Page 14 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

and generate fluid flows around the MBs, known as acoustic enhancing the i.c. bioavailability of therapeutics. For
microstreaming. Both of these biophysical processes exert instance, Chen et al. demonstrated transient BBB
57
shear stress on biological barriers, enhancing their natural permeabilization using ND-assisted US in the rat model,
permeability to therapeutics. 35 showing more homogeneous dextran delivery to the
At much higher acoustic pressures, MBs exhibit a targeted hippocampus without inducing inertial cavitation
nonlinear acoustic behavior, characterized by larger or compromising safety. In addition, the ADV process
expansion amplitude relative to compression. This may occur within the cerebral parenchyma due to ND
more violent oscillation often leads to the collapse and extravasation. In this case, therapeutics are released in close
destruction of MBs, a phenomenon termed inertial proximity to targeted cerebral cells. The stable cavitation of
cavitation. This disruption of MBs during inertial MBs can then further permeabilize these cells, facilitating
cavitation generates shock waves in the surrounding the intracellular uptake of therapeutics.
medium, producing greater shear stress on biological One significant limitation of NDs is that they cannot
barriers and thereby increasing their permeability. 30,48,49 be imaged before ADV, unlike MBs. To address this,
In addition, the asymmetrical collapse of MBs can create multimodal imaging NDs have been developed by
high-velocity jets (i.e., microjets) that transiently damage incorporating imaging tracers for various modalities,
biological barriers, further enhancing the permeability such as gadolinium for MRI, 58,18 -F for positron emission
of tracers (e.g. MR contrast agent, fluorescent dyes) tomography, or DiR fluorescent dye for fluorescence
59
and/or therapeutic molecules (e.g. monoclonal antibodies, imaging. 60
recombinant proteins, nucleic acids). These biophysical
processes promote the permeabilization of the BBB by 4. US devices
stimulating paracellular pathways (i.e., disruption of TJs) Several pre-clinical and clinical investigations have
and/or transcellular pathways (i.e., transcytosis), thereby
facilitating the extravasation of therapeutics. They demonstrated significant progress in the development,
47
also improve the intracellular uptake of therapeutics by optimization, and validation of acoustic sequences to
forming membrane pores and or stimulating endocytosis achieve efficient and safe i.c. delivery of therapeutics. Among
/
50
pathways. 51,52 At present, scientific and medical consensus these studies, two main categories of US devices have been
favors the use of stable cavitation of MBs over inertial highlighted: lab-made US devices and clinically approved
cavitation due to the potential tissue damage associated US devices specifically designed for therapeutic delivery.
with the latter. 4.1. Lab-made US devices
3.2.2. NDs The lab-made US devices typically consist of three main

As previously mentioned, the core of NDs remains in a components: a generator, an amplifier, and a commercial or
liquid state at body temperature but vaporizes into MBs custom-built single-element US transducer. The US waves
through the process of ADV. Vaporization occurs when are generated by the US transducer which operates at a
the vapor pressure of volatile liquids in the liquid state fixed center frequency (ranging from 0.250 to 1 MHz). The
(e.g., PFCs) exceeds the surrounding gas phase pressure. 44,45 transducer is driven by an electrical signal produced by an
This phenomenon is presented in Shpak et al. US reduces arbitrary waveform generator and subsequently amplified
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the pressure around the NDs below the vapor pressure of using a power amplifier. To ensure effective coupling with
the volatile liquid in their core, triggering vaporization and the animal’s head and precise targeting of the focal point
the subsequent formation of MBs. 45,53,54 In recent years, within the brain region of interest, the transducer can either
PFCs have become the primary volatile candidates for ND be placed in direct contact with the animal’s head using
cores due to their low solubility in aqueous formulations, US gel, or inserted into a dedicated degassed water-filled
low toxicity, and suitability as low-boiling-point liquids. 55 adaptor, allowing for proper alignment and positioning of
the focal point within the targeted brain area (Figure 8). 61
The ADV process depends on various factors, including
ND properties (e.g., the type of volatile liquid and ND Spherically focused US (FUS) transducers are
size), acoustic parameters (e.g., pressure and frequency), commonly used to significantly increase US intensity
and ambient parameters (e.g., pressure and temperature). within a small, targeted brain area. These transducers are
53
Following i.v. administration, the ADV process can occur typically calibrated in a separate setup using a calibrated
in the vascular compartment, enabling the release of hydrophone. Lab-made US devices provide flexibility to
62
therapeutics from NDs when used as drug nanocarriers. control various US parameters (i.e., center frequency, pulse
56
Subsequently, the stable or inertial cavitation of newly repetition frequency, duty cycle, acoustic pressure, and total
formed MBs can transiently permeabilize the BBB, exposure time), allowing these parameters to be optimized

Volume 11 Issue 2 (2025) 8 doi: 10.36922/jctr.24.00061