Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain

For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle.

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Vascular Dysfunction Induced by Mercury Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms20102435 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2435 ◽

Cited By ~ 4

Author(s):

Tetsuya Takahashi ◽

Takayoshi Shimohata

Keyword(s):

Oxidative Stress ◽

Vascular Dysfunction ◽

Brain Parenchyma ◽

Transport Systems ◽

Mehg Exposure ◽

In Vivo Models ◽

The Central Nervous System ◽

The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

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Fatal Parasitic Meningoencephalomyelitis Caused By Halicephalobus deletrix: A Case Report and Review of the Literature

Archives of Pathology & Laboratory Medicine ◽

10.5858/134.4.625 ◽

2010 ◽

Vol 134 (4) ◽

pp. 625-629

Author(s):

Sarah L. Ondrejka ◽

Gary W. Procop ◽

Keith K. Lai ◽

Richard A. Prayson

Keyword(s):

Fatal Case ◽

Brain Biopsy ◽

Altered Mental Status ◽

Brain Parenchyma ◽

Review Of The Literature ◽

Inflammatory Infiltration ◽

Granulomatous Vasculitis ◽

Helminthic Infection ◽

The Central Nervous System ◽

The Brain

Abstract Infection with the saprophagous nematode Halicephalobus species is uncommon but has been reported in horses worldwide. Only 3 human cases have been previously described, all of which have been fatal. We report a fourth fatal case, which occurred in a 39-year-old woman who presented with meningeal signs, altered mental status, and a prodromal pruritic rash. Diagnostic evaluation included an open brain biopsy, which was diagnosed as granulomatous vasculitis. The patient subsequently died after a course of steroids and cyclophosphamide. At autopsy, a robust perivascular mixed inflammatory infiltration of the brain parenchyma, meninges, and ventricular system was present with larval forms and mature nematodes morphologically consistent with Halicephalobus deletrix. Although extremely rare, this organism needs to be considered in the differential diagnosis of human helminthic infection of the central nervous system.

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Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Molecules ◽

10.3390/molecules25081929 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1929 ◽

Cited By ~ 6

Author(s):

Salman Ul Islam ◽

Adeeb Shehzad ◽

Muhammad Bilal Ahmed ◽

Young Sup Lee

Keyword(s):

Drug Delivery ◽

Neurological Disorders ◽

Neurological Diseases ◽

Nasal Delivery ◽

Intranasal Route ◽

Drug Molecules ◽

Surface Enhanced ◽

Effective Delivery ◽

The Central Nervous System ◽

The Brain

Although the global prevalence of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs’ entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.

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Immune cells and CNS physiology: Microglia and beyond

Journal of Experimental Medicine ◽

10.1084/jem.20180199 ◽

2018 ◽

Vol 216 (1) ◽

pp. 60-70 ◽

Cited By ~ 42

Author(s):

Geoffrey T. Norris ◽

Jonathan Kipnis

Keyword(s):

Central Nervous System ◽

Immune Cells ◽

Brain Function ◽

Brain Parenchyma ◽

The Body ◽

Immune Repertoire ◽

Perivascular Macrophages ◽

The Central Nervous System ◽

Cns Immunity ◽

The Brain

Recent advances have directed our knowledge of the immune system from a narrative of “self” versus “nonself” to one in which immune function is critical for homeostasis of organs throughout the body. This is also the case with respect to the central nervous system (CNS). CNS immunity exists in a segregated state, with a marked partition occurring between the brain parenchyma and meningeal spaces. While the brain parenchyma is patrolled by perivascular macrophages and microglia, the meningeal spaces are supplied with a diverse immune repertoire. In this review, we posit that such partition allows for neuro–immune crosstalk to be properly tuned. Convention may imply that meningeal immunity is an ominous threat to brain function; however, recent studies have shown that its presence may instead be a steady hand directing the CNS to optimal performance.

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Immune System in the Brain: A Modulatory Role on Dendritic Spine Morphophysiology?

