Improving performance of nanoscale ultrasound contrast agents using N,N-diethylacrylamide stabilization

The design of nanoscale yet highly echogenic agents for imaging outside of the vasculature and for ultrasound-mediated drug delivery remains a formidable challenge. We have previously reported on formulation of echogenic perfluoropropane gas nanobubbles stabilized by a lipid-pluronic surfactant shell. In the current work we describe the development of a new generation of these nanoparticles which consist of perfluoropropane gas stabilized by a surfactant and lipid membrane and a crosslinked network of N,N-diethylacrylamide. The resulting crosslinked nanobubbles (CL-PEG-NB) were 95.2 ± 25.2 nm in diameter and showed significant improvement in stability and retention of echogenic signal over 24 h. In vivo analysis via ultrasound and fluorescence mediated tomography showed greater tumor extravasation and accumulation with CL-PEG-NB compared to microbubbles. Together these results demonstrate the capabilities and advantages of a new, more stable, nanometer-scale ultrasound contrast agent that can be utilized in future work for diagnostic scans and molecular imaging.

Graphical AbstractTraditional ultrasound contrast agents are too large to extravasate beyond the vasculature, making them ineffective for imaging of target biomarkers located on the cancer cell surface. This work describes the formulation and comprehensive characterization of nanoparticle-sized (~100 nm) ultrasound contrast agents which are based on lipid/surfactant stabilized perfluorocarbon gas. To add stability and improve longevity of ultrasound signal, the nanobubbles are further stabilized by a crosslinked polymer component. Such agents can be inherently be imaged at ultrasound frequencies that are clinically relevant with little post-formulation modification have not been previously described.254