Effects of microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain

Lipid-shelled microbubbles have been used in ultrasound-mediated drug delivery. The physicochemical properties of the microbubble shell could affect the delivery efficiency since they determine the microbubble mechanical properties, circulation persistence, and dissolution behavior during cavitation. Therefore, the aim of this study was to investigate the shell effects on drug delivery efficiency in the brain via blood-brain barrier (BBB) opening in vivo using monodisperse microbubbles with different phospholipid shell components. The physicochemical properties of the monolayer were varied by using phospholipids with different hydrophobic chain lengths (C16, C18, and C24). The dependence on the molecular size and acoustic energy (both pressure and pulse length) were investigated. Our results showed that a relatively small increase in the microbubble shell rigidity resulted in a significant increase in the delivery of 40-kDa dextran, especially at higher pressures. Smaller (3 kDa) dextran did not show significant difference in the delivery amount, suggesting the observed shell effect was molecular size-dependent. In studying the impact of acoustic energy on the shell effects, it was found that they occurred most significantly at pressures causing microbubble fragmentation (450 kPa and 600 kPa); by increasing the pulse length to deliver the 40-kDa dextran, the difference between C16 and C18 was eliminated while C24 achieved the highest delivery efficiency. These findings indicated that the acoustic parameters could be adjusted to modulate the shell effects. The acoustic cavitation emission revealed the physical mechanisms associated with different shells. Overall, lipid-shelled microbubbles with long hydrophobic chain length could achieve high delivery efficiency for larger molecules especially with high acoustic energy. Our study offered, for the first time, evidence directly linking the microbubble monolayer shell with their efficacy for drug delivery in vivo.