Abstract
Microbubbles (MBs) are versatile ultrasound contrast agents that can be used for ultrasound molecular imaging and targeted drug delivery. However, a uniform and controlled response to ultrasound is essential for safe and effective use of targeted MBs in the clinic. It is suggested that the heterogeneous lipid distribution of currently available MB formulations causes variability in acoustic response. Hence, the objective of this study was to develop and characterize a new MB formulation with all coating components miscible and in the same lipid phase. MBs with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as main lipid were produced by probe sonication (MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">probe</inf> ) or by amalgamation, with 10% (MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -10) or 30% (MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -30) propylene glycol (PG). The lipid phase distribution, shelf-life, and acoustic attenuation were investigated. MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">probe</inf> and MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -30 had a homogeneous lipid distribution, while MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -10 had circular condensed phase domains. For all MBs the condensed phase increased over time. The PG concentration also affected the size and concentration: MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -30 had the largest mean diameter 20 min after production, while MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -10 had a tenfold higher concentration. All types of MBs had a short shelf-life stability, decreasing in size during the first hour post-production. The coating composition had a more significant effect on size and concentration than the production method. The MBs had a size-dependent resonance behavior and MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -10 and MB <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">shake</inf> -30 had the highest peak attenuation, revealing a stabilizing role for PG in these MB formulations. Even though the in vivo applications for the DSPE-based MBs may be limited because of the short shelf-life stability, the newly developed MB formulations are interesting candidates for further studies on the effect of lipid phase distribution on acoustic behavior of MBs.
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