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Intranasal delivery provides non-invasive delivery of drugs from the nose to the brain bypassing the blood-brain barrier (BBB). We previously reported the focused ultrasound (FUS)-mediated intranasal delivery (FUSIN) of various agents in mice using FUS. However, no study has investigated the feasibility of FUSIN in large animals. The objective of this study was to investigate the feasibility of MR-guided FUS-mediated intranasal delivery in a large animal model. Pigs were used as the large animal model due to their clinical relevance to humans. Fluorescence-labeled albumin was mixed with an MRI contrast agent and administrated intranasally to the pig using a catheter. Followed by intravenous injection of microbubbles, FUS sonication was performed at two brain regions, the cortex and brainstem. T1-weighted MR images showed enhancement of MRI contrast agent at the olfactory region of the pig nose. Fluorescence imaging displayed enhanced fluorescence intensity at the FUS-targeted brain regions. These findings suggest that MR-guided FUS can achieve noninvasive and localized delivery of intranasally administered agents to the brain in large animals.

The glymphatic system, a perivascular network in the brain, regulates the exchange of cerebrospinal fluid and interstitial fluid in the perivascular space. Focused ultrasound combined with microbubbles (FUSMB) has been recently shown feasible to manipulate the glymphatic transportation by enhancing the intranasal delivery of agents in the perivascular space. The objective of this study was to reveal the dynamics of FUSMB-enhanced agent transport in the glymphatic system. A ring-shaped FUS transducer was confocally aligned with an objective of a two-photon microscope (2PM). Fluorescently labeled albumin was administered to the mouse nose, where it transported along olfactory nerve and trigeminal nerve from nose to brain and then spread in perivascular space in the brain. FUS sonication was performed after intravenous injection of microbubbles. In vivo 2PM recorded the dynamics of agent transportation before, during, and after FUS sonication. Time-lapse recording showed that FUSMB enhanced the agent accumulation at the perivascular space. FUS significantly increased the accumulation of the agent in the perivascular space by 1.2-folds immediately after the sonication (p = 0.0325), and 1.6-folds at 5 min after the sonication (p

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.

The static magnetic field of an MRI scanner was found to dampen the microbubble cavitation activity and decrease the focused ultrasound-combined with microbubble-mediated blood-brain barrier opening.

Cavitation is widely existing in focused ultrasound (FUS)-mediated therapies in the brain, such as FUS in combination with microbubble-induced blood-brain barrier disruption, nonthermal ablation, as well as transcranial histotripsy therapy. Accurately knowing the 3-D location of cavitation in real time can improve the treatment targeting accuracy and avoid off-target tissue damage. However, the skull induces strong phase and amplitude aberration to the cavitation signals and presents a significant challenge to the transcranial cavitation localization. Existing techniques for 3-D cavitation localization use hemispherical multi-element arrays combined with passive beamforming and adaptive skull-specific correction algorithm. However, these techniques require expensive equipment and treatment planning. Their time-consuming computations limit applications in real-time cavitation monitoring, which is critically needed to ensure the safety and efficacy of the FUS treatment. The object of this study was to investigate the feasibility of using a four-sensor network to transcranially locate the cavitation source in 3-D by time difference of arrival algorithm. The positional error of transcranial cavitation localization with the human skull along x, y, and z axes were 1.7 ± 1.2 mm, 1.6 ± 1.7 mm, and 4.1 ± 1.5 mm, respectively. For comparison, the positional error of without the human skull were 1.2 ± 1.8 mm, 0.9 ± 1.6 mm, and 3.1 ± 2.3 mm, respectively.

