Lipid/PLGA Hybrid Microbubbles as a Versatile Platform for Noninvasive Image-Guided Targeted Drug Delivery

Microbubbles (MBs) have recently emerged as promising theranostic carriers for ultrasound contrast imaging and drug delivery. However, conventional lipid-based MBs have a poor drug encapsulation efficiency, and polymer-based MBs show a weak capability in contrast imaging and ultrasound triggered drug release. Here, we developed a novel type of multiporous lipid/PLGA hybrid MBs (lipid/PLGA MBs) that solved the dilemma of MBs as imaging agents and drug carriers. The lipid/PLGA MBs were designed through regulating the elasticity of the bubble shells using lipids to incorporate into the PLGA shells and ammonium bicarbonate as a gas-generating agent. The softened shells and the porous bubble structure make them be able to generate stronger harmonic signals and be more vulnerable to ultrasound irradiation, leading to their excellent performance in ultrasound contrast imaging and ultrasound-triggered MB destruction in vitro and in vivo. By using doxorubicin (Dox) as a model drug, the Dox-loaded lipid/PLGA MBs (Dox-lipid/PLGA MBs) were prepared and achieved a high drug encapsulation efficiency. The real-time tracking of drug delivery and on-command controlled drug release by ultrasound were successfully realized in the tumor-bearing mice. A significantly enhanced tumor growth inhibition effect could be observed when using Dox-lipid/PLGA MBs combined with ultrasound irradiation, compared with free Dox and Dox-lipid/PLGA MBs without ultrasound. Our study provides an innovative multifunctional platform of MBs for ultrasound contrast imaging and drug delivery applications.