Editorial

6 pages, 208 KiB

Open AccessEditorial

Advanced Blood–Brain Barrier Drug Delivery

by William M. Pardridge

Pharmaceutics 2023, 15(1), 93; https://doi.org/10.3390/pharmaceutics15010093 - 27 Dec 2022

Cited by 3 | Viewed by 1896

This Special Issue of Pharmaceutics, “Advanced Blood–Brain Barrier Drug Delivery,” comprises 16 articles or reviews, which cover a cross-section of brain drug delivery for either small-molecule or large-molecule therapeutics [...] Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

Research

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20 pages, 7636 KiB

Open AccessArticle

Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice

by Weijun Ou, Yuu Ohno, Joshua Yang, Devaraj V. Chandrashekar, Tamara Abdullah, Jiahong Sun, Riley Murphy, Chuli Roules, Nataraj Jagadeesan, David H. Cribbs and Rachita K. Sumbria

Pharmaceutics 2022, 14(10), 2200; https://doi.org/10.3390/pharmaceutics14102200 - 16 Oct 2022

Cited by 6 | Viewed by 2412

Abstract

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI [...] Read more.

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1-42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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17 pages, 2672 KiB

Open AccessArticle

The 46.1 Antibody Mediates Neurotensin Uptake into the CNS and the Effects Depend on the Route of Intravenous Administration

by Julia V. Georgieva, Moriah Katt, Zhou Ye, Benjamin J. Umlauf, Cody J. Wenthur and Eric V. Shusta

Pharmaceutics 2022, 14(8), 1706; https://doi.org/10.3390/pharmaceutics14081706 - 16 Aug 2022

Cited by 4 | Viewed by 2539

Abstract

Central nervous system (CNS) exposure to blood-borne biotherapeutics is limited by the restrictive nature of the brain vasculature. In particular, tightly sealed endothelial cells of the blood–brain barrier (BBB) prevent the uptake of protein and gene medicines. An approach to increase the bioavailability [...] Read more.

Central nervous system (CNS) exposure to blood-borne biotherapeutics is limited by the restrictive nature of the brain vasculature. In particular, tightly sealed endothelial cells of the blood–brain barrier (BBB) prevent the uptake of protein and gene medicines. An approach to increase the bioavailability of such therapeutics is harnessing the BBB endothelial cells’ own receptor-mediated transcytosis (RMT) mechanisms. Key to this process is a targeting ligand that can engage a BBB-resident RMT receptor. We recently identified an antibody, named 46.1, that accumulates in the mouse brain after intravenous injection. To further characterize the brain targeting and penetrating properties of clone 46.1, we conjugated neurotensin (NT) to an scFv-Fc form of the antibody (46.1-scFv-Fc-LongLinker-NT). While centrally administered NT decreases the core body temperature and locomotor activity, effects attributed to two spatially segregated brain areas, systemically administered NT has limited effects. Hence, NT can be used as a model therapeutic payload to evaluate the brain penetration of BBB-targeting antibodies and their capability to accumulate in discrete brain areas. We demonstrate that intravenously administered 46.1-scFv-Fc-LL-NT can elicit transient hypothermia and reduce drug-induced hyperlocomotion, confirming that 46.1 can deliver drug cargo to the CNS at pharmacologically relevant doses. Interestingly, when two intravenous administration routes in mice, retro-orbital and tail vein, were compared, only retro-orbital administration led to transient hypothermia. We further explored the retro-orbital route and demonstrated that the 46.1-scFv-Fc-LL-NT could enter the brain arterial blood supply directly from the retro-orbital/cavernous sinus. Taken together, the 46.1 antibody is capable of transporting drug cargo into the CNS, and at least of a portion of its CNS accumulation occurs via the cavernous sinus–arterial route. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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19 pages, 3139 KiB

Open AccessArticle

Proteomics-Based Transporter Identification by the PICK Method: Involvement of TM7SF3 and LHFPL6 in Proton-Coupled Organic Cation Antiport at the Blood–Brain Barrier

by Toshiki Kurosawa, Yuma Tega, Yasuo Uchida, Kei Higuchi, Hidetsugu Tabata, Takaaki Sumiyoshi, Yoshiyuki Kubo, Tetsuya Terasaki and Yoshiharu Deguchi

Pharmaceutics 2022, 14(8), 1683; https://doi.org/10.3390/pharmaceutics14081683 - 12 Aug 2022

Cited by 4 | Viewed by 1918

Abstract

A proton-coupled organic cation (H⁺/OC) antiporter working at the blood–brain barrier (BBB) in humans and rodents is thought to be a promising candidate for the efficient delivery of cationic drugs to the brain. Therefore, it is important to identify the molecular [...] Read more.