Intranasal route provides therapeutics direct access to the brain through the nose-to-brain pathway, bypassing the BBB and minimizing systemic exposure. However, nasal delivery is limited by its low delivery efficiency and non-localized delivery. Focused ultrasound-enhanced intranasal (FUSIN) delivery is a new technique for noninvasive and localized delivery of therapeutic agents to the brain. Previous studies have shown its feasibility in the delivery of dextrans and brain-derived neurotrophic factor to the brain. The goal of this study was to demonstrate the application of FUSIN for the delivery of temozolomide (TMZ), a first-line drug for treating glioma tumors, for the treatment of glioblastoma in an orthotopic mouse model. U87 glioblastoma cells were trancranially implanted to nude mice. The tumor mice were divided into four groups: (1) FUSIN + TMZ (n = 7); (2) IN TMZ (n = 6); (3) Oral TMZ (n = 6); and (4) IN vehicle (n = 6), and were treated once each week for 4 weeks. Mice were weighed once a week. A body weight loss reaching 20% was selected as the endpoint criteria for the study. Mice in FUSIN group showed statistically significant higher survival rate when compared with mice in all other groups. This pilot study suggested that FUSIN can potentially be an effective technique for the treatment of brain diseases.Intranasal route provides therapeutics direct access to the brain through the nose-to-brain pathway, bypassing the BBB and minimizing systemic exposure. However, nasal delivery is limited by its low delivery efficiency and non-localized delivery. Focused ultrasound-enhanced intranasal (FUSIN) delivery is a new technique for noninvasive and localized delivery of therapeutic agents to the brain. Previous studies have shown its feasibility in the delivery of dextrans and brain-derived neurotrophic factor to the brain. The goal of this study was to demonstrate the application of FUSIN for the delivery of temozolomide (TMZ), a first-line drug for treating glioma tumors, for the treatment of glioblastoma in an orthotopic mouse model. U87 glioblastoma cells were trancranially implanted to nude mice. The tumor mice were divided into four groups: (1) FUSIN + TMZ (n = 7); (2) IN TMZ (n = 6); (3) Oral TMZ (n = 6); and (4) IN vehicle (n = 6), and were treated once each week for 4 weeks. Mice were weighed once a week....

Nanomedicine is the next-generation technology for cancer therapy. Liposomes are one of such nanomedicine that have well-established clinical applications. However, their large sizes make it challenging to deliver them to the brain due to the existence of the blood-brain barrier (BBB). Previous studies have demonstrated the potential of integrating focused ultrasound (FUS)-induced BBB opening with liposomes for brain drug delivery. However, no study has characterized the spatial distributions of the liposomes and released drugs in the brain parenchyma at a microscopic level after the BBB was disrupted by the FUS. In this study, we manufactured liposomes with a fluorescent dye embedded in the lipid layer and chemotherapeutic drug doxorubicin encapsulated in the core. These liposomes were intravenously injected into the mouse followed by FUS sonication of a targeted brain location in the presence of microbubbles. The mouse brains were coronally sectioned and imaged using fluorescence microscopy. Preliminary results confirmed the successful delivery of doxorubicin to the brain. However, the liposome distribution as indicated by the dye embedded in the lipid shell was not spatially correlated with the distribution of the doxorubicin. Further studies are needed to better understand the mechanism of FUS-enabled liposome delivery.Nanomedicine is the next-generation technology for cancer therapy. Liposomes are one of such nanomedicine that have well-established clinical applications. However, their large sizes make it challenging to deliver them to the brain due to the existence of the blood-brain barrier (BBB). Previous studies have demonstrated the potential of integrating focused ultrasound (FUS)-induced BBB opening with liposomes for brain drug delivery. However, no study has characterized the spatial distributions of the liposomes and released drugs in the brain parenchyma at a microscopic level after the BBB was disrupted by the FUS. In this study, we manufactured liposomes with a fluorescent dye embedded in the lipid layer and chemotherapeutic drug doxorubicin encapsulated in the core. These liposomes were intravenously injected into the mouse followed by FUS sonication of a targeted brain location in the presence of microbubbles. The mouse brains were coronally sectioned and imaged using fluorescence microscopy. Preliminary...