# Pulsed Focused Ultrasound (pFUS) exposures and devices for tissue permeabilization without contrast agents

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $547,894

## Abstract

ABSTRACT
Cavitation induced by ultrasound combined with systemically administered ultrasound contrast agents (UCAs)
has been extensively studied over the past decade, and successfully applied to the delivery of a number of
different drugs to solid tumours. A limitation of this approach is that the UCAs are confined to blood vessels and
the perivascular space, which limits their access to poorly vascularized regions of a tumor. Increased interstitial
pressure, high tumor cell density, and stromal barriers further inhibit drug delivery. Inducing de novo cavitation
throughout tumor tissue using pulsed focused ultrasound (pFUS) would thus be very beneficial for overcoming
these barriers to drug penetration. However, according to current consensus in the field, the focal pressure levels
required to nucleate and sustain inertial cavitation are substantially higher than for UCA-enhanced ultrasound
and can only be achieved with high-power, highly focused transducers with a large footprints. This limits the
practicality of this approach. Our preliminary data indicate that the inertial cavitation activity that results in tissue
permeabilization can be achieved at lower peak negative pressures if a shock front develops in the focal
waveform, due to nonlinear propagation effects. Further, we have demonstrated that the relationship between
the shock amplitude and peak negative pressure is primarily determined by the F-number of a FUS transducer,
with less focused transducers producing shocks at the lowest peak negative pressure values. We also showed
that shocked waveforms can be achieved using diagnostic ultrasound probes at relatively low mechanical index
(MI ~ 4-6) at relevant depth in attenuative tissue. The overall goal of this proposal is to develop feedback
controlled pFUS treatment protocols for drug delivery to solid tumours that can be implemented using small
footprint, (potentially diagnostic) ultrasound probes. Such permeabilization procedures could be performed just
prior to the administration of chemotherapy on any tumor that can be imaged with ultrasound. To achieve our
goal, we propose to determine the dependence of the focal waveform metrics and associated cavitation activity
on the shape and frequency of the transducer through numerical modelling and a series of experiments in
transparent tissue-mimicking gel phantoms and ex vivo tissues (Specific Aims 1 and 2 correspondingly). Direct
observation of bubble dynamics using high-speed photography in transparent gels will be correlated with active
and passive cavitation detection observations for use in subsequent experiments in tissue. The optimized pFUS
treatment protocols will then be applied to healthy porcine tissues (liver, kidney and pancreas), and to
subcutaneous Dunning rat prostatic adenocarcinoma, and will be followed by systemic administration of
fluorescent labelled dextrans of different molecular weights (Specific Aim 3). The permeabilization effect will be
evaluated acutely from t...

## Key facts

- **NIH application ID:** 9962154
- **Project number:** 5R01EB023910-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Tatiana Khokhlova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $547,894
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-09-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962154

## Citation

> US National Institutes of Health, RePORTER application 9962154, Pulsed Focused Ultrasound (pFUS) exposures and devices for tissue permeabilization without contrast agents (5R01EB023910-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962154. Licensed CC0.

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