Ye Dezhuang, Yuan Jinyun, Yue Yimei, Rubin Joshua B, Chen Hong
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
Pharmaceutics. 2021 Feb 1;13(2):190. doi: 10.3390/pharmaceutics13020190.
Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood-brain barrier (BBB). The objective of this study was to evaluate the capability of focused-ultrasound-mediated intranasal brain drug delivery (FUSIN) in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain. Both non-tumor mice and mice transcranially implanted with GL261 glioma cells at the brainstem were used in this study. aPD-L1 was labeled with a near-infrared fluorescence dye (IRDye 800CW) and administered to mice through the nasal route to the brain, followed by focused ultrasound sonication in the presence of systemically injected microbubbles. FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03- and 3.74-fold compared with intranasal (IN) administration alone in the non-tumor mice and glioma mice, respectively. Immunohistochemistry staining found that aPD-L1 was mainly located within the perivascular spaces after IN delivery, while FUSIN further enhanced the penetration depth and delivery efficiency of aPD-L1 to the brain parenchyma. The delivered aPD-L1 was found to be colocalized with the tumor cells after FUSIN delivery to the brainstem glioma. These findings suggest that FUSIN is a promising technique to enhance the delivery of immune checkpoint inhibitors to gliomas.
免疫检查点抑制剂在治疗胶质瘤方面具有巨大潜力；然而，它们的治疗效果部分受到无法有效穿过血脑屏障（BBB）的限制。本研究的目的是评估聚焦超声介导的鼻内脑药物递送（FUSIN）实现抗程序性细胞死亡配体1抗体（aPD-L1）在脑内局部增强递送的能力。本研究使用了非肿瘤小鼠和在脑干经颅植入GL261胶质瘤细胞的小鼠。aPD-L1用近红外荧光染料（IRDye 800CW）标记，并通过鼻内途径给药至小鼠脑内，随后在全身注射微泡的情况下进行聚焦超声照射。与非肿瘤小鼠和胶质瘤小鼠单纯鼻内（IN）给药相比，FUSIN分别使aPD-L1在FUS靶向的脑干处的蓄积平均增加了4.03倍和3.74倍。免疫组织化学染色发现，IN给药后aPD-L1主要位于血管周围间隙，而FUSIN进一步提高了aPD-L1向脑实质的渗透深度和递送效率。在将FUSIN递送至脑干胶质瘤后，发现递送的aPD-L1与肿瘤细胞共定位。这些发现表明，FUSIN是一种有前景的技术，可增强免疫检查点抑制剂向胶质瘤的递送。
