Characterization and Imaging of Lipid-Shelled Microbubbles for Ultrasound-Triggered Release of Xenon
- 263 Downloads
Xenon (Xe) is a bioactive gas capable of reducing and stabilizing neurologic injury in stroke. The goal of this work was to develop lipid-shelled microbubbles for xenon loading and ultrasound-triggered release. Microbubbles loaded with either xenon (Xe-MB) or xenon and octafluoropropane (Xe-OFP-MB) (9:1 v/v) were synthesized by high-shear mixing. The size distribution and the frequency-dependent attenuation coefficient of Xe-MB and Xe-OFP-MB were measured using a Coulter counter and a broadband acoustic attenuation spectroscopy system, respectively. The Xe dose was evaluated using gas chromatography/mass spectrometry. The total Xe doses in Xe-MB and Xe-OFP-MB were 113.1 ± 13.5 and 145.6 ± 25.5 μl per mg of lipid, respectively. Co-encapsulation of OFP increased the total xenon dose, attenuation coefficient, microbubble stability (in an undersaturated solution), and shelf life of the agent. Triggered release of gas payload was demonstrated with 6-MHz duplex Doppler and 220-kHz pulsed ultrasound. These results constitute the first step toward the use of lipid-shelled microbubbles for applications such as neuroprotection in stroke.
Key WordsBioactive gas delivery xenon delivery lipid-shelled microbubbles ultrasound cytoprotection.
This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke through grant R01 NS047603. Kevin Haworth, Ph.D., was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute through grant K25HL133452. The authors thank Prof. Jack Rubinstein, Dr. Sheryl Koch, and Michelle Nieman for their help with in vivo imaging and Dr. Karla Mercado-Shekhar for assistance with in vitro imaging. Prof. Dong Zhang and Prof. Xiasheng Guo are acknowledged for providing the 220-kHz transducer used in this study, and Robert Kleven for calibrating it. The authors are grateful to Prof. Kenneth Setchell for sharing his expertise on gas chromatography/mass spectroscopy measurements.
Required Author Forms
Disclosure forms provided by the authors are available with the online version of this article.
- 7.Rajah GB, Ding Y. Experimental neuroprotection in ischemic stroke: a concise review. Neurosurg Focus 2017;42:E2.Google Scholar
- 12.Dickinson R, Franks NP. Bench-to-bedside review: molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection. Crit Care 2010;14.Google Scholar
- 18.Peng T, Britton GL, Kim H, et al. Therapeutic time window and dose dependence of xenon delivered via echogenic liposomes for neuroprotection in stroke. CNS Neurosci Ther 2013;19:773–784.Google Scholar
- 20.Kim H, Britton GL, Peng T, et al. Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage. Int J Nanomedicine 2014;9:155–165.Google Scholar
- 29.Owen J, McEwan C, Nesbitt H, et al. Reducing tumour hypoxia via oral administration of oxygen nanobubbles. PLoS One 2016;11.Google Scholar
- 35.Altman PL. Handbook of respiration. Philadelphia: W. B. Saunders; 1959.Google Scholar
- 49.Debbage PL, Griebel J, Ried M, et al. Lectin intravital perfusion studies in tumor-bearing mice: micrometer-resolution, wide-area mapping of microvascular labeling, distinguishing efficiently and inefficiently perfused microregions in the tumor. J Histochem Cytochem 1998;46:627–639.CrossRefGoogle Scholar
- 50.Widmaier EP, Raff H, Strang KT, Vander AJ. Vander’s human physiology: the mechanisms of body function. Fourteenth edition. ed. New York, NY: McGraw-Hill; 2016. 1 volume (various pagings) p.Google Scholar
- 61.Widmaier EP, Raff H, Strang KT. Vander’s human physiology: the mechanisms of body function. 2006.Google Scholar