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Formulation and characterisation of drug-loaded antibubbles for image-guided and ultrasound-triggered drug delivery |
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| Affiliation: | 1. Department of Clinical Medicine, University of Bergen, Bergen, Norway;2. National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway;3. Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway;4. Neoety AS, Kløfta, Norway;5. Department of Clinical Science, University of Bergen, Bergen, Norway;6. Department of Quality and Development, Hospital Pharmacies Enterprise in Western Norway, Bergen, Norway;7. Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway;8. Cancer Clinic, St. Olav’s Hospital, Trondheim, Norway;9. Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway;10. Department of Health Research, SINTEF Digital, Trondheim, Norway;11. KinN Therapeutics, Bergen, Norway;12. CCBIO, Department of Clinical Science, University of Bergen, Norway;13. Polymer Technology, Eindhoven University of Technology, Eindhoven, the Netherlands |
| Abstract: | The aim of this study was to develop high load-capacity antibubbles that can be visualized using diagnostic ultrasound and the encapsulated drug can be released and delivered using clinically translatable ultrasound.The antibubbles were developed by optimising a silica nanoparticle stabilised double emulsion template.We produced an emulsion with a mean size diameter of 4.23 ± 1.63 µm where 38.9 ± 3.1% of the droplets contained a one or more cores. Following conversion to antibubbles, the mean size decreased to 2.96 ± 1.94 µm where 99% of antibubbles were <10 µm. The antibubbles had a peak attenuation of 4.8 dB/cm at 3.0 MHz at a concentration of 200 × 103 particles/mL and showed distinct attenuation spikes at frequencies between 5.5 and 13.5 MHz. No increase in subharmonic response was observed for the antibubbles in contrast to SonoVue®. High-speed imaging revealed that antibubbles can release their cores at MIs of 0.6. In vivo imaging indicated that the antibubbles have a long half-life of 68.49 s vs. 40.02 s for SonoVue®. The antibubbles could be visualised using diagnostic ultrasound and could be disrupted at MIs of ≥0.6. The in vitro drug delivery results showed that antibubbles can significantly improve drug delivery (p < 0.0001) and deliver the drug within the antibubbles. In conclusion antibubbles are a viable concept for ultrasound guided drug delivery. |
| Keywords: | Ultrasound Microbubbles Antibubble Targeted drug delivery Sonoporation |
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