Bi-modal confirmation of liposome delivery to the brain after focused ultrasound-induced blood-brain barrier opening

Focused ultrasound-mediated opening of the blood-brain barrier offers a great opportunity to deliver therapeutics into hard-to-treat brain tumors such as glioblastoma multiforme or diffuse midline glioma. However, the potential of the technique to offer a time window for efficient nanomedicine delivery has not been thoroughly studied. Non-invasive and targeted delivery of large drug-loaded nanocarriers, such as liposomes, could offer a safe and scalable method of personalized therapy for the treatment of brain pathologies. Additionally, it is essential to monitor the safety and efficacy of such treatments, tracking drug delivery in real-time through quantitative medical imaging. In this study, liposomes were modified to have an MRI contrast agent (i.e., Gd) in both lipid membrane and core, while an infrared dye (i.e., CW800) was coupled to lipids introduced in the lipid bilayer for bimodal detection and treatment verification. Targeted delivery of 110 nm-in-diameter liposomes to the brain was quantified using 9.4-T MRI and near infrared fluorescence imaging. The spatiotemporal distribution of liposomes <i>in vivo</i> was assessed up to 4 h post treatment using T₁ weighted MRI. <i>In vivo</i> MRI signal co-localized with NIRF signal from excised brains <i>ex vivo</i>. Passive acoustic detection during treatments revealed a correlation between acoustic signal and MRI contrast, providing a scalable metric for assessing clinical treatment efficacy in real-time. In conclusion, therapeutic ultrasound exposure can enhance delivery of large trackable nanoparticles into the brain, while enabling real-time treatment monitoring and verification.