691 Introduction he current lack of targeted drug delivery systems limits medical therapy. his limitation is particularly evident within oncology where systemic administration of cyto- static drugs afects all dividing cells thereby imposing dose limitations. Hence, there is a need for eicient delivery of therapeutic drugs at the disease target while limiting toxicity to healthy tissue. Encapsulating drugs in a protective shell, such as liposomes and polymer particles, have to a certain extent accommodated this challenge. he development of such drug delivery vehicles has faced two opposing challenges: the need for stable non-leaking particles in the general circula- tion, and the need for drug release at the diseased site (Drummond et al., 1999). Ultrasound (US) has been suggested as a physical means to trigger speciic drug release in target tissues (for reviews see Pitt et al., 2004; Frenkel, 2008; Böhmer et al., 2009). Such delivery technology would be characterized by robust drug carrying particles, accumulation of particles in tumors, and their disintegration upon exposure to acoustic energy leading to drug release. US has the additional beneit of increasing cell permeability, thus providing a two-fold efect: drug-carrier disruption and increased intracellular drug uptake (Liu et al., 1998; Sundaram et al., 2003; Larina et al., 2005; Frenkel, 2008; Schroeder et al., 2009a). Currently, ive main types of US responsive particles have been reported: micelles, nanoemulsions, microbubbles, gas-illed echogenic liposomes, and gas-free liposomes (Rapoport et al., RESEARCH ARTICLE Feasibility study of cavitation-induced liposomal doxorubicin release in an AT2 Dunning rat tumor model Cyril Lafon 1 , Lucie Somaglino 1 , Guillaume Bouchoux 1 , Jean Martial Mari 1 , Sabrina Chesnais 1 , Jacqueline Ngo 1 , Jean-Louis Mestas 1 , Sigrid L. Fossheim 2 , Esben A. Nilssen 2 , and Jean-Yves Chapelon 1 1 INSERM, U1032, Lyon, F-69003, France; Université de Lyon, Lyon, F-69003, France, 2 Université de Lyon, Lyon, France, and 3 Epitarget AS, Majorstuen, Oslo, Norway Abstract Background: Targeted and triggered release of liposomal drug using heat or ultrasound represents a promising treatment modality able to increase the therapeutic-totoxicity ratio of encapsulated drugs. Purpose: To study the ability for high-intensity focused ultrasound to induce liposomal drug release mainly by focused inertial cavitation in vitro and in an animal model. Methods: A 1 MHz ultrasound setup has been developed for in vitro and in vivo drug release from a speciic liposomal doxorubicin formulation at a target cavitation dose. Results: Controlled cavitation at 1 MHz was applied within the tumors 48 hours after liposome injection according to preliminary pharmacokinetic study. A small non-signiicant therapeutic efect of US-liposomal treatment was observed compared to liposomes alone suggesting no beneicial efect of ultrasound in the current setup. Conclusion: The in vitro study provided a suitable ultrasound setup for delivering a cavitation dose appropriate for safe liposomal drug release. However, when converting to an in vivo model, no therapeutic beneit was observed. This may be due to a number of reasons, one of which may be the diiculty in converting in vitro indings to an in vivo model. In light of these indings, we discuss important design features for future studies. Keywords: Ultrasound, drug delivery, liposome, sonosensitivity Address for Correspondence: Cyril Lafon, INSERM U1032, 151 Cours Albert homas, 69424 Lyon Cedex 03, France. Tel: +33 4 72 68 19 20. Fax: +33 4 72 68 19 31. E-mail: Cyril.lafon@inserm.fr (Received 17 February 2012; revised 02 July 2012; accepted 11 July 2012) Journal of Drug Targeting, 2012; 20(8): 691–702 © 2012 Informa UK, Ltd. ISSN 1061-186X print/ISSN 1029-2330 online DOI: 10.3109/1061186X.2012.712129 Journal of Drug Targeting Downloaded from informahealthcare.com by University Claude Bernard Lyon 1 on 08/31/12 For personal use only.