Sonopermeation to improve drug delivery to tumors: from fundamental understanding to clinical translation

Abstract

IntroductionUltrasound in combination with microbubbles can make cells and tissues more accessible for drugs and thereby achieve improved therapeutic activity. In this review we establish the term "sonopermeation", covering mechanisms such as pore formation (sonoporation), opening of tight junctions, stimulated endocytosis/transcytosis, altered perfusion and changes in stromal compartment. Sonopermeation has gained a lot of interest in the last decade, especially for delivering drugs through the otherwise impermeable blood-brain barrier, but also to tumors. Areas coveredIn this review we summarize various in vitro assays and in vivo setups that have been employed to unravel the fundamental mechanisms involved in ultrasound-enhanced drug delivery, as well as clinical trials that are ongoing in patients with brain, pancreatic, liver and breast cancer. We summarize the basic principles of sonopermeation, describe recent findings obtained in (pre-) clinical trials, and discuss future directions. Expert OpinionWe suggest that an improved mechanistic understanding, and microbubbles and ultrasound equipment specialized for drug delivery (and not imaging) are key aspects to create more effective treatment regimens by sonopermeation. Real time feedback and tools to stratify which tumors will benefit from sonopermeation will be important for clinical success.

The Role of Ultrasound-Driven Microbubble Dynamics in Drug Delivery: From Microbubble Fundamentals to Clinical Translation

“…Yet, the exact mechanism behind this approach, as well as the safety in clinical translation has not yet been fully clarified. Likely, a variety of other factors will be involved in the complex in vivo situation, which is why it was very recently suggested to refer to ultrasound and microbubble-mediated enhanced drug delivery in general, as 'sonopermeation' 186 .…”

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

“…BBB can be disrupted with focused ultrasound (FUS) (Figure 8), but for more location specific drug delivery is combined with intravenously injected microbubbles (MBs), by widening interendothelial clefts and tight-junctions [187]. This method, also called as sonoporation, relies on the mechanical action of the gas MBs in ultrasonic pressure waves [188]. These MBs are about 1 to 10 um in diameter with a lipid or protein shell, containing heavy gasses, which can be excreted by exhalation and make MBs more stable [188].…”

“…This method, also called as sonoporation, relies on the mechanical action of the gas MBs in ultrasonic pressure waves [188]. These MBs are about 1 to 10 um in diameter with a lipid or protein shell, containing heavy gasses, which can be excreted by exhalation and make MBs more stable [188]. These particles also can be used as a drug delivery system by itself, for example, molecules can be attached to the shell [189][190][191] and they have also been used to deliver stem cells [192] and viral vectors [158,160,193].…”

“…Adenosine receptor (AR) substrates can modulate BBB permeability [208]. They can be used for Sonopermeation was defined by Snipstad and coworkers as the collective name for pore formation and other additional changes in the BBB permeability due to the microbubbles and ultrasound, such as the opening of tight junctions, stimulated endo-and transcytosis, enhanced perfusion, and stromal alterations [188]. This method has many advantages: 1) It can be focused just on the area of the tumor or diseased parts of the brain; 2) the poration does not require high energy ultrasound, therefore, does not cause damage in intermediery tissues; 3) however, the ultrasound can cause some overheating, just enough to increase blood flow [187,195], vascular permeability [196,197] that also modifies the effectiveness of drug delivery [198][199][200][201] in the target area, and 4) membrane integrity regenerates fast (within hours) after the intervention [202].…”

Cell barrier characterization in transwell inserts by electrical impedance spectroscopy

“…The effect of sonoporation was monitored by EIS. During sonoporation, ultrasound is used to oscillate or destroy gas-filled microbubbles, which temporarily increase cell membrane permeability, and thus is a promising tool to transport substances across barriers (Snipstad et al, 2018). The penetration of cell barriers can be investigated via the impedance-derived data TEER and capacitance (Kooiman et al, 2009;Lelu et al, 2016;Stewart et al, 2018).…”