Brain-Targeted Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 August 2022) | Viewed by 34050

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Special Issue Editor

Istituto Italiano di Tecnologia, 16163 Genova, Italy
Interests: drug delivery; nanotechnology; biomaterials
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

At present, brain diseases affect 1 in 6 people worldwide, and include a wide range of neurological diseases from Alzheimer’s and Parkinson’s disease to epilepsy, brain injuries, brain cancer, neuroinfections and strokes. The treatment of these diseases is complex and limited due to the presence of the blood–brain barrier (BBB), which covers the entirety of the brain. The BBB not only has the function of protecting the brain from harmful substances, but is also a metabolic barrier and a transport regulator of nutrients/serum factors/neurotoxins. Knowing these characteristics when it comes the treatment of brain diseases makes it easy to understand the lack of efficacy of therapeutic drugs, resulting from the innate resistance of the BBB to permeation. To overcome this limitation, drug delivery systems based on nanotechnology/microtechnology have been wisely developed. Brain-targeted drug delivery allows targeted therapy with a higher therapeutic efficacy and low side effects because it targets moieties present in the drug delivery systems

Dr. Flávia Sousa
Guest Editor

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Keywords

  • drug delivery systems 
  • brain diseases
  • targeted therapy
  • neurodegenerative diseases
  • nanoparticles
  • microparticles
  • brain therapy
  • nanomedicine
  • blood–brain barrier

Published Papers (13 papers)

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Editorial

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3 pages, 196 KiB  
Editorial
Brain-Targeted Drug Delivery
by Flávia Sousa
Pharmaceutics 2022, 14(9), 1835; https://doi.org/10.3390/pharmaceutics14091835 - 31 Aug 2022
Cited by 1 | Viewed by 1466
Abstract
At present, brain diseases affect one in six people worldwide, and they include a wide range of neurological diseases from Alzheimer’s and Parkinson’s diseases to epilepsy, brain injuries, brain cancer, neuroinfections and strokes [...] Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)

