# Microbubble Dose Optimization for Image-Guided Drug Delivery

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $352,275

## Abstract

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 ...

## Key facts

- **NIH application ID:** 9973211
- **Project number:** 5R01CA239465-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Mark Andrew Borden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,275
- **Award type:** 5
- **Project period:** 2019-07-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973211

## Citation

> US National Institutes of Health, RePORTER application 9973211, Microbubble Dose Optimization for Image-Guided Drug Delivery (5R01CA239465-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973211. Licensed CC0.

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