High-Speed Optical Characterization of Protein-and-Nanoparticle–Stabilized Microbubbles for Ultrasound-Triggered Drug Release

Abstract

BackgroundUltrasound-triggered bubble-mediated local drug delivery has shown potential to increase therapeutic efficacy and reduce systemic side effects, by loading drugs into the microbubble shell and triggering delivery of the payload on demand using ultrasound. Understanding the behavior of the microbubbles in response to ultrasound is crucial for efficient and controlled release. MethodsIn this work, we characterize the response of microbubbles with a coating consisting of poly(2-ethyl-butyl cyanoacrylate) (PEBCA) nanoparticles and denatured casein. High-speed recordings are taken of single microbubbles, both in bright-field and fluorescence. ResultsThe nanoparticle-loaded microbubbles show resonance behavior, but with a large variation in response, demonstrating a substantial inter-bubble variation in mechanical shell properties. The probability of shell rupture and the probability of nanoparticle release were found to strongly depend on the microbubble size, and the most effective size was inversely proportional to the driving frequency. Both the rupture and release probabilities increased with increasing driving pressure amplitude. Rupture of the microbubble shell occurred after fewer cycles of ultrasound as the driving pressure amplitude or driving frequency was increased. ConclusionsThe results highlight the importance of careful selection of the driving frequency, driving pressure amplitude, and duration of the ultrasound to achieve the most efficient ultrasound-triggered shell rupture and nanoparticle release of protein-and-nanoparticle-stabilized microbubbles.