Regulating nonlinear properties of lipid-coated microbubbles using polymer network scaffolds for ultrasound drug delivery applications

Abstract

Stable and inertial cavitation of microbubbles can enhance drug delivery efficiency, but inertial cavitation poses a very high risk of mechanical damage in vivo. Stiff polymershelled microbubbles may exhibit weaker inertial cavitation but also weaker stable cavitation. We developed lipid-polymer composite microbubbles (LP-MBs) that exhibit lower inertial cavitation activity without compromising their performance to exhibit stable cavitation. The regulation of these nonlinear properties, making them more preferable for ultrasound drug delivery. Polymer materials including monomers (butyl methacrylate) and crosslinkers (ethylene glycol dimethacrylate) were incorporated into the inner shell of C3F8 MBs stablized by DSPC and DSPEPEG2000, followed by a polymerization process for 2 h under increased temperature. LP-MBs had a mean size of ∼1.8 µm. The integrity of the polymer network was observed under negative-stain TEM even after removal of the lipids. Although no significant differences in the resonance frequencies of 10–15 MHz and stable cavitation activity were observed due to the polymerization process, the inertial cavitation dose was decreased by up to 30% under sonication above 1000 kPa. The polymer network may have served as a flexible scaffold to stabilize the lipids and impede inertial collapse of LP-MBs, rendering them safer for in vivo use. Research is underway to validate the in vivo feasibility (e.g., blood brain barrier disruption or gene delivery).