Biodistribution, kinetics, and biological fate of SPION microbubbles in the rat

Åsa Barrefelt,1,2,* Maryam Saghafian,2,* Raoul Kuiper,3 Fei Ye,4 Gabriella Egri,5 Moritz Klickermann,5 Torkel B Brismar,1 Peter Aspelin,1 Mamoun Muhammed,4 Lars Dähne,5 Moustapha Hassan2,6 1Department of Clinical Science, Intervention and Technology, Division of Medical Imaging and Technology, Karolinska Institutet, and Department of Radiology, Karolinska University Hospital-Huddinge, Stockholm, Sweden; 2Experimental Cancer Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 3Karolinska Institute Core Facility for Morphologic Phenotype Analysis, Clinical Research Center, Karolinska University Hospital-Huddinge, Stockholm, Sweden; 4Division of Functional Materials, Department of Materials and Nano Physics, Royal Institute of Technology, Stockholm, Sweden; 5Surflay Nanotec GmbH, Berlin, Germany; 6Clinical Research Center, Karolinska University Hospital-Huddinge, Stockholm, Sweden *These authors contributed equally to this work Background: In the present investigation, we studied the kinetics and biodistribution of a contrast agent consisting of poly(vinyl alcohol) (PVA) microbubbles containing superparamagnetic iron oxide (SPION) trapped between the PVA layers (SPION microbubbles). Methods: The biological fate of SPION microbubbles was determined in Sprague-Dawley rats after intravenous administration. Biodistribution and elimination of the microbubbles were studied in rats using magnetic resonance imaging for a period of 6 weeks. The rats were sacrificed and perfusion-fixated at different time points. The magnetic resonance imaging results obtained were compared with histopathologic findings in different organs. Results: SPION microbubbles could be detected in the liver using magnetic resonance imaging as early as 10 minutes post injection. The maximum signal was detected between 24 hours and one week post injection. Histopathology showed the presence of clustered SPION microbubbles predominantly in the lungs from the first time point investigated (10 minutes). The frequency of microbubbles declined in the pulmonary vasculature and increased in pulmonary, hepatic, and splenic macrophages over time, resulting in a relative shift from the lungs to the spleen and liver. Meanwhile, macrophages showed increasing signs of cytoplasmic iron accumulation, initially in the lungs, then followed by other organs. Conclusion: The present investigation highlights the biological behavior of SPION microbubbles, including organ distribution over time and indications for biodegradation. The present results are essential for developing SPION microbubbles as a potential contrast agent and/or a drug delivery vehicle for specific organs. Such a vehicle will facilitate the use of multimodality imaging techniques, including ultrasound, magnetic resonance imaging, and single positron emission computed tomography, and hence improve diagnostics, therapy, and the ability to monitor the efficacy of treatment. Keywords: biodistribution, microbubbles, superparamagnetic iron oxide, pharmacokinetics, magnetic resonance imaging, histopatholog

Die ökonomische Bewertung rechtlicher Schutzfragen bezüglich virtueller Objekte auf Online-Plattformen, insbesondere MMORPGs

The spread of broadband Internet access as well as Internet flat rates pushes the emergence and growth of virtual worlds especially Massive Multiplayer Online Role-Playing Games (MMORPGs) such as World of Warcraft. The increase in the economic role of this sector has given rise to many economic and legal questions. This interdisciplinary paper examines the assignment of (intellectual) property rights to the players as well as to the licensee considering intangible property rights. We analyze the legal as well as economic characteristics of virtual goods differing two types of virtual goods: the avatar, a virtual character that is driven by the player, and virtual objects that can be gathered by the avatar during the game. Although Terms of Service prohibit the Real Money Trade of avatars and virtual objects, a sizeable market came to existence, where trade between players as well as between players and newly founded commercial enterprises takes place. Therefore it has to be clarified on the one hand, if customization of those avatars and items means that they also become the players (intellectual) property and on the other hand, if this trade does make economic sense at all. Finally, we develop a pricing model which assigns different property rights to the players and the licensee according to the players' preferences to solve the arising legal as well as economic problems matching all interests.Received: October 8, 2008Accepted: March 21, 200