Comparing the delivery of free and liposomal-encapsulated doxorubicin across the blood-brain barrier with microbubble-mediated focused ultrasound

This work investigates the effect of drug formulation (free, small molecule drug or liposomal-encapsulated nanoparticle) on Focused Ultrasound (FUS) and microbubble-mediated delivery of doxorubicin (Dox) across the blood-brain barrier (BBB) in healthy and F98 tumor-bearing rats. Dox is auto-fluorescent (Ex: 470 nm; Em: 560 nm). 1, 4, and 24 h after FUS and the administration of Dox, brain samples were collected and homogenized, and the concentration of Dox was measured using a fluorometer. In healthy brains, at 1, 4 and 24 h, FUS significantly increased the delivery of both formulations (p<0.05). At 1 h, the mean concentration of Dox was 47% more in the striatum (p = 0.010) and 51% more in the hippocampus (n.s.; p = 0.072) compared to Lipo Dox. No differences in Dox versus Lipo Dox delivery were observed at 4 and 24 h. In F98 tumors, at 1 and 24 h, FUS significantly increased the concentrations of both formulations (p<0.05). No significant difference was observed in the concentrations of Dox and Lipo Dox at 1 h (p = 0.291). However, at 24 h, 96% higher drug concentrations were measured in tumors in animals that received Lipo Dox compared to Dox (p = 0.045). The results of this study may have important implications for drug selection in clinical applications of FUS-mediated BBB opening.