Microbubble Shell Stiffness Engineering Enhances Ultrasound Imaging, Drug Delivery, and Sonoporation

Abstract

Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US-enhanced drug delivery. While the majority of studies utilize commercial MB formulations, increasing experimental evidence indicates that distinct MB features critically determine their diagnostic and therapeutic performance. Here, it is shown that shell stiffness engineering of poly(alkyl cyanoacrylate) (PACA) MB, via introducing monomers with varying alkyl chain lengths and glass transition temperatures, preserves a narrow size distribution ≈2-3 µm, while enhancing MB drug loading, in vitro sonoporation capability, and in vitro and in vivo acoustic responses. All-atom molecular dynamics simulations and spectroscopic experiments demonstrate that MB shell engineering increases drug diffusion rates in the shell, maximizing the loading capacity of the formulations. Atomic force microscopy demonstrates that the stiffness of the MB shell can be tailored by more than ten-fold, boosting sonoporation and imaging performance. Altogether, the work provides new insights into the control of polymeric MB structure and performance via dedicated shell engineering, promoting applications in US imaging and therapy.