Abstract
Microbubbles (MBs) are widely used as contrast enhancement agents for ultrasound imaging and have the potential to enhance therapeutic delivery to diseases such as cancer. Yet, they are only stable in solution for a few hours to days after production, which limits their potential application. Freeze-drying provides long-term storage, ease of transport, and consistency in structure and composition, thereby facilitating their use in clinical settings. Therapeutic microbubbles (thMBs) consisting of MBs with attached therapeutic payload potentially face even greater issues for production, stability, and well-defined drug delivery. The ability to freeze-dry thMBs represents an important step for their translation to the clinic. Here, we show that it is possible to freeze-dry and reconstitute thMBs that consist of lipid-coated MBs with an attached liposomal payload. The thMBs were produced microfluidically, and the liposomes contained either calcein, as a model drug, or gemcitabine. The results show that drug-loaded thMBs can be freeze-dried and stored for at least 6 months. Upon reconstitution, they maintain their structural integrity and drug loading. Furthermore, we show that their in vivo echogenicity is maintained post-freeze-drying. Depending on the gas used in the original bubbles, we also demonstrate that the approach provides a method to exchange the gas core to allow the formulation of thMBs with different gases for combination therapies or improved drug efficacy. Importantly, this work provides an important route for the facile off-site production of thMBs that can be reformulated at the point of care.
Highlights
Microbubbles (MBs) are widely used as contrast enhancement agents in ultrasound (US) imaging and typically consist of a perfluorocarbon gas core and a biocompatible shell.[1−4] The enhanced US contrast arises from the high mismatch in acoustic impedance between the gas core and the surrounding medium
Liposomes fluorescently labeled with Texas Red in the shell were loaded with gem. and used to prepare gem. therapeutic microbubbles (thMBs)
We have demonstrated that drug-loaded liposomes attached to MBs can be freeze-dried and reconstituted without adversely affecting either the attachment of the liposomes to the MBs or causing leakage of the therapeutic agents from the liposome
Summary
Microbubbles (MBs) are widely used as contrast enhancement agents in ultrasound (US) imaging and typically consist of a perfluorocarbon gas core and a biocompatible shell (e.g., protein, phospholipid, or polymer).[1−4] The enhanced US contrast arises from the high mismatch in acoustic impedance between the gas core and the surrounding medium. The properties of the shell and the encapsulated gas affect the MB stability in vitro and in vivo as well as their US response.[5−10] MBs undergo US-induced oscillations that result in microstreaming, or at higher amplitude, MB destruction.[11,12] These processes can create pores in cell membranes and enhance the passage of drug molecules across the cell membrane. The thMB complex can be further targeted toward the required delivery site using antibodies, or other targeting ligands, for localized delivery.[20]
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