Comparing the Delivery of Free and Liposomal Doxorubicin Across the Blood-Brain Barrier Following Microbubble-Mediated Focused Ultrasound.

Abstract

OBJECTIVE: Microbubble-mediated Focused Ultrasound (FUS) allows targeted therapeutic delivery across the Blood-Brain Barrier (BBB) and Blood-Tumor Barrier (BTB). This study aimed to investigate the effect of drug formulation on FUS-mediated delivery using free doxorubicin (freeDox) and liposomal doxorubicin (lipoDox). METHODS: FUS (274.3 kHz) was used to disrupt the BBB/BTB in healthy and F98 tumor-bearing rats. At 1, 4, and 24 h after FUS and doxorubicin administration, brain samples were collected and homogenized, and doxorubicin autofluorescence (excitation: 470 nm, emission: 560 nm) was quantified. RESULTS: In healthy brains, at 1, 4 and 24 h, FUS significantly increased the delivery of both formulations compared to the contralateral hemisphere (p < 0.05). At 1 hr post-FUS, mean concentrations of freeDox were 42% more in the striatum (p = 0.010) and 51% more in the hippocampus (n.s.; p = 0.072) compared to lipoDox. No post-FUS differences between freeDox and lipoDox were observed at 4 and 24 h. In tumors, at 1 and 24 h, FUS significantly increased the concentrations of both formulations compared to untreated tumors (p < 0.05). No significant difference was observed between post-FUS freeDox and lipoDox in tumors (p = 0.291) at 1 h. However, at 24 h, 113% higher drug concentrations were measured with lipoDox compared to freeDox (p = 0.018). CONCLUSIONS: The results of this study show that lipoDox can yield either equivalent (healthy brain) or superior (tumors) doxorubicin delivery compared to freeDox after FUS-mediated BBB opening. This may have important implications for drug selection in clinical applications.