Page 13 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

3.2. Mechanisms of acoustically mediated drug microenvironment, etc.); (2) The US setup, including the
delivery type of probe (e.g., mono-element US transducer versus
The effectiveness of i.c. delivery of therapeutics dependents transducer array, focused versus unfocused transducer,
heavily on: (1) The presence of sufficient amounts of etc.), the device used (i.e., laboratory-made device, US
sonoresponsive agents (i.e., MBs and NDs) and therapeutics imaging scanner, clinically approved therapeutic US
near the biological targets (i.e., BBB and cerebral cells). device), and the parameters applied (e.g., frequency,
This is influenced by their physiochemical properties acoustic pressure, pulse duration, etc.), which must
(e.g., size, composition, etc.) and pharmacological be optimized to ensure safe and efficient activation of
characteristics (i.e., pharmacokinetics, pharmacodynamics, the sonoresponsive agents near the biological targets;
bioavailability), as well as their mode of administration (i.e., (3) The treatment protocol including the time interval
i.v. bolus vs. perfusion, co-administration versus sequential between the administration of sonoresponsive agents and
administration) and the physiological state of biological therapeutics on one hand and the subsequent US exposure
targets (e.g., healthy versus pathological cells/tissues, on the other, the number of treatments, and the intervals
between sessions. 47

3.2.1. Microbubbles
As described above, the properties of US and MBs, along
with in vivo environmental conditions (e.g., hydrostatic
pressure and dissolved gas saturation) influence the
response of MBs to US waves. The high compressibility and
the low density of the gas core of MBs create a significant
impedance mismatch with the surrounding medium,
making MBs highly responsive to US waves. During the
rarefaction and compression phases of the wave, MBs
alternately expand and contract, a phenomenon referred to
as MB oscillation. At low acoustic pressures, MBs oscillate
40
in a symmetrical and linear manner, a process known as
Figure 6. Schematic representation of the acoustic droplet vaporization stable cavitation. 25,30,48 When in close proximity to biological
process. Vaporization of perfluorocarbon droplets following exposure
to ultrasonic pulses leads to the formation of gas bubbles. Created with barriers (e.g., cell membrane and BBB), these oscillations
BioRender.com. can induce “cell massage” (i.e., a pushing and pulling effect)

A B

Figure 7. Acoustic activation of NDs. (A) Transient permeabilization of the BBB promoted by ADV under specific US conditions. (B) Upon extravasation
of NDs through the EPR effect, ADV facilitates the release of therapeutics loaded into NDs and reversible permeabilization of cerebral cells. Adapted from
“Blood–brain barrier (simple longitudinal)”. Retrieved from https://app.biorender.com/biorender-templates.
Abbreviations: ADV: Acoustic droplet vaporization; BBB: Blood–brain barrier; EPR: Enhanced penetration and retention; NDs: Nanodroplets;
US: Ultrasound.

Volume 11 Issue 2 (2025) 7 doi: 10.36922/jctr.24.00061