Fadera Siaka, Chukwu Chinwendu, Stark Andrew H, Yue Yimei, Xu Lu, Chien Chih-Yen, Yuan Jinyun, Chen Hong
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Pharmaceutics. 2023 Oct 17;15(10):2479. doi: 10.3390/pharmaceutics15102479.
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.
免疫检查点抑制剂（ICI）疗法通过利用人体免疫系统对抗癌细胞，彻底改变了癌症治疗方式。然而，其在脑癌治疗中的有效性受到血脑屏障（BBB）的阻碍，阻碍了ICI向脑肿瘤细胞的递送。本研究旨在评估使用聚焦超声联合微泡介导的血脑屏障开放（FUS-BBBO）促进ICI抗程序性细胞死亡配体1抗体（aPD-L1）向大型动物模型脑部跨血脑屏障递送的安全性和可行性。在猪模型中，静脉注射微泡后对靶向脑区进行FUS超声处理，随后静脉注射用近红外荧光染料标记的aPD-L1。使用体内对比增强MRI评估血脑屏障的通透性，同时对离体猪脑进行荧光成像和组织学分析。结果显示，与非靶向区域相比，FUS靶向区域的MRI对比增强体积显著增加了4.8倍。根据荧光成像，FUS超声处理使aPD-L1的递送平均提高了2.1倍。体内MRI和离体染色显示该过程未造成明显的急性组织损伤。这些发现表明，FUS-BBBO为大型动物模型中ICI的递送提供了一种非侵入性、局部化且安全的递送方法，展示了其临床转化的潜力。
