Focused Ultrasound-Enhanced Delivery of Intranasally Administered Anti-Programmed Cell Death-Ligand 1 Antibody to an Intracranial Murine Glioma Model

Abstract

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.

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

“…Even if promising, this groundwork on nose-to-brain delivery still exposes mAb to the cellular and extracellular barriers of the nasal mucosa (see Section 2). Lately, a combination of brain-focused ultrasound and intranasal drug administration was found to enhance the delivery of antibodies to gliomas in mice ( Ye, Yuan, Yue, Rubin, & Chen, 2021 ). Ferreira and her colleagues also showed that nanoparticles coated with a mAb targeting EGFR were successfully delivered to glioblastoma following intranasal administration ( Ferreira et al, 2021 ).…”

Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy

“…UTMD can increase antigen release, heat shock protein expression, calreticulin levels and pro-phagocytic signals, affecting the tumor microenvironment and comprehensively stimulating tumor immunity (85,86). In a study by Ye et al (21), the authors evaluated the ability of UTMD to enhance the targeted accumulation of aPD-L1 in the brain stem. They used UTMD to deliver the study drug to a brain of a mouse glioma model via the intranasal route.…”

Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy

“…Strategies that can improve antigen presentation and immune recognition, reinforce the activity and infiltration of CD8 T cells, and reduce immunosuppression can potentially be combined with ICIs to improve the efficacy of ICI therapy [27]. Meanwhile, novel drug delivery strategies that enable the targeted delivery of ICIs within the TME have the potential to reduce the toxicities associated with ICIs [29,30].…”