The blood-brain barrier: Physiology and strategies for drug delivery.

Testing of a hypothesis for osmotic opening of the blood-brain barrier.

Central nervous system (CNS) cancers are among the most common and treatment-resistant diseases. The main reason for the low treatment efficiency of the disorders is the barriers against targeted delivery of anticancer agents to the site of interest, including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). BBB is a strong biological barrier separating circulating blood from brain extracellular fluid that selectively and actively prevents cytotoxic agents and majority of anticancer drugs from entering the brain. BBB and BBTB are the major impediments against targeted drug delivery into CNS tumors. Nanotechnology and its allied modalities offer interesting and effective delivery strategies to transport drugs across BBB to reach brain tissue. Integrating anticancer drugs into different nanocarriers improves the delivery performance of the resultant compounds across BBB. Surface engineering of nanovehicles using specific ligands, antibodies and proteins enhances the BBB crossing efficacy as well as selective and specific targeting to the target cancerous tissues in CNS tumors. Multifunctional nanoparticles (NPs) have brought revolutionary advances in targeted drug delivery to brain tumors. This study reviews the main anatomical, physiological and biological features of BBB and BBTB in drug delivery and the recent advances in targeting strategies in NPs-based drug delivery for CNS tumors. Moreover, we discuss advances in using specific ligands, antibodies, and surface proteins for designing and engineering of nanocarriers for targeted delivery of anticancer drugs to CNS tumors. Finally, the current clinical applications and the perspectives in the targeted delivery of therapeutic molecules and genes to CNS tumors are discussed.

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Gliomas make up virtually 80% of all lethal primary brain tumors and are categorized based on their cell of origin. Glioblastoma is an astrocytic tumor that has an inferior prognosis despite the ongoing advances in treatment modalities. One of the main reasons for this shortcoming is the presence of the blood-brain barrier and blood-brain tumor barrier. Novel invasive and non-invasive drug delivery strategies for glioblastoma have been developed to overcome both the intact blood-brain barrier and leverage the disrupted nature of the blood-brain tumor barrier to target cancer cells after resection—the first treatment stage of glioblastoma. Exosomes are among non-invasive drug delivery methods and have emerged as a natural drug delivery vehicle with high biological barrier penetrability. There are various exosome isolation methods from different origins, and the intended use of the exosomes and starting materials defines the choice of isolation technique. In the present review, we have given an overview of the structure of the blood-brain barrier and its disruption in glioblastoma. This review provided a comprehensive insight into novel passive and active drug delivery techniques to overcome the blood-brain barrier, emphasizing exosomes as an excellent emerging drug, gene, and effective molecule delivery vehicle used in glioblastoma therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-023-03365-0.

One of the major recommendations emerging from the NINDS Stroke Progress Review Group was to shift the emphasis from a purely neurocentric view of cell death toward a more integrative approach whereby responses in all brain cells and matrix are considered during cerebral ischemia (see Figure). The concept of the neurovascular unit (fundamentally comprising endothelium, astrocyte, and neuron) provides a modular framework where cell-cell signaling and cell-matrix interactions mediate the overall tissue response to stroke and its treatments.1 There is no doubt that reperfusing blood vessels mechanically or pharmacologically prevents cell death and rescues brain when performed in a timely manner, as it does in ischemic myocardium. However, under some circumstances, thrombolysis and reperfusion lead to cerebral hemorrhage and edema. Here, we examine the hypothesis that beneficial versus potentially deleterious outcomes after tissue plasminogen activator (tPA) stroke therapy may relate in part to matrix proteolysis within the neurovascular unit, and review recent advances in this area. Schematic of the basic neurovascular unit showing functional interactions between neuron, astrocyte, and cerebral endothelium. This conceptual construct provides a framework for investigating the integrative response of brain to stroke and therapy. Note: ultimately, all cell types should be considered including smooth muscle cells, pericytes, as well as oligodendrocytes and axons in white matter. More than 7 years after the major ECASS and NINDS trials,2,3 use of tPA therapy remains limited.4 In part, this may be due to narrow time-to-treatment windows and apparent complications …

