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bioRxiv · 10.1101/2025.06.16.659954

PET imaging for non-invasive monitoring of 89Zr-Talidox delivery to the brain following focused ultrasound-mediated blood-brain barrier opening

Mishra, A.·Payne, C.·Carrascal-Minino, A.·Halbherr, S.·Pouliopoulos, A.·de Rosales, R. T. M.
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Abstract

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(R), with a smaller size ([~]36 nm), increased blood circulation half-life, and better stability than previous clinical formulations, can be a suitable choice for brain delivery. This study investigated Talidox(R) delivery to the brain through focused ultrasound (FUS)-mediated BBB transient opening. Radiolabelling of Talidox(R) via intraliposomal 89Zr enabled Positron Emission Tomography (PET) imaging for whole-body non-invasive, real-time monitoring of biodistribution and pharmacokinetics. Following FUS-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(R) 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.

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Mishra, A., Payne, C., Carrascal-Minino, A., Halbherr, S., Pouliopoulos, A., de Rosales, R. T. M.. 2025-06-19. PET imaging for non-invasive monitoring of 89Zr-Talidox delivery to the brain following focused ultrasound-mediated blood-brain barrier opening. https://doi.org/10.1101/2025.06.16.659954

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