Abstract
Serotonin plays a pivotal role in the pathophysiology of major depressive disorder, with a deficiency therein being a hallmark of the condition. However, the efficacies of conventional treatments for depression involving the regulation of serotonin are limited by delayed onset, high drug dosing, and requirement for daily administration due to the obstacle of the blood-brain barrier. This study investigated an innovative approach that combines focused ultrasound (FUS) with escitalopram-loaded liposomes (Esc-lip) tethered to microbubbles (Esc-MBs) for targeted drug delivery to the serotonin-transporter-rich hippocampus. This approach elevates the serotonin level rapidly and sustainably with minimal drug doses and repeated treatments. Esc-MBs were synthesized by encapsulating escitalopram within biotinylated liposomes conjugated to MBs' outer surface. The results demonstrated that exposing Esc-MBs to FUS at 1 MHz and 600 kPa for 160 cycles and 1800 s induced the transient release of free Esc and Esc-lip, resulted in the local accumulation of escitalopram in the hippocampus of a chronic unpredictable mild stress model of depression. After Esc-MBs with FUS treatment, the intracerebral levels of escitalopram and serotonin immediately elevated 32.2-fold and 1.1-fold, respectively, higher than for oral administration, and these levels remained high at 144 h after the treatment. We have also demonstrated that the proposed Esc-MBs with FUS treatment strategy can ameliorate depression-like behaviors in an animal model of depression, achieving therapeutic outcomes comparable to those for the oral administration of escitalopram. These results highlight the potential of this strategy for addressing critical unmet needs in depression therapy.