Research

Jump to: Editorial, Review

20 pages, 2906 KiB  
Article
Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery
by Ghazal Naseri Kouzehgarani, Pankaj Kumar, Susan E. Bolin, Edward B. Reilly and Didier R. Lefebvre
Pharmaceutics 2022, 14(7), 1441; https://doi.org/10.3390/pharmaceutics14071441 - 12 Jul 2022
Cited by 7 | Viewed by 2601
Abstract
Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation [...] Read more.
Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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21 pages, 4411 KiB  
Article
Improving the Efficacy and Accessibility of Intracranial Viral Vector Delivery in Non-Human Primates
by Devon J. Griggs, Aaron D. Garcia, Wing Yun Au, William K. S. Ojemann, Andrew Graham Johnson, Jonathan T. Ting, Elizabeth A. Buffalo and Azadeh Yazdan-Shahmorad
Pharmaceutics 2022, 14(7), 1435; https://doi.org/10.3390/pharmaceutics14071435 - 08 Jul 2022
Cited by 5 | Viewed by 1660
Abstract
Non-human primates (NHPs) are precious resources for cutting-edge neuroscientific research, including large-scale viral vector-based experimentation such as optogenetics. We propose to improve surgical outcomes by enhancing the surgical preparation practices of convection-enhanced delivery (CED), which is an efficient viral vector infusion technique for [...] Read more.
Non-human primates (NHPs) are precious resources for cutting-edge neuroscientific research, including large-scale viral vector-based experimentation such as optogenetics. We propose to improve surgical outcomes by enhancing the surgical preparation practices of convection-enhanced delivery (CED), which is an efficient viral vector infusion technique for large brains such as NHPs’. Here, we present both real-time and next-day MRI data of CED in the brains of ten NHPs, and we present a quantitative, inexpensive, and practical bench-side model of the in vivo CED data. Our bench-side model is composed of food coloring infused into a transparent agar phantom, and the spread of infusion is optically monitored over time. Our proposed method approximates CED infusions into the cortex, thalamus, medial temporal lobe, and caudate nucleus of NHPs, confirmed by MRI data acquired with either gadolinium-based or manganese-based contrast agents co-infused with optogenetic viral vectors. These methods and data serve to guide researchers and surgical team members in key surgical preparations for intracranial viral delivery using CED in NHPs, and thus improve expression targeting and efficacy and, as a result, reduce surgical risks. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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19 pages, 1961 KiB  
Article
Gene Targeting to the Cerebral Cortex Following Intranasal Administration of Polyplexes
by Asya I. Petkova, Ilona Kubajewska, Alexandra Vaideanu, Andreas G. Schätzlein and Ijeoma F. Uchegbu
Pharmaceutics 2022, 14(6), 1136; https://doi.org/10.3390/pharmaceutics14061136 - 26 May 2022
Cited by 4 | Viewed by 1887
Abstract
Gene delivery to the cerebral cortex is challenging due to the blood brain barrier and the labile and macromolecular nature of DNA. Here we report gene delivery to the cortex using a glycol chitosan—DNA polyplex (GCP). In vitro, GCPs carrying a reporter plasmid [...] Read more.
Gene delivery to the cerebral cortex is challenging due to the blood brain barrier and the labile and macromolecular nature of DNA. Here we report gene delivery to the cortex using a glycol chitosan—DNA polyplex (GCP). In vitro, GCPs carrying a reporter plasmid DNA showed approximately 60% of the transfection efficiency shown by Lipofectamine lipoplexes (LX) in the U87 glioma cell line. Aiming to maximise penetration through the brain extracellular space, GCPs were coated with hyaluronidase (HYD) to form hyaluronidase-coated polyplexes (GCPH). The GCPH formulation retained approximately 50% of the in vitro hyaluronic acid (HA) digestion potential but lost its transfection potential in two-dimensional U87 cell lines. However, intranasally administered GCPH (0.067 mg kg−1 DNA) showed high levels of gene expression (IVIS imaging of protein expression) in the brain regions. In a separate experiment, involving GCP, LX and naked DNA, the intranasal administration of the GCP formulation (0.2 mg kg−1 DNA) resulted in protein expression predominantly in the cerebral cortex, while a similar dose of intranasal naked DNA led to protein expression in the cerebellum. Intranasal LX formulations did not show any evidence of protein expression. GCPs may provide a means to target protein expression to the cerebral cortex via the intranasal route. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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15 pages, 2660 KiB  
Article
Micro- and Nano-Systems Developed for Tolcapone in Parkinson’s Disease
