Phospholipids-based microbubbles sonoporation pore size and reseal of cell membrane culturedin vitro

Enhancement of Non-Invasive Trans-Membrane Drug Delivery Using Ultrasound and Microbubbles During Physiologically Relevant Flow

“…Enhanced drug delivery of large molecules (>150 kDa) was previously shown to be a result of ultrasound-induced endocytosis (Meijering et al, 2009), which may be the 20 cause of the delayed detection of PI fluorescence (2 hours post-sonication). PI could be delivered through endocytosis, but its small molecular weight (668.4 Da) may allow it to be transported through other routes which larger compounds cannot utilize (e.g., through mechanically-induced pores) (Zhao et al 2008). Our results were consistent with previous studies that verified enhanced cell membrane permeability of endothelial cells due to ultrasound exposure and microbubbles (van Wamel et al, 2006).…”

“…First, it has been shown that the interaction between the microbubble oscillation and the cell membrane can produce short-lived pores that allow drug uptake. These pores are up to 1 μm in size and have been shown to reseal within seconds (Hu et al, 2013;Newman 5 and Bettinger, 2007;Qiu et al, 2010;Zhou et al, 2009), minutes (Schlicher et al, 2006) or even hours (Zhao et al, 2008). Inertial cavitation produces higher rates of intracellular delivery than stable cavitation (Fan et al, 2013;Karshafian et al, 2009;Park et al, 2011;Qiu et al, 2010), however the cellular membrane is more likely to be disrupted and that influences cell viability (Newman and Bettinger, 2007).…”

Potential and problems in ultrasound-responsive drug delivery systems

“…31 If cells are located in close proximity to gas-filled microbubbles which serve as cavitation nuclei, permeability of the cell membrane will be increased. 6,44 In the last decade, microbubble agents have been investigated as carriers for systemic drug administration. Plasmid DNA and other therapeutic materials may adhere to the microbubbles or be packed into the microbubbles, which is beneficial for targeted drug delivery.…”

“…When drugs are loaded into ultrasound contrast agents, acoustic cavitation can be used as a trigger to release drugs at desired sites. [4][5][6][7] In recent times, drug-loaded ultrasound contrast agent systems, also termed ultrasound-responsive drug delivery systems (URDDS), have become an increasing focus of research. URDDS include microbubbles, [8][9][10] nanobubbles, 11,12 nanodroplets, 13 liposomes, 14,15 emulsion, 16 and micelles.…”

Ultra-high-speed fluorescence imaging

“…Aside from TMC measurements, other techniques are used to judge the pore size after bubble-induced sonoporation or sonolysis, such as scanning electron microscopy (SEM) [92,96,97] and atomic force microscopy (AFM) [83,85,98] of which only Prentice et al [83] were able to link the induced pore to an observed microbubble cavitation event. The estimated pore sizes were typically in the order of 50 to 500 nm, in some cases confirmed by confocal microscopy of the uptake of large dextran-coupled fluorophores [92,97], up to 16 µm [83] and were obtained several seconds to minutes after the sonoporation event itself.…”