Although blood-based liquid biopsies have emerged as a promising non-invasive method to detect biomarkers in various cancers, limited progress has been made for brain tumors. One major obstacle is the blood-brain barrier (BBB), which hinders efficient passage of tumor biomarkers into the peripheral circulation. The objective of this study was to determine whether FUS in combination with microbubbles can enhance the release of biomarkers from the brain tumor to the blood circulation. Two glioblastoma tumor models (U87 and GL261), developed by intracranial injection of respective enhanced green fluorescent protein (eGFP)-transduced glioblastoma cells, were treated by FUS in the presence of systemically injected microbubbles. Effect of FUS on plasma eGFP mRNA levels was determined using quantitative polymerase chain reaction. eGFP mRNA were only detectable in the FUS-treated U87 mice and undetectable in the untreated U87 mice (maximum cycle number set to 40). This finding was replicated in GL261 mice across three different acoustic pressures. The circulating levels of eGFP mRNA were 1,500–4,800 fold higher in the FUS-treated GL261 mice than that of the untreated mice for the three acoustic pressures. This study demonstrated the feasibility of FUS-enabled brain tumor liquid biopsies in two different murine glioma models across different acoustic pressures.

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Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered Cu-alloyed AuNCs (Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the Cu-AuNCs. Second,Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. Cu-AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution ofCu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery ofCu-AuNCs and TR-AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure.

Background: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain.Objective: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and celltype-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. Methods: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. Results: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. Conclusions: This noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

The goal of this study was to establish the feasibility of integrating focused ultrasound (FUS)-mediated delivery of Cu-integrated gold nanoclusters (Cu-AuNCs) to the pons for in vivo quantification of the nanocluster brain uptake using positron emission tomography (PET) imaging. FUS was targeted at the pons for the blood-brain barrier (BBB) disruption in the presence of systemically injected microbubbles, followed by the intravenous injection of Cu-AuNCs. The spatiotemporal distribution of theCu-AuNCs in the brain was quantified using in vivo microPET/CT imaging at different time points post injection. Following PET imaging, the accumulation of radioactivity in the pons was further confirmed using autoradiography and gamma counting, and the gold concentration was quantified using inductively coupled plasma-mass spectrometry (ICP-MS). We found that the noninvasive and localized BBB opening by the FUS successfully delivered the Cu-AuNCs to the pons. We also demonstrated that in vivo real-time microPET/CT imaging was a reliable method for monitoring and quantifying the brain uptake ofCu-AuNCs delivered by the FUS. This drug delivery platform that integrates FUS, radiolabeled nanoclusters, and PET imaging provides a new strategy for noninvasive and localized nanoparticle delivery to the pons with concurrent in vivo quantitative imaging to evaluate delivery efficiency. The long-term goal is to apply this drug delivery platform to the treatment of pontine gliomas.

Although blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers. We previously demonstrated focused ultrasound-enabled liquid biopsy (FUS-LBx) that uses FUS to increase BBB permeability in murine glioblastoma models and thus enhance the release of tumor-specific biomarkers into the bloodstream. The objective of this study was to evaluate the feasibility and safety of FUS-LBx in the normal brain tissue of a porcine model. Increased BBB permeability was confirmed by the significant increase (p = 0.0053) in K trans (the transfer coefficient from blood to brain extravascular extracellular space) when comparing the FUS-sonicated brain area with the contralateral non-sonicated area. Meanwhile, there was a significant increase in the blood concentrations of glial fibrillary acidic protein (GFAP, p = 0.0074) and myelin basic protein (MBP, p = 0.0039) after FUS sonication as compared with before FUS. There was no detectable tissue damage by t 2 *-weighted MRi and histological analysis. findings from this study suggest that FUS-LBx is a promising technique for noninvasive and localized diagnosis of the molecular profiles of brain diseases with the potential to translate to the clinic. Tissue biopsy has been used to characterize and track the tumor molecular landscape. However, tissue biopsy for brain tumor diagnosis requires invasive surgical procedures, which carry a 5-7% risk of major morbidity 1. It may not be possible at all to perform this procedure on medically inoperable patients or patients with tumors in surgically inaccessible locations. Repeated tissue biopsies to assess treatment response and cancer recurrence are often not feasible given the increased risk for complications and morbidity. These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches. Liquid biopsy (LBx), which refers to the detection of tumor-derived components in body fluids (e.g., blood, urine, saliva, ascitic fluid, cerebrospinal fluid, etc.), has been gaining enormous attention in both medical research and clinical applications 2,3. Various substances from liquid biopsies have been found to be closely related to the stage of a tumor and might serve as biomarkers for cancer diagnosis and prognosis, such as circulating tumor cells, circulating tumor DNAs, RNAs, extracellular vesicles, and a series of cancer-related proteins 4. Blood-based LBx enables physicians to noninvasively interrogate the dynamic evolution of a tumor and monitor a patient's response to therapies through a simple blood test. Blood-based LBx-guided personalized therapy has already entered clinical practice in the management of several cancers. An import...

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