Ddel-11. focused ultrasound-mediated delivery of anti-programmed cell death-ligand 1 antibody to the brain of a porcine model

Abstract Focused ultrasound-combined with microbubble-mediated blood-brain barrier opening (FUS-BBBO) has been established as a promising brain drug delivery technology for the treatment of brain tumors. Immune checkpoint inhibitor therapy is a form of cancer immunotherapy that has revolutionized the treatment of cancer and shown remarkable efficacy in a range of cancers. Previous studies reported successful delivery of a checkpoint inhibitor anti-PD-L1 antibody (aPD-L1) by FUS-BBBO in the mouse brain. The objective of this study was to evaluate the feasibility and safety of FUS-BBBO in the delivery of aDP-L1 to the brain of a large animal model. Pigs (4 weeks old, male, n=3) were used as the large animal model. A FUS transducer (frequency of 650 kHz, aperture of 65 mm, and a focal length of 65 mm) was used to sonicate three different brain regions in the presence of systemically injected microbubbles (Definity) for every pig. Near-infrared fluorescent dye-labeled aPD-L1 was injected intravenously to the pig after FUS sonication. Contrast-enhanced MRI was conducted to evaluate the BBB permeability. Pig brains were then harvested and imaged by the Licor Pear imaging system. Successful BBBO was confirmed by in vivo T1-weighted MR imaging. The average MR contrast enhancement volume in the FUS-targeted regions was 4.8× of that in the contralateral non-targeted regions. Ex vivo fluorescence imaging found that FUS sonication enhanced aPD-L1 delivery by 2.1× compared with the non-targeted regions. Histological analysis by hematoxylin and eosin (H&E) staining did not find evidence for tissue damage. These findings suggest that FUS-BBBO can achieve noninvasive, localized, and safe delivery of aPD-L1 to the brain of large animals, providing strong preclinical data to support the clinical translation of this promising technique for brain cancer immunotherapy.