Perspectives on cavitation enhanced endothelial layer permeability

Abstract

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques.

Magnetic Resonance Methods for Focused Ultrasound-Induced Blood-Brain Barrier Opening

“…(ALS) as well as Parkinson's Disease Dementia 9 . In addition to INSIGHTEC, recently, CarThera (France) has developed a FUS system for permeabilizing the BBB in humans.…”

“…During this phenomenon (called cavitation), microbubbles expand toward the capillaries and small vessels wall, loosening the tight junctions of endothelial cells and creating gaps between these cells. Particles of interest exploit these gaps to can cross from the bloodstream to the brain [8,9] (Figure 1B). LIFUS-mediated BBB disruption has been widely demonstrated in animal models [7,[10][11][12][13][14], and it has been tested in clinical settings for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's Disease [15][16][17].…”

Ultrasound-Responsive Materials for Drug/Gene Delivery

“…While the non-thermal effects are mainly generated from ultrasound pressure, acoustic streaming, shockwaves, liquid microjet, and ultrasound-induced oscillation or cavitation (Marin et al, 2002;Husseini et al, 2008a;Mannaris et al, 2020). In particular, in the presence of cavitation nuclei, a type of particles which can lower acoustic intensity to induce cavitation, ultrasound shows higher delivery efficiency (Miller et al, 1999;Ward et al, 1999;Peruzzi et al, 2018;Mannaris et al, 2020).…”

Optimization of microbubble enhancement of hyperthermia for cancer therapy in an in vivo breast tumour model

“…In recent years, ultrasound-stimulated microbubbles (USMB) mediated drug and gene delivery is receiving considerable attention. Cavitation of microbubbles caused by ultrasound pulses leads to transient pore formation at the plasma membranes of cells facilitating the extravasation of drugs and genes [16,17]. This technique has also been applied for permeabilizing biological barriers such as the brain tumour microvessels/capillaries and or the blood-brain barrier (BBB).…”