The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia.

Blood-brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia-ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model.

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell-cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a - 53% versus - 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Blood-Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of human brain tumors. Dismantling the suppressed immune microenvironment is an effective therapeutic strategy against GBM; however, GBM does not respond to exogenous immunotherapeutic agents due to low immunogenicity. Manipulating the mitochondrial electron transport chain (ETC) elevates the immunogenicity of GBM, rendering previously immune-evasive tumors highly susceptible to immune surveillance, thereby enhancing tumor immune responsiveness and subsequently activating both innate and adaptive immunity. Here, we report a nanomedicine-based immunotherapeutic approach that targets the mitochondria in GBM cells by utilizing a Trojan-inspired nanovector (ABBPN) that can cross the blood-brain barrier. We propose that the synthetic photosensitizer IrPS can alter mitochondrial electron flow and concurrently interfere with mitochondrial antioxidative mechanisms by delivering si-OGG1 to GBM cells. Our synthesized ABBPN coloaded with IrPS and si-OGG1 (ISA) disrupts mitochondrial electron flow, which inhibits ATP production and induces mitochondrial DNA oxidation, thereby recruiting immune cells and endogenously activating intracranial antitumor immune responses. The results of our study indicate that strategies targeting the mitochondrial ETC have the potential to treat tumors with limited immunogenicity.

Targeting blood-brain barrier for sepsis-associated encephalopathy: Regulation of immune cells and ncRNAs.

Sepsis causes significant morbidity and mortality worldwide, most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). SAE involves many pathological processes, including the blood-brain barrier (BBB) damage. The BBB is located at the interface between the central nervous system and the surrounding environment, which protects the central nervous system (CNS) from the invasion of exogenous molecules, harmful substances or microorganisms in the blood. Recently, a growing number of studies have indicated that the BBB destruction was involved in SAE and played an important role in SAE-induced brain injury. In the present review, we firstly reveal the pathological processes of SAE such as the neurotransmitter disorders, oxidative stress, immune dysfunction and BBB destruction. Moreover, we introduce the structure of BBB, and describe the immune cells including microglia and astrocytes that participate in the BBB destruction after SAE. Furthermore, in view of the current research on non-coding RNAs (ncRNAs), we explain the regulatory mechanism of ncRNAs including long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) on BBB in the processes of SAE. Finally, we propose some challenges and perspectives of regulating BBB functions in SAE. Hence, on the basis of these effects, both immune cells and ncRNAs may be developed as therapeutic targets to protect BBB for SAE patients.

Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol.

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Blood-Brain Barrier Disruption for the Treatment of Primary Brain Tumors: Advances in the Past Half-Decade.

PURPOSE OF REVIEW: To review relevant advances in the past half-decade in the treatment of primary brain tumors via modification of blood-brain barrier (BBB) permeability. RECENT FINDINGS: BBB disruption is becoming increasingly common in the treatment of primary brain tumors. Use of mannitol in BBB disruption for targeted delivery of chemotherapeutics via superselective intra-arterial cerebral infusion (SIACI) is the most utilized strategy to modify the BBB. Mannitol is used in conjunction with chemotherapeutics, oligonucleotides, and other active agents. Convection-enhanced delivery has become an attractive option for therapeutic delivery while bypassing the BBB. Other technologic innovations include laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) which have emerged as prime modalities to directly target tumors and cause significant local BBB disruption. In the past 5 years, interest has significantly increased in studying modalities to disrupt the BBB in primary brain tumors to enhance treatment responses and improve clinical outcomes.

Development of Ru-polypyridyl complexes for real-time monitoring of Aß oligomers and inhibition of Aß fibril formation.

The aggregation of amyloid-ß (Aß) is one of the important pathological markers of Alzheimer's disease. Ruthenium(II) complexes have good stability, low cytotoxicity, a high fluorescence quantum yield, and a good Stokes shift as fluorescent probes. Based on this, we constructed a fluorescent probe for in vivo real-time imaging and inhibition of Aß-fibril formation using a complex of Ru polypyridine with organic fluorophores (N,N-dimethylaniline) and hydrophobic peptides (KLVFF). DLS and TEM studies have shown that Ru-YH has an inhibitory effect on the fibrotic aggregation of Aß. Both in vivo and in vitro studies have shown that Ru-WJ and Ru-YH can quickly cross the blood-brain barrier and successfully detect Aß in early (2.5-month old) transgenic mouse models. In summary, we have explored the potential of Ru complex based biological probes for early diagnosis and inhibition of AD.

