Non-spherical oscillations drive the ultrasound-mediated release from targeted microbubbles

Guillaume Lajoinie,Frits Mastik,Benjamin Dollet,Nico De Jong,Ine Lentacker,Heleen Dewitte,Ying Luan,Erik Gelderblom,Michel Versluis

doi:10.1038/s42005-018-0020-9

Abstract

Ultrasound-driven microbubbles are attractive for a variety of applications in medicine, including real-time organ perfusion imaging and targeted molecular imaging. In ultrasound-mediated drug delivery, bubbles decorated with a functional payload become convenient transport vehicles and offer highly localized release. How to efficiently release and transport these nanomedicines to the target site remains unclear owing to the microscopic length scales and nanoseconds timescales of the process. Here, we show theoretically how non-spherical bubble oscillations lead first to local oversaturation, thereby inducing payload release, and then to microstreaming generation that initiates transport. Experimental validation is achieved through ultra-high-speed imaging in an unconventional side-view at tens of nanoseconds timescales combined with high-speed fluorescence imaging to track the release of the payload. Transport distance and intrinsic bubble behavior are quantified and agree well with the model. These results will allow for optimizing the therapeutic use of targeted microbubbles for precision medicine.

Highlights

Ultrasound-driven microbubbles are attractive for a variety of applications in medicine, including real-time organ perfusion imaging and targeted molecular imaging
The unique acoustic properties of microbubbles that present a typical radius of 1−3 μm have been used for two decades to boost perfusion imaging in the clinic, making them unrivaled blood pool agents[2]
Targeting ligands can be attached to the periphery of the shell to recognize and adhere to diseased cells and tissues[5, 6], thereby bringing a molecular imaging dimension to the clinical use of microbubbles

Summary

Introduction

Ultrasound-driven microbubbles are attractive for a variety of applications in medicine, including real-time organ perfusion imaging and targeted molecular imaging. Driven near its resonance frequency, a bubble displays maximal radial response and generates secondary effects, such as harmonics and subharmonics[11, 12], streaming, acoustic radiation forces, shape instabilities[13], and non-spherical oscillations[14, 15]. These effects are of prime importance in applications such as cleaning, (bacterial) biofilms removal[16], mechanical destruction of thrombus[17] or tumors[18, 19] or inducing vessel wall permeation, e.g for blood brain barrier opening[20]. The combination of the mechanical action of targeted microbubbles adherent to a surface with the release of a drug payload is of great interest for therapeutic applications as medicine is becoming increasingly focused towards personalized[21] and localized therapy[22, 23]

Methods

Results

Conclusion