Nanoparticle-stabilized microbubbles for multimodal imaging and drug delivery Ýrr Mørch a *, Rune Hansen b , Sigrid Berg b , Andreas K. O. Åslund c , Wilhelm R. Glomm a,d , Siv Eggen c , Ruth Schmid a , Heidi Johnsen a , Stephan Kubowicz a , Sofie Snipstad c , Einar Sulheim c , Sjoerd Hak c,e , Gurvinder Singh d , Birgitte H. McDonagh d , Hans Blom f , Catharina de Lange Davies c and Per M. Stenstad a Microbubbles (MBs) are routinely used as contrast agents for ultrasound imaging. The use of ultrasound in combina- tion with MBs has also attracted attention as a method to enhance drug delivery. We have developed a technology platform incorporating multiple functionalities, including imaging and therapy in a single system consisting of MBs stabilized by polyethylene glycol (PEG)-coated polymeric nanoparticles (NPs). The NPs, containing lipophilic drugs and/or contrast agents, are composed of the widely used poly(butyl cyanoacrylate) (PBCA) polymer and prepared in a single step. MBs stabilized by these NPs are subsequently prepared by self-assembly of NPs at the MB air–liquid interface. Here we show that these MBs can act as contrast agents for conventional ultrasound imaging. Successful encapsulation of iron oxide NPs inside the PBCA NPs is demonstrated, potentially enabling the NP–MBs to be used as magnetic resonance imaging (MRI) and/or molecular ultrasound imaging contrast agents. By precise tuning of the applied ultrasound pulse, the MBs burst and the NPs constituting the shell are released. This could result in increased local deposit of NPs into target tissue, providing improved therapy and imaging contrast compared with freely distributed NPs. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: poly(butyl cyanoacrylate); nanoparticle; microbubble; targeted drug delivery; theranostics; focused ultrasound 1. INTRODUCTION Nanoparticles (NPs) as carriers for cytotoxic drugs are of great interest in cancer therapy due to the enhanced permeability and retention effect (1). However, the uptake of NPs in tumors is often low and the distribution heterogeneous (2). In recent years, ultrasound has been shown to enhance the delivery of various NPs to tumors in small animals (3–5). Thus, ultrasound-mediated enhancement in delivery of NPs, which might be further enhanced in the presence of microbubbles (MBs), is clinically interesting. MBs might increase the heteroge- neous vascular permeability by causing shear stress and jet streams, and the jet streams might also improve the penetra- tion through the extracellular matrix. Ultrasound and MBs might also improve the delivery of non-encapsulated drugs, as recently demonstrated in a clinical study combining ultra- sound and co-injection of gemcitabine and commercially available MBs to treat pancreatic cancer (6). In pre-clinical studies, the combination of ultrasound and MBs also facilitates a transient and local opening of the blood–brain barrier (7), thereby permitting various drugs to enter the brain and potentially treat central nervous system (CNS) disorders. As for all tissues, the exact mechanism by which ultrasound and MBs causes blood–brain barrier disruptions is not fully understood, but cavitation, i.e. volume oscillations of MBs in an ultrasound field, is obviously an important factor (8,9). Poly(alkylcyanoacrylate) (PACA), first introduced to the medi- cal field as surgical glue, has in recent years been extensively studied as a material for drug delivery vehicles (10,11). PACA NPs can easily be prepared by in situ polymerization of alkylcyanoacrylate monomers encapsulating a wide range of drugs with high loading capacity. As the monomers are hydro- phobic, PACAs are especially suitable for encapsulating lipophilic drugs, thereby improving the delivery of poorly blood-soluble * Correspondence to: Ý. Mørch, SINTEF Materials and Chemistry, P.O. Box 4760 Sluppen, 7465 Trondheim, Norway. E-mail: yrr.morch@sintef.no a Ý. Mørch, W. R. Glomm, R. Schmid, H. Johnsen, S. Kubowicz, P. M. Stenstad SINTEF Materials and Chemistry, P.O. Box 4760 Sluppen, 7465 Trondheim, Norway b R. Hansen, S. Berg SINTEF Technology and Society, P.O. Box 4760 Sluppen, 7465 Trondheim, Norway c A. K. O. Åslund, S. Eggen, S. Snipstad, E. Sulheim, S. Hak, C. Davies Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway d W. R. Glomm, G. Singh, B. H. McDonagh Department of Chemical Engineering, Norwegian University of Science and Technology, 7491 Trondheim, Norway e S. Hak Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7030 Trondheim, Norway f H. Blom Science for Life Laboratory, Box 1031, 17121 Solna, Sweden Full Paper Received: 12 August 2014, Revised: 06 February 2015, Accepted: 13 February 2015, Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cmmi.1639 Contrast Media Mol. Imaging (2015) Copyright © 2015 John Wiley & Sons, Ltd.