Angiopep-2-Functionalized Lipid Cubosomes for Blood-Brain Barrier Crossing and Glioblastoma Treatment.

Glioblastoma multiforme (GBM) is an aggressive brain cancer with high malignancy and resistance to conventional treatments, resulting in a bleak prognosis. Nanoparticles offer a way to cross the blood-brain barrier (BBB) and deliver precise therapies to tumor sites with reduced side effects. In this study, we developed angiopep-2 (Ang2)-functionalized lipid cubosomes loaded with cisplatin (CDDP) and temozolomide (TMZ) for crossing the BBB and providing targeted glioblastoma therapy. Developed lipid cubosomes showed a particle size of around 300 nm and possessed an internal ordered inverse primitive cubic phase, a high conjugation efficiency of Ang2 to the particle surface, and an encapsulation efficiency of more than 70% of CDDP and TMZ. In vitro models, including BBB hCMEC/D3 cell tight monolayer, 3D BBB cell spheroid, and microfluidic BBB/GBM-on-a-chip models with cocultured BBB and glioblastoma cells, were employed to study the efficiency of the developed cubosomes to cross the BBB and showed that Ang2-functionalized cubosomes can penetrate the BBB more effectively. Furthermore, Ang2-functionalized cubosomes showed significantly higher uptake by U87 glioblastoma cells, with a 3-fold increase observed in the BBB/GBM-on-a-chip model as compared to that of the bare cubosomes. Additionally, the in vivo biodistribution showed that Ang2 modification could significantly enhance the brain accumulation of cubosomes in comparison to that of non-functionalized particles. Moreover, CDDP-loaded Ang2-functionalized cubosomes presented an enhanced toxic effect on U87 spheroids. These findings suggest that the developed Ang2-cubosomes are prospective for improved BBB crossing and enhanced delivery of therapeutics to glioblastoma and are worth pursuing further as a potential application of nanomedicine for GBM treatment.

Disruption of the Mouse Blood-Brain Barrier by Small Extracellular Vesicles from Hypoxic Human Placentas.

Cerebrovascular complications, including cerebral edema and ischemic and hemorrhagic stroke, constitute the leading cause of maternal mortality associated with preeclampsia. The underlying mechanisms of these cerebrovascular complications remain unclear. However, they are linked to placental dysfunction and blood-brain barrier (BBB) disruption. Nevertheless, the connection between these two distant organs is still being determined. Increasing evidence suggests that the placenta releases signaling molecules, including extracellular vesicles, into maternal circulation. Extracellular vesicles are categorized according to their size, with small extracellular vesicles (sEVs smaller than 200 nm in diameter) considered critical signaling particles in both physiological and pathological conditions. In preeclampsia, there is an increased number of circulating sEVs in maternal circulation, the signaling function of which is not well understood. Placental sEVs released in preeclampsia or from normal pregnancy placentas exposed to hypoxia induce brain endothelial dysfunction and disruption of the BBB. In this protocol, we assess whether sEVs isolated from placental explants cultured under hypoxic conditions (modeling one aspect of preeclampsia) disrupt the BBB in vivo.

Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial.

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.

Exploring adjunctive therapies for cerebral malaria.

Cerebral malaria (CM) is one of the most severe complications of malaria infection characterized by coma and neurological effects. Despite standardized treatment of malaria infection with artemisinin-based combination therapies (ACT), the mortality rate is still high, and it primarily affects pediatric patients. ACT reduces parasitemia but fails to adequately target the pathogenic mechanisms underlying CM, including blood-brain-barrier (BBB) disruption, endothelial activation/dysfunction, and hyperinflammation. The need for adjunctive therapies to specifically treat this form of severe malaria is critical as hundreds of thousands of people continue to die each year from this disease. Here we present a summary of some potential promising therapeutic targets and treatments for CM, as well as some that have been tested and deemed ineffective or, in some cases, even deleterious. Further exploration into these therapeutic agents is warranted to assess the effectiveness of these potential treatments for CM patients.

