期刊
PHARMACEUTICS
卷 13, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13020190
关键词
focused ultrasound; intranasal delivery; brain drug delivery; immune checkpoint inhibitor; blood-brain barrier; brainstem glioma
资金
- National Institutes of Health (NIH) [R01EB027223, R01EB030102, R01MH116981]
- Charlie Teo Foundation
- Little Legs Foundation
The study demonstrated that FUSIN technique could effectively enhance the delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain, providing a potential approach to improve the therapeutic efficacy of immune checkpoint inhibitors for gliomas.
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.
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