Optimization of Acoustic Liposomes for Improved In Vitro and In Vivo Stability
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RESEARCH PAPER
Optimization of Acoustic Liposomes for Improved In Vitro and In Vivo Stability Nicolas Sax & Tetsuya Kodama
Received: 12 March 2012 / Accepted: 13 August 2012 / Published online: 1 September 2012 # Springer Science+Business Media, LLC 2012
ABSTRACT Purpose Liposomes encapsulating perfluoropropane gas, termed acoustic liposomes (ALs), which can serve both for ultrasound (US) imaging and US-mediated gene delivery, have been reported. However, the echogenicity of ALs decreases within minutes in vivo due to gas diffusion and leakage, hindering time-consuming procedures such as contrast-enhanced 3D US imaging and raising the need for improvement of their stability. Methods The stability of ALs preparations incorporating increasing ratios of anionic / unsaturated phospholipids, polyethylene glycol (PEG)ylated phospholipid and cholesterol was investigated by measurement of their reflectivity over time using a high-frequency US imaging system, both in vitro and in vivo. Results The retention of echogenicity of ALs in vitro is enhanced with increasing molar ratios of PEGylated lipids. Addition of 10 molar percent of an anionic phospholipid resulted in a 31% longer half-life, while cholesterol had the opposite effect. Assessment of the stability of an optimized composition showed a more than 2-fold increase of the detection half-life in mice. Conclusions Presence of a PEG coating not only serves to provide “stealth” properties in vivo, but also contributes to the retention of the encapsulated gas. The optimized ALs reported here can be used as a contrast agent for lengthier imaging procedures.
N. Sax : T. Kodama (*) Molecular Delivery System Laboratory Graduate School of Biomedical Engineering Tohoku University 4-1 Seiryo-machi, Aoba-ku Sendai 980-0872, Japan e-mail: [email protected]
KEY WORDS contrast agent . drugdelivery . gas encapsulation . microbubbles . polyethylene glycol . ultrasound
INTRODUCTION Acoustic liposomes, liposomes encapsulating perfluoropropane (C3F8) gas inside PEGylated liposomes, were previously reported for use as ultrasound contrast agents (UCAs) for ultrasound imaging (1) and for ultrasound-mediated gene delivery, both in vivo (2,3) and in vitro (4). These liposomes simultaneously encapsulate both liquid and gas (5), but their structure remains unclear and multiple models have been proposed (Reviewed by Huang (6)). While easy to prepare, displaying a low toxicity and a good biocompatibility, these liposomes lose most of their echogenicity within a few minutes after injection. Similarly to some commercially available first generation contrast agents such as Levovist or Albunex (7–9), the encapsulated gas rapidly vanishes due to bubble collapse or diffusion to the outer, gas-undersaturated surrounding solution, i.e. blood (10,11). Given the recent popularity of PEGylated ALs (2,3,12–15), improvement of their stability is a question of interest. ALs with a better stability would allow for a longer imaging time in vivo and can be of great use for time-consuming imaging techniqu
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