Controlled nanoparticle release from stable magnetic microbubble oscillations

Abstract

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 doxorubicin-containing 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. Microsized gas bubbles containing magnetic nanoparticles and drug nanoparticles (nanodrugs) can eject nanodrugs across biobarriers in cell, tissue and animals. Drug-delivery technologies use triggers such as enzymes, shear stress or magnetic fields to deposit medicinal payloads directly to afflicted tissues and organs. Chenjie Xu at Nanyang Technological University reports non-invasive drug delivery can be realized by using ultrasonic triggers to ‘magnetic microbubbles’ — spherical complexes of iron oxide nanoparticles and nanodrugs. The team loaded magnetic microbubbles with doxorubicin-containing polymer nanoparticles and used ultrasound irradiation to make the microspheres shrink and expand at their resonant frequencies. The constant oscillation caused the doxorubicin–nanoparticle complexes to be expelled hundreds of micrometres from the bubbles. The on-demand delivery proved powerful enough to cross tricky physiological barriers such as zebrafish heart/brain tissue and the vasculature of solid tumor in mouse. Drug-encapsulated nanoparticles (NPs) are emerging as therapeutic agents to deliver DNA\drugs into cells. However, clinical applications demand a technique to concentrate NPs at the diseased cells that are beneath other tissues. We report a strategy to achieve this goal with magnetic- and therapeutic NP-coated microbubbles as carriers. Although external magnetic field concentrates them at the targeted tissue, moderate ultrasound irradiation at their resonance frequency drives stable oscillation and microstreaming flow. Consequently, the NP armor detaches, penetrates into tissues and is later internalized by the cells. This technique would greatly improve the on-target delivery of nanomedicine, thereby reduces cost and side effects.