Neural Plasticity ◽

10.1155/2012/348642 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 31

Author(s):

Oscar Kurt Bitzer-Quintero ◽

Ignacio González-Burgos

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune System ◽

Dendritic Spines ◽

Cell Lineage ◽

Myeloid Cell ◽

Brain Parenchyma ◽

Immune Mediators ◽

The Central Nervous System ◽

The Brain

The central nervous system is closely linked to the immune system at several levels. The brain parenchyma is separated from the periphery by the blood brain barrier, which under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell lineage plays a crucial role in the development of immune responses at the central level, and it comprises two main subtypes: (1) resident microglia, distributed throughout the brain parenchyma; (2) perivascular macrophages located in the brain capillaries of the basal lamina and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and, to a lesser extent, neurons are implicated in the immune response in the central nervous system. By modulating synaptogenesis, microglia are most specifically involved in restoring neuronal connectivity following injury. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and that alter the morphology of dendritic spines during the inflammatory process following injury. Thus, the expression and release of immune mediators in the brain parenchyma are closely linked to plastic morphophysiological changes in neuronal dendritic spines. Based on these observations, it has been proposed that these immune mediators are also implicated in learning and memory processes.

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Biotechnology of Nanostructures Micronutrients Vitamins for Human Health

10.47363/jnsrr/2021(3)119 ◽

2021 ◽

Vol 3 (2) ◽

pp. 1-13

Author(s):

Loutfy H Madkour ◽

Keyword(s):

Human Health ◽

Polymeric Nanoparticles ◽

Well Being ◽

Hybrid Nanoparticles ◽

Food Ingredients ◽

Improved Stability ◽

The Central Nervous System ◽

Product Forms ◽

The Brain ◽

New Strategies

Nowadays, nanotechnology is used as a way to increase bioavailability and decrease the side effects of drugs and nutrients. Micronutrients and nutraceuticals such as vitamins, carotenoids, polyunsaturated fatty acids and polyphenols are classes of food ingredients that are essential for human health and well-being. These compounds are rarely added purely to the targeted food application but rather in encapsulated, solid, dry product forms with added functionalities such as improved stability, bioavailability or handling. Development of new strategies, like nanocarriers, that help to promote the access of neuroprotective molecules to the brain, is needed for providing more effective therapies for the disorders of the central nervous system (CNS). Polymer–lipid hybrid nanoparticles, encapsulating vitamin D3 and vitamin K2, with improved features in terms of stability, loading and mucoadhesiveness were produced for potential nutraceutical and pharmaceutical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. Active targeting of nanoparticles loaded with vitamin D to cancer cells.

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A Rhombencephalitis Revealing HIV Virorachia

10.21203/rs.3.rs-465507/v1 ◽

2021 ◽

Author(s):

Annick Melanie MAGNEROU ◽

Martine NIDA ◽

Daniel MASSI GAMS ◽

Hugues Martial ZANGA ◽

Fidelie Scolastique NGOUNGOURE HALIMA ◽

...

Keyword(s):

Viral Suppression ◽

Treated Patient ◽

Brain Mri ◽

Undetectable Viral Load ◽

Brain Parenchyma ◽

Hiv Replication ◽

Csf Analysis ◽

Persistent Inflammation ◽

The Central Nervous System ◽

The Brain

Abstract One of the possible causes of persistent inflammation of the brain parenchyma in the age of antiretrovirals is residual HIV replication, despite effective viral suppression in the bloodstream with Antiretroviral treatment (ART). The central nervous system (CNS) is infected early during primary HIV infection and is one of the reservoirs of this virus during chronic infection. Inadequate penetration of certain ART into the CNS could promote some degree of intrathecal HIV replication.We describe the case of an HIV-infected patient compliant to ART with an undetectable viral load in the blood but present in the cerebrospinal fluid (CSF). The patient presented with subacute rhombencephalitis due to HIV which was fatal to him.An HIV-infected and treated patient, well controlled on ART, with new neurological disorders, should be promptly investigated by brain MRI and CSF analysis for exhaustive detection of viruses including that of HIV itself.

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Heparin-derived theranostic nanoprobes overcome the blood-brain barrier and target glioma in murine model

10.1101/2022.01.07.475195 ◽

2022 ◽

Author(s):

Sumanta Samanta ◽

Vadim Le Joncour ◽

Olivia Wegrzyniak ◽

Vigneshkumar Rangasami ◽

Harri Ali-Loytty ◽

...

