><Cell Signaling><Circulation><Cognitive Discrimination><Contrast Agent><Contrast Drugs><Contrast Media><Custom><DNA><DNA Binding><DNA Binding Interaction><DNA Hybridization Probes><DNA Probes><DNA bound><Deoxyribonucleic Acid><Detection><Development><Diagnosis><Diagnostic><Diagnostic Sensitivity><Diameter><Discrimination><Dorsum><Dose><Echography><Echotomography><Encapsulated><Endothelial Cells><Extravasation><FDA approved><Fluorocarbons><Formulation><Future><Gases><Half-Life><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Intracellular Communication and Signaling><Kidney><Kidney Urinary System><Knowledge><Label><Leakage><Lipids><Liquid substance><Malignant><Malignant - descriptor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Measures><Medical Ultrasound><Methods><Microbubbles><Molecular><Molecular Target><Normal Tissue><Normal tissue morphology><Organ><Perfluorocarbons><Permeability><Phase><Physiologic pulse><Polymerase Chain Reaction><Proteins><Public Health><Pulse><Radiopaque Media><Reagent><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Spillage><Staining method><Stains><Techniques><Temperature><Testing><Time><Tissues><Tumor Tissue><Tumor Volume><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><Vascular Endothelium><Vitamin H><anti-cancer therapy><anticancer therapy><biological signal transduction><breast cancer diagnosis><breast lesion><cancer biomarkers><cancer diagnosis><cancer markers><cancer therapy><coenzyme R><contrast enhanced><density><developmental><diagnostic ultrasound><fluid><imaging><imaging agent><in vivo><interstitial><liquid><malignant breast neoplasm><malignant breast tumor><molecular imaging><molecule imaging><nano><nano droplet><nano meter scale><nano meter sized><nano particle><nano scale><nano-sized particle><nanoDroplet><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><novel><phase change><pressure><prevent><preventing><renal><sonogram><sonography><sound measurement><targeted agent><tumor><ultrasound><ultrasound imaging><ultrasound scanning><vascular>