The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications.

Degenerative diseases, encompassing a wide range of conditions affecting various organ systems, pose significant challenges to global healthcare systems. This comprehensive review explores the intricate interplay between the vascular system and degenerative diseases, shedding light on the underlying mechanisms and profound implications for disease progression and management. The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denominator of degenerative diseases across multiple systems. In the nervous system, we explored the influence of vascular factors on neurodegenerative diseases such as Alzheimer's and Parkinson's, emphasizing the critical role of cerebral blood flow regulation and the blood-brain barrier. Within the kidney system, the intricate relationship between vascular health and chronic kidney disease is scrutinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding vascular involvement in degenerative diseases and potential therapeutic interventions targeting vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a profound appreciation of the role of the vascular system in degenerative diseases is essential for advancing our understanding of degenerative disease pathogenesis and developing innovative approaches for prevention and treatment. This review provides a comprehensive foundation for researchers, clinicians, and policymakers seeking to address the intricate relationship between vascular health and degenerative diseases in pursuit of improved patient outcomes and enhanced public health.

The contribution of ß-amyloid, Tau and α-synuclein to blood-brain barrier damage in neurodegenerative disorders.

Central nervous system (CNS) accumulation of fibrillary deposits made of Amyloid ß (Aß), hyperphosphorylated Tau or α-synuclein (α-syn), present either alone or in the form of mixed pathology, characterizes the most common neurodegenerative diseases (NDDs) as well as the aging brain. Compelling evidence supports that acute neurological disorders, such as traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition of toxic Aß, Tau and α-syn species. While the contribution of these pathological proteins to neurodegeneration has been experimentally ascertained, the cellular and molecular mechanisms driving Aß, Tau and α-syn-related brain damage remain to be fully clarified. In the last few years, studies have shown that Aß, Tau and α-syn may contribute to neurodegeneration also by inducing and/or promoting blood-brain barrier (BBB) disruption. These pathological proteins can affect BBB integrity either directly by affecting key BBB components such as pericytes and endothelial cells (ECs) or indirectly, by promoting brain macrophages activation and dysfunction. Here, we summarize and critically discuss key findings showing how Aß, Tau and α-syn can contribute to BBB damage in most common NDDs, TBI and stroke. We also highlight the need for a deeper characterization of the role of these pathological proteins in the activation and dysfunction of brain macrophages, pericytes and ECs to improve diagnosis and treatment of acute and chronic neurological disorders.

Neuroinflammation, blood-brain barrier dysfunction, hippocampal atrophy and delayed neurodevelopment: Contributions for a rat model of congenital Zika syndrome.

The congenital Zika syndrome (CZS) has been characterized as a set of several brain changes, such as reduced brain volume and subcortical calcifications, in addition to cognitive deficits. Microcephaly is one of the possible complications found in newborns exposed to Zika virus (ZIKV) during pregnancy, although it is an impacting clinical sign. This study aimed to investigate the consequences of a model of congenital ZIKV infection by evaluating the histopathology, blood-brain barrier, and neuroinflammation in pup rats 24 h after birth, and neurodevelopment of the offspring. Pregnant rats were inoculated subcutaneously with ZIKV-BR at the dose 1 × 107 plaque-forming unit (PFU mL-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). A set of pups, 24 h after birth, was euthanized. The brain was collected and later evaluated for the histopathology of brain structures through histological analysis. Additionally, analyses of the blood-brain barrier were conducted using western blotting, and neuroinflammation was assessed using ELISA. Another set of animals was evaluated on postnatal days 3, 6, 9, and 12 for neurodevelopment by observing the developmental milestones. Our results revealed hippocampal atrophy in ZIKV animals, in addition to changes in the blood-brain barrier structure and pro-inflammatory cytokines expression increase. Regarding neurodevelopment, a delay in important reflexes during the neonatal period in ZIKV animals was observed. These findings advance the understanding of the pathophysiology of CZS and contribute to enhancing the rat model of CZS.