Keyword(s):

Blood Brain Barrier ◽

Xenograft Model ◽

Brain Parenchyma ◽

Brain Barrier ◽

Treatment Modalities ◽

Mouse Strains ◽

Tail Vein ◽

Blood Brain ◽

Theranostic Agents ◽

The Brain

The poor permeability of theranostic agents across the blood-brain-barrier (BBB) significantly hampers the development of new treatment modalities for neurological diseases. We have discovered a new biomimetic nanocarrier using heparin (HP) that effectively passes the BBB and targets glioblastoma. Specifically, we designed HP coated gold nanoparticles (HP-AuNPs) that were labeled with three different imaging modalities namely, fluorescein (FITC-HP-AuNP), radioisotope 68Gallium (68Ga-HP-AuNPs), and MRI active gadolinium (Gd-HP-AuNPs). The systemic infusion of FITC-HP-AuNPs in three different mouse strains (C57BL/6JRj, FVB, and NMRI-nude) displayed excellent penetration and revealed uniform distribution of fluorescent particles in the brain parenchyma (69-86%) with some accumulation in neurons (8-18%) and microglia (4-10%). Tail-vein administration of radiolabeled 68Ga-HP-AuNPs in healthy rats also showed 68Ga-HP-AuNP inside the brain parenchyma and in areas containing cerebrospinal fluid, such as the lateral ventricles, the cerebellum, and brain stem. Finally, tail-vein administration of Gd-HP-AuNPs (that display ~3 fold higher relaxivity than that of commercial Gd-DTPA) in an orthotopic glioblastoma (U87MG xenograft) model in nude mice demonstrated enrichment of T1-contrast at the intracranial tumor with a gradual increase in the contrast in the tumor region between 1h-3h. We believe, our finding offers the untapped potential of HP-derived-NPs to deliver cargo molecules for treating neurological disorders.

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Unexpected intracranial location of a Cephenemyia stimulator larva in a roe deer, Capreolus capreolus, revealed by computed tomography

Galemys Spanish Journal of Mammalogy ◽

10.7325/galemys.2021.a2 ◽

2021 ◽

Vol 33 ◽

pp. 1-7

Author(s):

Luis E. Fidalgo ◽

Ana M. López-Beceiro ◽

Carlos Martínez-Carrasco ◽

Noelia Caparrós-Fontarosa ◽

Antonio Sánchez ◽

...

Keyword(s):

Computed Tomography ◽

Central Nervous System ◽

Roe Deer ◽

Capreolus Capreolus ◽

Brain Parenchyma ◽

Anatomical Location ◽

Migration Route ◽

The Central Nervous System ◽

Hemorrhagic Lesion ◽

The Brain

In this study we describe the finding of a Cephenemyia stimulator larva in the brain of a roe deer (Capreolus capreolus) after performing a computed tomography (CT) scan of its head. Despite this anatomical location of oestrid larvae could be relatively frequent in other genera, such as Oestrus, to our knowledge, this is the first reported case involving the genus Cephenemyia. Concretely, a second-instar C. stimulator larvae was found in the basis of the cranium. The location of a macroscopic hemorrhagic lesion involving the brain parenchyma peripheral to the location of the larva suggests that tissue colonization occurred before the animal was hunted. Since no detectable alterations or damage to the cranial bones were observed, we suggest a possible larval migration route drilling the skull bones. Finally, we propose the use of the term “neuromyiasis” to be referred to the invasion of the central nervous system by dipteran larvae, particularly oestrids.

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Immovable Object Meets Unstoppable Force? Dialogue Between Resident and Peripheral Myeloid Cells in the Inflamed Brain

Frontiers in Immunology ◽

10.3389/fimmu.2020.600822 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alanna G. Spiteri ◽

Claire L. Wishart ◽

Nicholas J. C. King

Keyword(s):

Myeloid Cells ◽

Cell Types ◽

Brain Parenchyma ◽

Specific Cell ◽

Novel Treatments ◽

Experimental Systems ◽

Immune Mediated ◽

Recent Developments ◽

The Central Nervous System ◽

The Brain

Inflammation of the brain parenchyma is characteristic of neurodegenerative, autoimmune, and neuroinflammatory diseases. During this process, microglia, which populate the embryonic brain and become a permanent sentinel myeloid population, are inexorably joined by peripherally derived monocytes, recruited by the central nervous system. These cells can quickly adopt a morphology and immunophenotype similar to microglia. Both microglia and monocytes have been implicated in inducing, enhancing, and/or maintaining immune-mediated pathology and thus disease progression in a number of neuropathologies. For many years, experimental and analytical systems have failed to differentiate resident microglia from peripherally derived myeloid cells accurately. This has impeded our understanding of their precise functions in, and contributions to, these diseases, and hampered the development of novel treatments that could target specific cell subsets. Over the past decade, microglia have been investigated more intensively in the context of neuroimmunological research, fostering the development of more precise experimental systems. In light of our rapidly growing understanding of these cells, we discuss the differential origins of microglia and peripherally derived myeloid cells in the inflamed brain, with an analysis of the problems resolving these cell types phenotypically and morphologically, and highlight recent developments enabling more precise identification.

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