Comparing Strategies for Magnetic Functionalization of Microbubbles

Abstract

The advancement of ultrasound-mediated therapy has stimulated the development of drug-loaded microbubble agents that can be targeted to a region of interest through an applied magnetic field prior to ultrasound activation. However, the need to incorporate therapeutic molecules while optimizing the responsiveness to both magnetic and acoustic fields and maintaining adequate stability poses a considerable challenge for microbubble synthesis. The aim of this study was to evaluate three different methods for incorporating iron oxide nanoparticles (IONPs) into phospholipid-coated microbubbles using (1) hydrophobic IONPs within an oil layer below the microbubble shell, (2) phospholipid-stabilized IONPs within the shell, or (3) hydrophilic IONPs noncovalently bound to the surface of the microbubble. All microbubbles exhibited similar acoustic response at both 1 and 7 MHz. The half-life of the microbubbles was more than doubled by the addition of IONPs by using both surface and phospholipid-mediated loading methods, provided the lipid used to coat the IONPs was the same as that constituting the microbubble shell. The highest loading of IONPs per microbubble was also achieved with the surface loading method, and these microbubbles were the most responsive to an applied magnetic field, showing a 3-fold increase in the number of retained microbubbles compared to other groups. For the purpose of drug delivery, surface loading of IONPs could restrict the attachment of hydrophilic drugs to the microbubble shell, but hydrophobic drugs could still be incorporated. In contrast, although the incorporation of phospholipid IONPs produced more weakly magnetic microbubbles, it would not interfere with hydrophilic drug loading on the surface of the microbubble.

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“…Magnetized microbubbles can be produced by incorporating MNPs in microbubbles' coating. The magnetic material can be loaded on the outside surface of the microbubbles within the coating, or within an oil layer underneath the coating [118,119]. To properly interact with the shell constituents of the microbubbles and to be efficiently loaded, the MNPs have to be coated with different phospholipids or dendrons, which eventually affect the physical properties and stability of the overall microsystems.…”

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“…The ligands may be attached to the membrane layer to target these microbubbles to various other tissues or organs. This layer is responsible for the elastic modulus or the compressive strength of the microbubbles [ 75 – 78 ]. The more flexible the component of the shell layer, the higher the acoustic intensity.…”