by Yaquelyn Casanova, Sofía Negro, Karla Slowing, Luis García-García, Ana Fernández-Carballido, Mahdieh Rahmani and Emilia Barcia
Pharmaceutics 2022, 14(5), 1080; https://doi.org/10.3390/pharmaceutics14051080 - 17 May 2022
Cited by 5 | Viewed by 1826
Abstract
To date there is no cure for Parkinson’s disease (PD), a devastating neurodegenerative disorder with levodopa being the cornerstone of its treatment. In early PD, levodopa provides a smooth clinical response, but after long-term therapy many patients develop motor complications. Tolcapone (TC) is [...] Read more.
To date there is no cure for Parkinson’s disease (PD), a devastating neurodegenerative disorder with levodopa being the cornerstone of its treatment. In early PD, levodopa provides a smooth clinical response, but after long-term therapy many patients develop motor complications. Tolcapone (TC) is an effective adjunct in the treatment of PD but has a short elimination half-life. In our work, two new controlled delivery systems of TC consisting of biodegradable PLGA 502 (poly (D,L-lactide-co-glycolide acid) microparticles (MPs) and nanoparticles (NPs) were developed and characterized. Formulations MP-TC4 and NP-TC3 were selected for animal testing. Formulation MP-TC4, prepared with 120 mg TC and 400 mg PLGA 502, exhibited a mean encapsulation efficiency (EE) of 85.13%, and zero-order in vitro release of TC for 30 days, with around 95% of the drug released at this time. Formulation NP-TC3, prepared with 10 mg of TC and 50 mg of PLGA 502, exhibited mean EE of 56.69%, particle size of 182 nm, and controlled the release of TC for 8 days. Daily i.p. (intraperitoneal) doses of rotenone (RT, 2 mg/kg) were given to Wistar rats to induce neurodegeneration. Once established, animals received TC in saline (3 mg/kg/day) or encapsulated within formulations MP-TC4 (amount of MPs equivalent to 3 mg/kg/day TC every 14 days) and NP-TC3 (amount of NPs equivalent to 3 mg/kg/day TC every 3 days). Brain analyses of Nissl-staining, GFAP (glial fibrillary acidic protein), and TH (tyrosine hydroxylase) immunohistochemistry as well as behavioral testing (catalepsy, akinesia, swim test) showed that the best formulation was NP-TC3, which was able to revert PD-like symptoms of neurodegeneration in the animal model assayed. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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14 pages, 1462 KiB  
Article
High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
by Junzhi Yang, Robert D. Betterton, Erica I. Williams, Joshua A. Stanton, Elizabeth S. Reddell, Chidinma E. Ogbonnaya, Emma Dorn, Thomas P. Davis, Jeffrey J. Lochhead and Patrick T. Ronaldson
Pharmaceutics 2022, 14(5), 949; https://doi.org/10.3390/pharmaceutics14050949 - 27 Apr 2022
Cited by 2 | Viewed by 2074
Abstract
The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley [...] Read more.
The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose “leak” and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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19 pages, 2898 KiB  
Article
IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma
by Julian S. Rechberger, Kendra A. Porath, Liang Zhang, Cody L. Nesvick, Randy S. Schrecengost, Jann N. Sarkaria and David J. Daniels
Pharmaceutics 2022, 14(5), 922; https://doi.org/10.3390/pharmaceutics14050922 - 24 Apr 2022
Cited by 5 | Viewed by 2109
Abstract
High-grade gliomas (HGG) are devastating diseases in children and adults. In the pediatric population, diffuse midline gliomas (DMG) harboring H3K27 alterations are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of [...] Read more.
High-grade gliomas (HGG) are devastating diseases in children and adults. In the pediatric population, diffuse midline gliomas (DMG) harboring H3K27 alterations are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains largely intractable, with a median survival of approximately 14 months despite standard clinical care of radiation and temozolomide. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in many HGGs, including DMG and adult GBM, posing a potentially promising therapeutic target for these tumors. In this study, we investigated the pharmacological effects of GB-13 (also known as IL13.E13K-PE4E), a novel peptide–toxin conjugate that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. Glioma cell lines demonstrated a spectrum of IL-13Rα2 expression at both the transcript and protein level. Anti-tumor effects of GB-13 strongly correlated with IL-13Rα2 expression and were reflected in apoptosis induction and decreased cell proliferation in vitro. Direct intratumoral administration of GB-13 via convection-enhanced delivery (CED) significantly decreased tumor burden and resulted in prolonged survival in IL-13Rα2-upregulated orthotopic xenograft models of HGG. In summary, administration of GB-13 demonstrated a promising pharmacological response in HGG models both in vitro and in vivo in a manner strongly associated with IL-13Rα2 expression, underscoring the potential of this IL-13Rα2-targeted therapy in a subset of HGG with increased IL-13Rα2 levels. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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13 pages, 2053 KiB  
