High-speed fluorescence microscopy of near-wall shedding of drug-lipid complexes from phase-change droplets

Phase-change droplets are promising for drug delivery owing to the ability to undergo acoustic droplet vaporization (ADV) under ultrasound exposure, but the drug release process is not visible with conventional microscopy techniques. Our previous work has shown that drug-surfactant complexes are released in the form of micro-sized vesicles from a vaporizing droplet at above specific acoustic pressure thresholds. Further investigation on the spatial distribution and dynamics of the released vesicles is required to gain more insights into the mechanism of ADV-mediated drug release behaviors. Herein, we utilized concurrent bright-field and fluorescence high-speed microscopy at 40 kfps to visualize the drug release dynamics and spatial distribution for perfluoropentane droplets with diameters of 7-10 μm. DiI-C₁₈ was incorporated in the droplets to model hydrophobic drugs. When the droplets were arranged in different orientations in a 200-μm tube by using acoustic radiation forces, the released vesicles of DiI-lipid complexes were observed mainly on the sides in contact with the tube wall. The same phenomenon was observed in the images of single droplets settling on the tube wall captured at different positions with respect to the predicted positions of produced bubbles. These findings suggest that near-wall streaming flows may play an important role in the mechanism of the observed phenomena. The near-wall distribution of vesicle release from droplets after ADV means that ADV may be a useful technique in ultrasound drug delivery particularly in therapies that utilize vascular targeting. This study provides valuable information for the optimization of ADV-based drug delivery.