Magnetic microbubbles (MMBs) are microbubbles (MBs) coated with magnetic nanoparticles (NPs). MMBs not only maintain the acoustic properties of MBs, but also serve as an important contrast agent for magnetic resonance imaging. Such dual-modality functionality makes MMBs particularly useful for a wide range of biomedical applications, such as localized drug/gene delivery. This article reports the ability of MMBs to release their particle cargo on demand under stable oscillation. When stimulated by ultrasound at resonant frequencies, MMBs of 450 nm to 200 μm oscillate in volume and surface modes. Above an oscillation threshold, NPs are released from the MMB shell and can travel hundreds of micrometers from the surface of the bubble. The migration of NPs from MMBs can be described with a force balance model. With this technology, we deliver doxorubicincontaining poly(lactic-co-glycolic acid) particles across a physiological barrier both in vitro and in vivo, with a 18-fold and 5-fold increase in NP delivery to the heart tissue of zebrafish and tumor tissue of mouse, respectively. The penetration of released NPs in tissues is also improved. The ability to remotely control the release of NPs from MMBs suggests opportunities for targeted drug delivery through/into tissues that are not easily diffused through or penetrated. NPG Asia Materials (2016) 8, e260; doi:10.1038/am.2016.37; published online 8 April 2016
INTRODUCTIONTargeted drug delivery and controlled release is the 'holy grail' of nanomedicine. In this regard, one emerging strategy employs a localized stimulus to precisely deposit drug-containing nanoparticles (NPs) at the tissue/organ of interest. The deposited NPs then continuously release drug molecules in a localized and sustained manner. Current strategies trigger the release of NPs from carriers via enzymes, 1 magnetic fields 2 and shear stress. 3 However, these methods are limited to specific organs/tissues, such as blocked blood vessels. A more versatile technology is desired that allows the targeted delivery of NPs to any organ/tissue while maintaining traceability using a non-invasive imaging modality.The present paper reports a strategy toward this end. Magnetic microbubbles (MMBs), the combination of multi-modal contrastenhanced imaging (both magnetic resonance imaging and ultrasound imaging) with targeted drug delivery (magnetic targeting) and controlled release (bubble cavitation) at any site of interest represents an emerging theranostic platform. However, the current formulations of MMBs, stabilized by a polymeric, lipid or silica shell, need a high acoustic energy field to trigger the release through bubble