Article
Improved Efficiency of Pomegranate Seed Oil Administrated Nasally
by Hiba Natsheh and Elka Touitou
Pharmaceutics 2022, 14(5), 918; https://doi.org/10.3390/pharmaceutics14050918 - 22 Apr 2022
Cited by 3 | Viewed by 1410
Abstract
Pomegranate seed oil (PSO) is currently administrated orally as a food supplement for improving memory. However, the efficiency of the oral dosage forms for such purposes is low, mainly due to the blood brain barrier impeding a good delivery to brain. In this [...] Read more.
Pomegranate seed oil (PSO) is currently administrated orally as a food supplement for improving memory. However, the efficiency of the oral dosage forms for such purposes is low, mainly due to the blood brain barrier impeding a good delivery to brain. In this work, we designed and characterized a PSO phospholipid oily gel for nasal administration. We tested the performance of the new PSO delivery system in animal models for impaired memory and locomotor activity. The experimental results indicated a statistically significant improvement (p < 0.05) of more than 1.5 fold in the behavior of animals treated nasally, in comparison to those treated with orally administrated oil. Furthermore, in multiphoton microscopy and near infrared imaging studies, the nasal administration of fluorescent probes, fluorescein isothiocyanate (FITC), and indocyanine green (ICG) incorporated in the PSO system showed enhanced delivery to the brain. Results of the histopathologic examination of the nasal cavity and mucosa, as carried out by a pathologist, indicated the safety of the PSO phospholipid oily gel. In conclusion, the results of this work encourage further investigation of the phospholipid oily gel composition as a new way of PSO administration. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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22 pages, 3657 KiB  
Article
Thymoquinone-Enriched Naringenin-Loaded Nanostructured Lipid Carrier for Brain Delivery via Nasal Route: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Treatment of Depression
by Farheen Fatima Qizilbash, Muhammad Usama Ashhar, Ameeduzzafar Zafar, Zufika Qamar, Annu, Javed Ali, Sanjula Baboota, Mohammed M. Ghoneim, Sultan Alshehri and Asgar Ali
Pharmaceutics 2022, 14(3), 656; https://doi.org/10.3390/pharmaceutics14030656 - 16 Mar 2022
Cited by 20 | Viewed by 3534
Abstract
In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via [...] Read more.
In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via the ultrasonication technique and optimized using a central composite rotatable design (CCRD). The optimized NLC exhibited the following properties: droplet size, 84.17 to 86.71 nm; PDI, 0.258 to 0.271; zeta potential, −8.15 to −8.21 mV; and % EE, 87.58 to 88.21%. The in vitro drug release profile showed the supremacy of the TQ-NGN-NLC in comparison to the NGN suspension, with a cumulative drug release of 82.42 ± 1.88% from the NLC and 38.20 ± 0.82% from the drug suspension. Ex vivo permeation study displayed a 2.21-fold increase in nasal permeation of NGN from the NLC compared to the NGN suspension. DPPH study showed the better antioxidant potential of the TQ-NGN-NLC in comparison to NGN alone due to the synergistic effect of NGN and TQ oil. CLSM images revealed deeper permeation of the NGN-NLC (39.9 µm) through the nasal mucosa in comparison to the NGN suspension (20 µm). Pharmacodynamic studies, such as the forced swim test and the locomotor activity test, were assessed in the depressed rat model, which revealed the remarkable antidepressant effect of the TQ-NGN-NLC in comparison to the NGN suspension and the marketed formulation. The results signify the potential of the TQ-enriched NGN-NLC in enhancing brain delivery and the therapeutic effect of NGN for depression treatment. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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18 pages, 14895 KiB  
Article
An On-Demand Drug Delivery System for Control of Epileptiform Seizures
by Takashi Nakano, Shakila B. Rizwan, David M. A. Myint, Jason Gray, Sean M. Mackay, Paul Harris, Christopher G. Perk, Brian I. Hyland, Ruth Empson, Eng Wui Tan, Keshav M. Dani, John NJ Reynolds and Jeffery R. Wickens
Pharmaceutics 2022, 14(2), 468; https://doi.org/10.3390/pharmaceutics14020468 - 21 Feb 2022
Cited by 5 | Viewed by 3702
Abstract
Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of [...] Read more.
Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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Review

