Abstract
Previous studies have reported substantial improvement of microbubble (MB)-mediated drug delivery with ultrasound when drugs are loaded onto the MB shell compared with a physical mixture. However, drug loading may affect shell properties that determine the acoustic responsiveness of MBs, producing unpredictable outcomes. The aim of this study is to reveal how the surface loaded drug (doxorubicin, DOX) affects the acoustic properties of MBs. A suitable formulation of MBs for DOX loading was first identified by regulating the proportion of two lipid materials (1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol sodium salt (DSPG)) with distinct electrostatic properties. We found that the DOX loading capacity of MBs was determined by the proportion of DSPG, since there was an electrostatic interaction with DOX. The DOX payload reduced the lipid fluidity of MBs, although this effect was dependent on the spatial uniformity of DOX on the MB shell surface. Loading DOX onto MBs enhanced acoustic stability 1.5-fold, decreased the resonance frequency from 12–14 MHz to 5–7 MHz, and reduced stable cavitation dose by 1.5-fold, but did not affect the stable cavitation threshold (300 kPa). Our study demonstrated that the DOX reduces lipid fluidity and decreases the elasticity of the MB shell, thereby influencing the acoustic properties of MBs.
Highlights
Accepted: 30 November 2021Microbubbles (MBs) with lipid shells and gaseous contents have been proposed as attractive drug carriers for achieving noninvasive diagnosis, therapy, and localized drug delivery in biological tissues, in combination with ultrasound (US)
We focused on loading doxorubicin (DOX), a clinically used chemotherapy drug that is usually associated with high cardiotoxicity [1], onto the MB shell
We first characterized the properties of different lipid formulations, including mean size, concentration, DOX payload, and surface charge
Summary
Microbubbles (MBs) with lipid shells and gaseous contents have been proposed as attractive drug carriers for achieving noninvasive diagnosis, therapy, and localized drug delivery in biological tissues, in combination with ultrasound (US). Translation of these findings to the clinic has been hindered by the naturally low drug capacity of MBs and the unknown acoustic properties of MBs after drug loading. In response to low-intensity US, MBs undergo a steady oscillation (stable cavitation) that can induce reversible vascular permeabilization with a low level of cargo release. The inertial cavitation of MBs can totally release their cargo and concurrently produces a strong mechanical stress that damages nearby tissues. The MBs emit nonlinear harmonic signals when stimulated at their resonance frequency with low-intensity US, providing a unique opportunity to distinguish between
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