Blood–Brain Barrier Drug Targeting: The Future of Brain Drug Development, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (10 June 2023) | Viewed by 8257

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Guest Editor
Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA
Interests: blood–brain barrier; pain therapeutics; drug delivery; drug development; CNS targeting
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Special Issue Information

Dear Colleagues,

Neurological disorders have been a challenge to target therapeutically given the presence of the blood–brain barrier (BBB). Blood–brain barrier (BBB)/Neurovascular unit (NVU) integrity is vital to the health of the central nervous system (CNS) and serves as the gateway for CNS drug delivery. However, the influence of pathological changes on BBB dynamics and ultimately on brain drug development is oft overlooked. Thus, it is important to the clinical success of new CNS-targeting agents to account for pathological changes, as well as those resulting from aging and sex differences, to fully understand BBB integrity, its impact on drug delivery, and how these issues will be addressed in the future.

The aim of this Special Issue of Pharmaceutics is to collect research and review papers on targeting the CNS during disease by understanding the role of the BBB in drug discovery and development. We welcome articles dealing with any aspect of BBB dynamics during physiological and pathophysiological states on CNS drug delivery and invite researchers and drug developers to publish their original research or review articles with expert opinions and perspectives in the area of therapeutics.

Dr. Tally Largent-Milnes
Guest Editor

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Keywords

  • blood–brain barrier
  • drug delivery
  • CNS targeting
  • drug development
  • pathologic influence on the neurovascular unit

Published Papers (4 papers)

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Research

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14 pages, 4791 KiB  
Article
CDR3 Variants of the TXB2 Shuttle with Increased TfR1 Association Rate and Enhanced Brain Penetration
by Pawel Stocki, Jaroslaw Szary, Mykhaylo Demydchuk, Leandra Northall, Charlotte L. M. Rasmussen, Diana Bahu Logan, Aziz Gauhar, Laura Thei, Shu-Fen Coker, Torben Moos, Frank S. Walsh and J. Lynn Rutkowski
Pharmaceutics 2023, 15(3), 739; https://doi.org/10.3390/pharmaceutics15030739 - 23 Feb 2023
Cited by 3 | Viewed by 1983
Abstract
Since the delivery of biologic drugs to the brain is greatly hampered by the existence of the blood–brain barrier (BBB), brain shuttles are being developed to enhance therapeutic efficacy. As we have previously shown, efficient and selective brain delivery was achieved with TXB2, [...] Read more.
Since the delivery of biologic drugs to the brain is greatly hampered by the existence of the blood–brain barrier (BBB), brain shuttles are being developed to enhance therapeutic efficacy. As we have previously shown, efficient and selective brain delivery was achieved with TXB2, a cross-species reactive, anti-TfR1 VNAR antibody. To further explore the limits of brain penetration, we conducted restricted randomization of the CDR3 loop, followed by phage display to identify improved TXB2 variants. The variants were screened for brain penetration in mice using a 25 nmol/kg (1.875 mg/kg) dose and a single 18 h timepoint. A higher kinetic association rate to TfR1 correlated with improved brain penetration in vivo. The most potent variant, TXB4, showed a 3.6-fold improvement over TXB2, which had on average 14-fold higher brain levels when compared to an isotype control. Like TXB2, TXB4 retained brain specificity with parenchymal penetration and no accumulation in other organs. When fused with a neurotensin (NT) payload, it led to a rapid drop in body temperature upon transport across the BBB. We also showed that fusion of TXB4 to four therapeutic antibodies (anti-CD20, anti-EGFRvIII, anti-PD-L1 and anti-BACE1) improved their brain exposure between 14- to 30-fold. In summary, we enhanced the potency of parental TXB2 brain shuttle and gained a critical mechanistic understanding of brain delivery mediated by the VNAR anti-TfR1 antibody. Full article
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39 pages, 8099 KiB  
Review
Living Cells and Cell-Derived Vesicles: A Trojan Horse Technique for Brain Delivery
by Ante Ou, Yuewei Wang, Jiaxin Zhang and Yongzhuo Huang
Pharmaceutics 2023, 15(4), 1257; https://doi.org/10.3390/pharmaceutics15041257 - 17 Apr 2023
Cited by 4 | Viewed by 1573
Abstract
Brain diseases remain a significant global healthcare burden. Conventional pharmacological therapy for brain diseases encounters huge challenges because of the blood–brain barrier (BBB) limiting the delivery of therapeutics into the brain parenchyma. To address this issue, researchers have explored various types of drug [...] Read more.
Brain diseases remain a significant global healthcare burden. Conventional pharmacological therapy for brain diseases encounters huge challenges because of the blood–brain barrier (BBB) limiting the delivery of therapeutics into the brain parenchyma. To address this issue, researchers have explored various types of drug delivery systems. Cells and cell derivatives have attracted increasing interest as “Trojan horse” delivery systems for brain diseases, owing to their superior biocompatibility, low immunogenicity, and BBB penetration properties. This review provided an overview of recent advancements in cell- and cell-derivative-based delivery systems for the diagnosis and treatment of brain diseases. Additionally, it discussed the challenges and potential solutions for clinical translation. Full article
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22 pages, 2311 KiB  
Review
ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers
by Reinaldo B. Oriá, Raul S. Freitas, Cássia R. Roque, José Carlos R. Nascimento, Ana Paula Silva, João O. Malva, Richard L. Guerrant and Michael P. Vitek
Pharmaceutics 2023, 15(4), 1086; https://doi.org/10.3390/pharmaceutics15041086 - 28 Mar 2023
Viewed by 1871
Abstract
Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein’s LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related [...] Read more.
Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein’s LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections. Full article
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17 pages, 4928 KiB  
Review
Photodynamic Opening of the Blood–Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors
by Oxana Semyachkina-Glushkovskaya, Andrey Terskov, Alexander Khorovodov, Valeria Telnova, Inna Blokhina, Elena Saranceva and Jürgen Kurths
Pharmaceutics 2022, 14(12), 2612; https://doi.org/10.3390/pharmaceutics14122612 - 26 Nov 2022
Cited by 13 | Viewed by 2195
Abstract
Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell [...] Read more.
Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood–brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM. Full article
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