Tuning microbubble-mediated endothelial drug delivery outcome with monodisperse microbubbles of different sizes

Abstract

Microbubble-mediated drug delivery using polydisperse microbubbles has shown differences in drug delivery outcome due to the microbubble’s differences in size and, thus, acoustic response. The aim of this study was to investigate whether monodisperse microbubbles can achieve controllable sonoporation and tunnel formation. Using the Horizon microfluidics platform, monodisperse phospholipid-coated microbubbles were produced with radii of 1.25–3.5 μm. Single microbubble-endothelial cell interactions (n = 82) upon insonification at 2 MHz (200 kPa PNP, 10 cycles) were investigated in vitro using confocal microscopy and ultra-high-speed imaging (10Mfps). No cellular response was observed for the 3.5 μm microbubbles having excursion amplitudes (Rmax-R0) ranging from 0.3 to 0.6 μm. PI uptake and resealing pores were observed more often for the 1.5 μm microbubbles (50%) with excursion amplitudes ranging from 0.5 to 0.9 μm than for the other microbubble sizes. PI uptake and tunnel formation was most observed for the 1.25 μm microbubbles (46.6%; 0.4–0.6 μm excursion amplitudes) and least for the 3 μm microbubbles (4.2%; 1.0 μm excursion amplitude). No other cellular responses were observed for the 3 μm microbubbles. The excursion ratio (Rmax-Rmin/R0) better separated the tunnel formation events (>0.6) from other cellular responses (0.1–0.6). This study shows the importance of monodisperse microbubbles for tuning drug delivery.