Sonoprinting promotes drug delivery with liposome-loaded microbubbles and ultrasound

Abstract

Ultrasound-triggered delivery from drug-loaded microbubbles has great potential due to its ability for localized release of the drugs while simultaneously enhancing delivery into the target tissue. We have recently proposed “sonoprinting” as a possible mechanism for the ultrasound-triggered delivery from nanoparticle-loaded microbubbles. It was shown that sonoprinting leads to the local deposition of nanoparticles and microbubble shell fragments in 2-D monolayer cultures. However, acoustic interactions between the bubbles and the rigid substrate could not be excluded. To verify whether sonoprinting can also occurs in more complex and physiologically more relevant tissues we study the US-triggered nanoparticle delivery from microbubbles to free-floating 3-D multicellular spheroids. Sonoprinting turned out to be a powerful tool to deliver large amounts of nanoparticles to the outer layers of tumor spheroids, followed by a complete drug release internalization into the deeper layers of the tumor spheroid. Sonoprinting significantly enhanced the cytotoxicity of both Doxil®-like and ThermoDOX®-like liposomes. We also provide evidence that only microbubble-associated nanoparticles become sonoprinted, while the uptake of free liposomal fraction is insignificant. As such, similar biological effects can be obtained through the use of substantially lower drug doses.