Acoustically active red blood cell carriers for ultrasound-triggered drug delivery with photoacoustic tracking

As a biological alternative to conventional microbubble and droplet based ultrasound therapeutic agents, red blood cell (RBC) carriers have a potentially higher drug payload and extended circulation lifetime. RBC carriers, however, lack remote triggering for active release of payload. In this work we conjugate perfluoropentane (PFP) and perfluorobutane (PFB) nanodroplets (NDs) to RBC carriers and show ultrasound-triggered release of a model drug from carrier RBCs. With a fluorescence release assay, we achieve a release of 55.0 +/- 5.0% and 46.5 +/- 10.8% for RBC carriers with PFP or PFB NDs, respectively. We load magnetic nanoparticles for magnetic targeting and the FDA approved optically absorbing dye, indocyanine green (ICG), into RBCs (ICG-RBCs) for photoacoustic (PA) imaging. ICG-RBCs generated a 17 dB increase in PA signal over background and lysis of ICG-RBCs was confirmed by PA imaging. Our results demonstrate the acoustic release mechanism of RBC drug carriers, and the ability to monitor these agents in real-time.