Jump to: Editorial, Research

37 pages, 4414 KiB  
Review
Drug Delivery Systems in the Development of Novel Strategies for Glioblastoma Treatment
by Wiam El Kheir, Bernard Marcos, Nick Virgilio, Benoit Paquette, Nathalie Faucheux and Marc-Antoine Lauzon
Pharmaceutics 2022, 14(6), 1189; https://doi.org/10.3390/pharmaceutics14061189 - 01 Jun 2022
Cited by 6 | Viewed by 3586
Abstract
Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood–brain barrier [...] Read more.
Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood–brain barrier (BBB) that limits the access of therapeutic drugs to the brain are the main reasons hampering the current standard treatment efficiency. Following the tumor resection, the infiltrative remaining GBM cells, which are resistant to chemotherapy and radiotherapy, can further invade the surrounding brain parenchyma. Consequently, the development of new strategies to treat parenchyma-infiltrating GBM cells, such as vaccines, nanotherapies, and tumor cells traps including drug delivery systems, is required. For example, the chemoattractant CXCL12, by binding to its CXCR4 receptor, activates signaling pathways that play a critical role in tumor progression and invasion, making it an interesting therapeutic target to properly control the direction of GBM cell migration for treatment proposes. Moreover, the interstitial fluid flow (IFF) is also implicated in increasing the GBM cell migration through the activation of the CXCL12-CXCR4 signaling pathway. However, due to its complex and variable nature, the influence of the IFF on the efficiency of drug delivery systems is not well understood yet. Therefore, this review discusses novel drug delivery strategies to overcome the GBM treatment limitations, focusing on chemokines such as CXCL12 as an innovative approach to reverse the migration of infiltrated GBM. Furthermore, recent developments regarding in vitro 3D culture systems aiming to mimic the dynamic peritumoral environment for the optimization of new drug delivery technologies are highlighted. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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20 pages, 1469 KiB  
Review
Current Approaches to Monitor Macromolecules Directly from the Cerebral Interstitial Fluid
by Marie-Laure Custers, Liam Nestor, Dimitri De Bundel, Ann Van Eeckhaut and Ilse Smolders
Pharmaceutics 2022, 14(5), 1051; https://doi.org/10.3390/pharmaceutics14051051 - 13 May 2022
Cited by 7 | Viewed by 2706
Abstract
Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that [...] Read more.
Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that allow for the direct sampling from the cerebral interstitial space. This review concerns the applicability of microdialysis and other approaches, such as cerebral open flow microperfusion and electrochemical biosensors, to monitor macromolecules (neuropeptides, proteins, …) in the brain. Microdialysis and cerebral open flow microperfusion can also be used to locally apply molecules at the same time at the site of sampling. Innovations in the field are discussed, together with the pitfalls. Moreover, the ‘nuts and bolts’ of the techniques and the current research gaps are addressed. The implementation of these techniques could help to improve drug development of brain-targeted drugs. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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21 pages, 4600 KiB  
Review
Delivery of Intravenously Administered Antibodies Targeting Alzheimer’s Disease-Relevant Tau Species into the Brain Based on Receptor-Mediated Transcytosis
by Toshihiko Tashima
Pharmaceutics 2022, 14(2), 411; https://doi.org/10.3390/pharmaceutics14020411 - 14 Feb 2022
Cited by 12 | Viewed by 3612
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory loss, cognitive decline, and eventually dementia. The etiology of AD and its pathological mechanisms remain unclear due to its complex pathobiology. At the same time, the number of patients with AD is increasing [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory loss, cognitive decline, and eventually dementia. The etiology of AD and its pathological mechanisms remain unclear due to its complex pathobiology. At the same time, the number of patients with AD is increasing worldwide. However, no therapeutic agents for AD are currently available for definitive care. Several phase 3 clinical trials using agents targeting amyloid β (Aβ) and its related molecules have failed, with the exception of aducanumab, an anti-Aβ monoclonal antibody (mAb), clinically approved by the US Food and Drug Administration in 2021, which could be modified for AD drug development due to controversial approval. Neurofibrillary tangles (NFTs) composed of tau rather than senile plaques composed of Aβ are correlated with AD pathogenesis. Moreover, Aβ and tau pathologies initially proceed independently. At a certain point in the progression of AD symptoms, the Aβ pathology is involved in the alteration and spreading of the tau pathology. Therefore, tau-targeting therapies have attracted the attention of pharmaceutical scientists, as well as Aβ-targeting therapies. In this review, I introduce the implementations and potential of AD immunotherapy using intravenously administered anti-tau and anti-receptor bispecific mAbs. These cross the blood-brain barrier (BBB) based on receptor-mediated transcytosis and are subsequently cleared by microglia based on Fc-mediated endocytosis after binding to tau and lysosomal degradation. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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