PET imaging for non-invasive monitoring of Zr-Talidox delivery to the brain following focused ultrasound-mediated blood-brain barrier opening.

The blood-brain barrier (BBB) significantly hinders the treatment of central nervous system (CNS) disorders and brain tumors with intact BBB by restricting the entry of most therapeutic agents, including small-molecule drugs and particularly larger macromolecules. Liposomal formulations, such as PEGylated liposomes with long blood half-lives, high drug-carrying capacity, and reduced off-site toxicity, can be useful for brain drug delivery, but their large size often limits BBB penetration. A novel liposomal doxorubicin formulation(Talidox®) with a smaller size (~36 nm, determined by TEM), increased blood circulation half-life (median reported half-life 96 h), and better stability than previous clinical formulations, can be a suitable choice for brain delivery. This study investigated Talidox® delivery to the brain through focused ultrasound (FUS) and microbubble-mediated BBB transient opening. Radiolabelling of Talidox® via intraliposomal Zr enabled Positron Emission Tomography (PET) imaging for whole-body non-invasive, real-time monitoring of biodistribution and pharmacokinetics. Following FUS and microbubble-mediated BBB opening in mice, PET imaging revealed a significant increase in brain uptake compared to non-FUS controls, achieving a 14-fold higher accumulation. Additional validation using passive acoustic detection, microscopy, autoradiography, and cryo-fluorescence tomography demonstrated successful brain distribution that correlated with PET imaging results. These findings underscore the potential of combining Talidox® with FUS for effective, non-invasive drug delivery to the brain and highlight the advantages of PET imaging as a modality for non-invasive, longitudinal quantification of drug delivery to the brain.