The vasculature of the brain consists of specialized endothelial cells that form a blood-brain barrier (BBB). This barrier, in conjunction with supporting cell types, forms the neurovascular unit (NVU). The NVU restricts the passage of certain substances from the bloodstream while selectively permitting essential nutrients and molecules to enter the brain. This protective role is crucial for optimal brain function, but presents a significant obstacle in treating neurological conditions, necessitating chemical modifications or advanced drug delivery methods for most drugs to cross the NVU. A deeper understanding of NVU in health and disease will aid in the identification of new therapeutic targets and drug delivery strategies for improved treatment of neurological disorders.To achieve this goal, we need models that reflect the human BBB and NVU in health and disease. Although animal models of the brain’s vasculature have proven valuable, they are often of limited translational relevance due to interspecies differences or inability to faithfully mimic human disease conditions. For this reason, human in vitro models are essential to improve our understanding of the brain’s vasculature under healthy and diseased conditions. This review delves into the advancements in in vitro modeling of the BBB and NVU, with a particular focus on microfluidic models. After providing a historical overview of the field, we shift our focus to recent developments, offering insights into the latest achievements and their associated constraints. We briefly examine the importance of chip materials and methods to facilitate fluid flow, emphasizing their critical roles in achieving the necessary throughput for the integration of microfluidic models into routine experimentation. Subsequently, we highlight the recent strides made in enhancing the biological complexity of microfluidic NVU models and propose recommendations for elevating the biological relevance of future iterations.Importantly, the NVU is an intricate structure and it is improbable that any model will fully encompass all its aspects. Fit-for-purpose models offer a valuable compromise between physiological relevance and ease-of-use and hold the future of NVU modeling: as simple as possible, as complex as needed.

Neurovascular unit protection—novel therapeutic targets and strategies

Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords 'borneol', 'neurovascular unit', 'endothelial cell', 'astrocyte', 'neuron', 'blood-brain barrier', 'neurodegenerative diseases' and 'brain disease' in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood-brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.

Preeclampsia and Cerebrovascular Disease.

Crossing Barriers From blood-to-brain and academia-to-industry

Strategies for drug delivery through the blood-brain barrier

The blood-brain barrier, a dynamic interface separating the brain from systemic circulation, is the major entry route for therapeutic compounds to the central nervous system. The blood-brain barrier phenotype of the endothelial cells of brain microvessels includes tight interendothelial junctions, the lack of pinocytosis and fenestrae, transendothelial transport pathways, and a metabolic barrier. The primary role of the blood-brain barrier is to create ionic homeostasis for neuronal functions, but it also provides the central nervous system with nutrients and protects it from toxic insults. The formation and maintenance of these organ-specific characteristics are based on cross talk between the cells of the neurovascular unit, such as brain endothelial cells, pericytes, astroglia, microglia and neurons. The problem of drug transport at the blood-brain barrier is two-fold: the great majority of neuropharmaceutical candidates, hydrophilic molecules, biopharmaceuticals and efflux transporter ligands do not penetrate the blood-brain barrier, while unwanted side effects develop if a drug with main peripheral action crosses the blood-brain barrier. Overcoming the major mechanisms restricting drug transport at the level of the blood-brain barrier, tight interendothelial junctions, efflux transporters and the enzymatic barrier can lead to better drug penetration to the brain. In addition, there are several physiological transport pathways – the carrier systems and the adsorptive and receptor-mediated transports – which can be exploited for drug targeting. Strategies for drug delivery and targeting to the brain include modification of the molecules, modification of the blood-brain barrier functions, and circumvention of the blood-brain barrier. Some of the techniques based on these strategies are already in clinical use, while others are promising new possibilities for improving the therapy of central nervous system diseases.

