Nanodroplet-Coated Microbubbles Used in Sonothrombolysis with Two-Step Cavitation Strategy

Thrombosis is a major cause of morbidity and mortality and sonothrombolysis is a promising method for its treatment. However, the slow diffusion of the thrombolytic agents into the thrombus results in slow recanalization. Here, nanodroplet-coated microbubbles (NCMBs) are designed and fabricated and a two-step cavitation strategy is used to accelerate the thrombolysis. The first cavitation of the NCMBs, cavitation and collapse of the microbubbles induced by low frequency ultrasound, drives the nanodroplets on the shell into the thrombus, while the second cavitation, the phase-change and volume expansion of drug-loaded nanodroplets triggered by high frequency ultrasound, loosens the thrombus by the sono-porosity effect. This two-step cavitation of the NCMBs is verified using a fibrin agarose model, where a rapid diffusion of the thrombolytic agents is observed. Furthermore, the NCMBs reach much higher thrombolysis efficiency in both in vitro and proof-of-concept experiments performed with living mice. The nanodroplet-coated microbubbles are a promising diffusion medicines carrier for efficient drug delivery.