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Principal Investigator: Mark Andrew Borden
Organization: UNIVERSITY OF COLORADO
Fiscal Year: 2020
Award: $352,275
Funding agency: National Cancer Institute
The development of new pharmaceuticals for the treatment of brain cancer and neurological disease has
outpaced our ability to deliver them safely, largely due to the blood-brain barrier (BBB). Bypassing the BBB to
access the brain parenchyma is often highly invasive, involving surgery to remove part of the skull and needle
insertion directly into the brain tissue, resulting in lasting damage and significant costs. An alternative,
microbubble-assisted focused ultrasound (MB+FUS), is a promising noninvasive, image-guided method of BBB
disruption (BBBD) currently undergoing three human clinical trials. MB+FUS induces transient openings in the
BBB via acoustically mediated pulsation of 1-10 µm diameter intravenously delivered gas-filled microbubbles,
allowing for targeted drug delivery to brain regions as small as 2-3 mm diameter. The safe dosage of these
microbubbles has become central to the polarizing debate that is ongoing in the MB+FUS community, and is
critical to clinical translation. With recent findings indicating acute sterile immune response (SIR) after MB+FUS
BBBD, elucidating the relationship between microbubble dose, pharmacokinetics (PK), ultrasound mechanical
index, and MB+FUS-associated tissue effects has become essential. Efforts to do so, however, have been
confounded by the product-to-product and batch-to-batch variations in the size, concentration and composition
of commercially available microbubble ultrasound contrast agent formulations.
Using size-isolated microbubbles (SIMBs) of different monodisperse sizes and uniform composition, our
team of researchers at the University of Colorado and NIDA recently discovered that microbubble dosing can be
simplified by unifying size and concentration into a single parameter: microbubble volume dose (MVD), which
trends linearly with key figures-of-merit for microbubble PK and BBBD magnitude. In this project, we will
investigate this effect further in order to create a clear framework for comparing results prospectively and
retrospectively between studies performed by different laboratories and different microbubble agents. In Aim 1,
we will test the hypothesis that figures-of-merit for PK scale linearly with MVD for FDA-approved ultrasound
contrast agents currently used in human clinical trials and most preclinical research, as well as our own SIMBs.
We will extend this research to establish a therapeutic window between the minimum MVDs to produce BBBD
and acute SIR. In Aim 2, we will test the hypothesis that the minimum MVD required for successful BBBD
decreases with increasing mechanical index (MI), which is a unifying ultrasound parameter incorporating
frequency and amplitude. The robustness of this relationship will be explored by examining effects of
microbubble size (using SIMB), ultrasound frequency and molecular weight of the model drug. Finally, in Aim 3,
we will establish a therapeutic window between BBBD (efficacy) and acute SIR (safety) on a diagram of MVD
vs. MI, which will help researchers and clinicians in the field to choose appropriate ultrasound and microbubble
dose settings for safe BBBD by MB+FUS, and to guide their procedures.
Terms: <(TNF)-α><70-kD Heat-Shock Protein><Acoustic><Acoustics><Acute><Adhesion Molecule><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Area Under Curve><Astrocytes><Astrocytus><Astroglia><BBB disruption><Blood - brain barrier anatomy><Blood-Brain Barrier><Body Tissues><Brain><Brain Cancer><Brain Nervous System><Brain region><Bypass><Cachectin><Caliber><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cells><Clinical Trials><Colorado><Comment><Commentary><Communities><Contrast Agent><Contrast Drugs><Contrast Media><Craniotomy><Definity><Development><Diameter><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Modelings><Drug Targeting><Drugs><Echography><Echotomography><Editorial Comment><Encephalon><FDA approved><Focused Ultrasound><Formulation><Frequencies><Gases><Gene Delivery><HSP 70><HSP70><Heat-Shock Proteins 70><Hemato-Encephalic Barrier><Hortega cell><Human><IFN-gamma-Inducing Factor><IGIF><IL-1><IL-1 Gamma><IL-18><IL-1g><IL1><IL18 Protein><IL1F4><Immune><Immune response><Immunes><Immunological response><In Situ Nick-End Labeling><Infiltration><Inflammatory><Innate Immune Response><Interferon-gamma-Inducing Factor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 Proprotein><Interleukin I><Interleukin-1><Interleukin-1 Gamma><Interleukin-18><Interleukin-18 Precursor><Intravenous><Investigators><Laboratories><Lymphocyte-Stimulating Hormone><MGC12320><Macrophage Cell Factor><Macrophage-Derived TNF><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mechanics><Mediating><Medical Ultrasound><Medication><Methods><Microbubbles><Microbubbles Ultrasound Contrast Agents><Microbubbles Ultrasound Contrast Medium><Microglia><Modern Man><Molecular><Molecular Weight><Monocyte-Derived TNF><NIDA><National Institute of Drug Abuse><National Institute on Drug Abuse><Needles><Nerve Cells><Nerve Unit><Nervous System Diseases><Neural Cell><Neurocyte><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Neurons><Occluding Junctions><Operative Procedures><Operative Surgical Procedures><Optison><Pathway interactions><Pattern><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Physiologic><Physiologic pulse><Physiological><Procedures><Process><Published Comment><Pulse><Radiopaque Media><Receptor Protein><Reporting><Research><Research Personnel><Researchers><Safety><Scheme><Skull><Sonication><Sterility><Surgical><Surgical Interventions><Surgical Procedure><T Helper Factor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TUNEL><Technology><Testing><Therapeutic><Therapeutic Agents><Tight Junctions><Time><Tissues><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><Universities><Variant><Variation><Viewpoint><Zonula Occludens><antiinflammatory><astrocytic glia><blood-brain barrier disruption><bloodbrain barrier><bloodbrain barrier disruption><brain parenchyma><brain tissue><cell adhesion protein><clinical translation><cost><cranium><developmental><diagnostic ultrasound><dosage><drug/agent><gitter cell><global gene expression><global transcription profile><host response><hsp70 Family><image guidance><image guided><image-based method><image-guided drug delivery><imaging method><imaging modality><immunoresponse><indexing><lipid nanoparticle><lymphocyte activating factor><macrophage><mechanical><mesoglia><microglial cell><microgliocyte><nervous system disorder><neurogenesis><neurological disease><neuronal><non-invasive imaging><noninvasive imaging><pathway><perivascular glial cell><pre-clinical research><pre-clinical study><preclinical research><preclinical study><prospective><receptor><regenerative><response><side effect><skull incision><sonogram><sonography><sound measurement><sterile><surgery><terminal nick end labeling><transcriptome><trend><ultrasound><ultrasound imaging><ultrasound scanning>