Potential of Nanocarrier-Associated Approaches for Better Therapeutic Intervention in the Management of Glioblastoma.

Glioblastoma, commonly known as glioblastoma multiforme (GBM), is one of the deadliest and most invasive types of brain cancer. Two factors account for the majority of the treatment limitations for GBM. First, the presence of the blood-brain barrier (BBB) renders malignancy treatment ineffective, leading to recurrence without full recovery. Second, several adverse effects are associated with the drugs used in conventional GBM treatment. Recent studies have developed nanocarrier systems, such as liposomes, polymeric micelles, dendrimers, nanosuspensions, nanoemulsions, nanostructured lipid carriers, solid lipid nanocarriers, metal particles, and silica nanoparticles, which allow drug-loaded formulations to penetrate the BBB more effectively. This has opened up new possibilities for overcoming therapy issues. Extensive and methodical searches of databases such as PubMed, Science Direct, Google Scholar, and others were conducted to gather relevant literature for this work, using precise keyword combinations such as "GBM," "brain tumor," and "nanocarriers." This review provides deep insights into the administration of drugs using nanocarriers for the management of GBM and explores new advancements in nanotechnology. It also highlights how scientific developments can be explained in connection with hopeful findings about the potential of nanocarriers for the future successful management of GBM.

Understanding the link between neurotropic viruses, BBB permeability, and MS pathogenesis.

Neurotropic viruses can infiltrate the CNS by crossing the blood-brain barrier (BBB) through various mechanisms including paracellular, transcellular, and "Trojan horse" mechanisms during leukocyte diapedesis. These viruses belong to several families, including retroviruses; human immunodeficiency virus type 1 (HIV-1), flaviviruses; Japanese encephalitis (JEV); and herpesviruses; herpes simplex virus type 1 (HSV-1), Epstein-Barr virus (EBV), and mouse adenovirus 1 (MAV-1). For entering the brain, viral proteins act upon the tight junctions (TJs) between the brain microvascular endothelial cells (BMECs). For instance, HIV-1 proteins, such as glycoprotein 120, Nef, Vpr, and Tat, disrupt the BBB and generate a neurotoxic effect. Recombinant-Tat triggers amendments in the BBB by decreasing expression of the TJ proteins such as claudin-1, claudin-5, and zona occludens-1 (ZO-1). Thus, the breaching of BBB has been reported in myriad of neurological diseases including multiple sclerosis (MS). Neurotropic viruses also exhibit molecular mimicry with several myelin sheath proteins, i.e., antibodies against EBV nuclear antigen 1 (EBNA1) aa411-426 cross-react with MBP and EBNA1 aa385-420 was found to be associated with MS risk haplotype HLA-DRB1*150. Notably, myelin protein epitopes (PLP139-151, MOG35-55, and MBP87-99) are being used to generate model systems for MS such as experimental autoimmune encephalomyelitis (EAE) to understand the disease mechanism and therapeutics. Viruses like Theiler's murine encephalomyelitis virus (TMEV) are also commonly used to generate EAE. Altogether, this review provide insights into the viruses' association with BBB leakiness and MS along with possible mechanistic details which could potentially use for therapeutics.

Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.

Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-ß were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier.

Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer.

Focused ultrasound (FUS) combined with intravascularly circulating microbubbles can transiently increase the permeability of the blood-brain barrier (BBB) to enable targeted therapeutic delivery to the brain, the clinical testing of which is currently underway in both adult and pediatric patients. Aside from traditional cancer drugs, this technique is being extended to promote the delivery of immunomodulating therapeutics to the brain, including antibodies, immune cells, and cytokines. In this manner, FUS approaches are being explored as a tool to improve and amplify the effectiveness of immunotherapy for both primary and metastatic brain cancer, a particularly challenging solid tumor to treat. Here, we present an overview of the latest groundbreaking research in FUS-assisted delivery of immunomodulating agents to the brain in pre-clinical models of brain cancer, and place it within the context of the current immunotherapy approaches. We follow this up with a discussion on new developments and emerging strategies for this rapidly evolving approach.