Double shelled perfluorocarbon microdroplets as a versatile ultrasound phase-change platform

Microdroplets (MDs) with a liquid perfluorocarbon (PFC) core can transform into microbubbles (MBs) when exposed to a proper ultrasound field through the processes known as Acoustic Droplet Vaporisation (ADV) [1]. The properties of the so-called “phase-change” ultrasound contrast agents rely on this process (Figure 1A, C). Thanks to the resonant acoustic response of the MBs formed after vaporisation, MDs can be considered suitable for enhancing the imaging contrast of pathological regions or even for tracking at high frame rate the dynamics in blood flows [2]. Furthermore, MDs may become promising theranostic agents due to their ability to conjugate the dramatically increased ultrasound echogenicity after vaporisation with the drug cargo capability [3]. Significant improvement in this respect mainly passes through the engineering of a shell conferring to the MDs a proper colloidal stability (even upon ADV), chemical versatility and size control [4]. Herein, we present micrometric decafluoropentane (DFP) MDs stabilized by a hybrid shell made up of a double biocompatible layer: the inner one made of dimethyldioctadecylammonium bromide (DDAB) cationic surfactant and an elastomeric external one of crosslinked dextran methacrylate (DexMa) (figure 1B). The high positive charge given by DDAB provides a stability, even to MDs encapsulated by the surfactant monolayer (DDAB MDs) only. It also enables the electrostatic decoration of the MDs with anionic gold nanoparticles (AuNPs), thus unlocking the possibility of optically improving the vaporisation efficiency. The long and saturated hydrocarbon chains of the DDAB shell stabilize the droplet and the drug cargo therein while the DexMa shell allows to obtain stable cavitating MBs upon ADV. Summing up, we obtain a stable and versatile multimodal “phase-change" contrast agent (DDAB+DexMa MDs) which can also act as a drug and/or nanoparticles carrier with several in vitro applications.