Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model

被引:3
作者
Fadera, Siaka [1 ]
Chukwu, Chinwendu [1 ]
Stark, Andrew H. [1 ]
Yue, Yimei [1 ]
Xu, Lu [1 ]
Chien, Chih-Yen [1 ]
Yuan, Jinyun [1 ]
Chen, Hong [1 ,2 ]
机构
[1] Washington Univ St Louis, Dept Biomed Engn, St Louis, MO 63130 USA
[2] Washington Univ, Sch Med, Dept Neurosurg, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
focused ultrasound; immunotherapy; immune checkpoint inhibitors; blood-brain barrier; brain drug delivery; CHECKPOINT; BARRIER;
D O I
10.3390/pharmaceutics15102479
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by leveraging the body's immune system to combat cancer cells. However, its effectiveness in brain cancer is hindered by the blood-brain barrier (BBB), impeding the delivery of ICIs to brain tumor cells. This study aimed to assess the safety and feasibility of using focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) to facilitate trans-BBB delivery of an ICI, anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain of a large animal model. In a porcine model, FUS sonication of targeted brain regions was performed after intravenous microbubble injection, which was followed by intravenous administration of aPD-L1 labeled with a near-infrared fluorescent dye. The permeability of the BBB was evaluated using contrast-enhanced MRI in vivo, while fluorescence imaging and histological analysis were conducted on ex vivo pig brains. Results showed a significant 4.8-fold increase in MRI contrast-enhancement volume in FUS-targeted regions compared to nontargeted regions. FUS sonication enhanced aPD-L1 delivery by an average of 2.1-fold, according to fluorescence imaging. In vivo MRI and ex vivo staining revealed that the procedure did not cause significant acute tissue damage. These findings demonstrate that FUS-BBBO offers a noninvasive, localized, and safe delivery approach for ICI delivery in a large animal model, showcasing its potential for clinical translation.
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页数:10
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