The brain targeting drug delivery system is the technique and process to deliver the drug into brain or central nerves system (CNS). The main problem arise during brain targeting in case of several brain related diseases and disorders such as CNS malignancy, brain abscess, multiple sclerosis, schizophrenia etc. selective and limiting permeation nature of barriers i.e. blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSF), these two barriers only allow highly lipophilic molecule enters into brain and is one of the greatest clinical impediment of treatment of brain and CNS diseases and disorders. To treated this type of diseases and disorders drugs are targeted into brain and drug must be cross these two barriers they’re by different types of approaches are used to delivered drug molecules.Aim of research. The main aim of this review paper is to compile all the approaches, strategies and techniques used for brain targeted drug delivery in a single paper/ article.Material and method. To prepare this manuscript, various keywords were searched in different engines such as Google, Yahoo and Bing etc. The available information in public domain was collected and classified according to brain drug delivery system. This review deals with approaches and current strategies used to enhance the brain targeted drug delivery system. The approaches for brain targeting – invasive, non- invasive and miscellaneous techniques, by using these approaches enhance the drugs delivery and drugs are easily across BBB and BCSF.Result. The different type of approaches and strategies used to enhance the drug delivery into brain and CNS. All these techniques described in this paper are applied for overcoming the problems that arises during treatment of brain related diseases. This review paper has a list of different types of models (In-vitro and In-vivo) used in study of brain and CNS drug delivery.Conclusions. Drug delivery to brain for treating a various diseases and disorders are very difficult and challenging because the delivery of drug molecules must be pass through the BBB and BCSF. Overcome this difficulties and challenges certain approaches and technique such as invasive, non-invasive, intranasal delivery of drug, ocular delivery of drug and focused ultrasound technique are used to brain targeting. They are help to penetrate the drug molecule through BBB and CSF very easily and enhance the efficacy of treatment. This review article covered current approaches and strategies of brain targeting drug delivery in past five to ten years. These approaches and strategies are used to the brain delivery of drug, proteins, peptides, amino acids, etc.

Brain metastasis is the most prevalent neurologic problem of systemic cancer and it can increase the mortality rate in patients with cancer. It occurs more in patients with lung cancer, breast cancer, and melanoma. There are several molecular mechanisms in cancer cell progression, invasion, and location in new places during brain metastasis. Significant interactions between cancer cells, the brain microenvironment, and the blood-brain barrier (BBB) play a major role in brain metastasis. This study will focus on molecular mechanisms that contribute to cancer metastasis into the brain and finding new treatments with molecular research. Treatment strategies in patients with brain metastasis include surgical resection, radiotherapy, and chemotherapy; however, the penetration of chemotherapy drugs beyond the BBB is limited. Studying molecular, cellular, and physical mechanisms in brain metastasis helps to improve new strategies in drug delivery across the BBB. There are significant impacts of ion channels in brain metastasis and cancer treatment failure. Targeting molecular mechanisms and ion channels in brain metastasis led to increasing the better response in these patients. In this way, nano-drugs have caused a revolution in effective targeting and drug delivery in cancer treatment. This review describes the advances to facilitate the penetration of drugs in the BBB by using nano-drugs especially those that are targeting ion channels.

The blood-brain barrier, essential for protecting the central nervous system, also restricts drug delivery to this region. Thus, delivering drugs across the blood-brain barrier is an active research area in immunology, oncology, and neurology; moreover, novel methods are urgently needed to expand therapeutic options for central nervous system pathologies. While previous strategies have focused on small molecules that modulate blood-brain barrier permeability or penetrate the barrier, there is an increased focus on biomedical devices—external or implanted—for improving drug delivery. Here, we review device-assisted drug delivery across the blood–brain barrier, emphasizing its application in glioblastoma, an aggressively malignant primary brain cancer in which the blood-brain barrier plays a central role. We examine the blood-brain barrier and its features in glioblastoma, emerging models for studying the blood-brain barrier, and device-assisted methods for crossing the blood-brain barrier. We conclude by presenting methods to monitor the blood-brain barrier and paradigms for combined cross-BBB drug delivery.