A proton-coupled organic cation (H⁺/OC) antiporter working at the blood–brain barrier (BBB) in humans and rodents is thought to be a promising candidate for the efficient delivery of cationic drugs to the brain. Therefore, it is important to identify the molecular entity that exhibits this activity. Here, for this purpose, we established the Proteomics-based Identification of transporter by Crosslinking substrate in Keyhole (PICK) method, which combines photo-affinity labeling with comprehensive proteomics analysis using SWATH-MS. Using preselected criteria, the PICK method generated sixteen candidate proteins. From these, knockdown screening in hCMEC/D3 cells, an in vitro BBB model, identified two proteins, TM7SF3 and LHFPL6, as candidates for the H⁺/OC antiporter. We synthesized a novel H⁺/OC antiporter substrate for functional analysis of TM7SF3 and LHFPL6 in hCMEC/D3 cells and HEK293 cells. The results suggested that both TM7SF3 and LHFPL6 are components of the H⁺/OC antiporter. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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12 pages, 3026 KiB

Open AccessArticle

pH-Responsive Lipid Nanoparticles Achieve Efficient mRNA Transfection in Brain Capillary Endothelial Cells

by Yu Sakurai, Himeka Watanabe, Kazuma Nishio, Kohei Hashimoto, Atsuki Harada, Masaki Gomi, Masayoshi Suzuki, Ryotaro Oyama, Takumi Handa, Risa Sato, Hina Takeuchi, Ryoga Taira, Kenta Tezuka, Kota Tange, Yuta Nakai, Hidetaka Akita and Yasuo Uchida

Pharmaceutics 2022, 14(8), 1560; https://doi.org/10.3390/pharmaceutics14081560 - 27 Jul 2022

Cited by 3 | Viewed by 2860

Abstract

The blood–brain barrier (BBB), which is comprised of brain capillary endothelial cells, plays a pivotal role in the transport of drugs from the blood to the brain. Therefore, an analysis of proteins in the endothelial cells, such as transporters and tight junction proteins, [...] Read more.

The blood–brain barrier (BBB), which is comprised of brain capillary endothelial cells, plays a pivotal role in the transport of drugs from the blood to the brain. Therefore, an analysis of proteins in the endothelial cells, such as transporters and tight junction proteins, which contribute to BBB function, is important for the development of therapeutics for the treatment of brain diseases. However, gene transfection into the vascular endothelial cells of the BBB is fraught with difficulties, even in vitro. We report herein on the development of lipid nanoparticles (LNPs), in which mRNA is encapsulated in a nano-sized capsule composed of a pH-activated and reductive environment-responsive lipid-like material (ssPalm). We evaluated the efficiency of mRNA delivery into non-polarized human brain capillary endothelial cells, hCMEC/D3 cells. The ssPalm LNPs permitted marker genes (GFP) to be transferred into nearly 100% of the cells, with low toxicity in higher concentration. A proteomic analysis indicated that the ssPalm-LNP had less effect on global cell signaling pathways than a Lipofectamine MessengerMAX/GFP-encoding mRNA complex (LFN), a commercially available transfection reagent, even at higher mRNA concentrations. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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18 pages, 4360 KiB

Open AccessArticle

Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor

by Alvaro Yogi, Greg Hussack, Henk van Faassen, Arsalan S. Haqqani, Christie E. Delaney, Eric Brunette, Jagdeep K. Sandhu, Melissa Hewitt, Traian Sulea, Kristin Kemmerich and Danica B. Stanimirovic

Pharmaceutics 2022, 14(7), 1452; https://doi.org/10.3390/pharmaceutics14071452 - 12 Jul 2022

Cited by 12 | Viewed by 3022

Abstract

The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way [...] Read more.

The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to increase drug delivery to the brain. In this study, we characterized IGF1R5, which is a single-domain antibody (sdAb) that binds to insulin-like growth factor-1 receptor (IGF1R) at the BBB, as a ligand that triggers RMT and could deliver cargo molecules that otherwise do not cross the BBB. Surface plasmon resonance binding analyses demonstrated the species cross-reactivity of IGF1R5 toward IGF1R from multiple species. To overcome the short serum half-life of sdAbs, we fused IGF1R5 to the human (hFc) or mouse Fc domain (mFc). IGF1R5 in both N- and C-terminal mFc fusion showed enhanced transmigration across a rat BBB model (SV-ARBEC) in vitro. Increased levels of hFc-IGF1R5 in the cerebrospinal fluid and vessel-depleted brain parenchyma fractions further confirmed the ability of IGF1R5 to cross the BBB in vivo. We next tested whether this carrier was able to ferry a pharmacologically active payload across the BBB by measuring the hypothermic and analgesic properties of neurotensin and galanin, respectively. The fusion of IGF1R5-hFc to neurotensin induced a dose-dependent reduction in the core temperature. The reversal of hyperalgesia by galanin that was chemically linked to IGF1R5-mFc was demonstrated using the Hargreaves model of inflammatory pain. Taken together, our results provided a proof of concept that appropriate antibodies, such as IGF1R5 against IGF1R, are suitable as RMT carriers for the delivery of therapeutic cargos for CNS applications. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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16 pages, 8544 KiB

Open AccessArticle

Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody

by Sahar Roshanbin, Ulrika Julku, Mengfei Xiong, Jonas Eriksson, Eliezer Masliah, Greta Hultqvist, Joakim Bergström, Martin Ingelsson, Stina Syvänen and Dag Sehlin

Pharmaceutics 2022, 14(7), 1412; https://doi.org/10.3390/pharmaceutics14071412 - 05 Jul 2022

Cited by 11 | Viewed by 2347

Abstract

Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for [...] Read more.

Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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16 pages, 2463 KiB

Open AccessArticle

A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson’s Disease

by Emily Clarke, Pawel Stocki, Elizabeth H. Sinclair, Aziz Gauhar, Edward J. R. Fletcher, Alicja Krawczun-Rygmaczewska, Susan Duty, Frank S. Walsh, Patrick Doherty and Julia Lynn Rutkowski

Pharmaceutics 2022, 14(7), 1335; https://doi.org/10.3390/pharmaceutics14071335 - 24 Jun 2022

Cited by 14 | Viewed by 3122

Abstract

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused [...] Read more.

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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Review

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17 pages, 2694 KiB

Open AccessEditor’s ChoiceReview

Blood–Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles

by Maj Schneider Thomsen, Kasper Bendix Johnsen, Krzysztof Kucharz, Martin Lauritzen and Torben Moos

Pharmaceutics 2022, 14(10), 2237; https://doi.org/10.3390/pharmaceutics14102237 - 19 Oct 2022

Cited by 26 | Viewed by 3683

Abstract

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes [...] Read more.

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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15 pages, 948 KiB

Open AccessReview

Blood–Brain Barrier Solute Carrier Transporters and Motor Neuron Disease

by Sana Latif and Young-Sook Kang

Pharmaceutics 2022, 14(10), 2167; https://doi.org/10.3390/pharmaceutics14102167 - 11 Oct 2022

Cited by 5 | Viewed by 1873

Abstract

Defective solute carrier (SLC) transporters are responsible for neurotransmitter dysregulation, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We provided the role and kinetic parameters of transporters such as ASCTs, Taut, LAT1, CAT1, MCTs, OCTNs, CHT, and CTL1, which are mainly [...] Read more.

Defective solute carrier (SLC) transporters are responsible for neurotransmitter dysregulation, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We provided the role and kinetic parameters of transporters such as ASCTs, Taut, LAT1, CAT1, MCTs, OCTNs, CHT, and CTL1, which are mainly responsible for the transport of essential nutrients, acidic, and basic drugs in blood–brain barrier (BBB) and motor neuron disease. The affinity for LAT1 was higher in the BBB than in the ALS model cell line, whereas the capacity was higher in the NSC-34 cell lines than in the BBB. Affinity for MCTs was lower in the BBB than in the NSC-34 cell lines. CHT in BBB showed two affinity sites, whereas no expression was observed in ALS cell lines. CTL1 was the main transporter for choline in ALS cell lines. The half maximal inhibitory concentration (IC₅₀) analysis of [³H]choline uptake indicated that choline is sensitive in TR-BBB cells, whereas amiloride is most sensitive in ALS cell lines. Knowledge of the transport systems in the BBB and motor neurons will help to deliver drugs to the brain and develop the therapeutic strategy for treating CNS and neurological diseases. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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13 pages, 5187 KiB

Open AccessReview

Peptide Shuttles for Blood–Brain Barrier Drug Delivery

by Macarena Sánchez-Navarro and Ernest Giralt

Pharmaceutics 2022, 14(9), 1874; https://doi.org/10.3390/pharmaceutics14091874 - 05 Sep 2022

Cited by 13 | Viewed by 2977

Abstract

The blood–brain barrier (BBB) limits the delivery of therapeutics to the brain but also represents the main gate for nutrient entrance. Targeting the natural transport mechanisms of the BBB offers an attractive route for brain drug delivery. Peptide shuttles are able to use [...] Read more.

The blood–brain barrier (BBB) limits the delivery of therapeutics to the brain but also represents the main gate for nutrient entrance. Targeting the natural transport mechanisms of the BBB offers an attractive route for brain drug delivery. Peptide shuttles are able to use these mechanisms to increase the transport of compounds that cannot cross the BBB unaided. As peptides are a group of biomolecules with unique physicochemical and structural properties, the field of peptide shuttles has substantially evolved in the last few years. In this review, we analyze the main classifications of BBB–peptide shuttles and the leading sources used to discover them. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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18 pages, 2264 KiB

Open AccessReview

Modeling Blood–Brain Barrier Permeability to Solutes and Drugs In Vivo

by Ulrich Bickel

Pharmaceutics 2022, 14(8), 1696; https://doi.org/10.3390/pharmaceutics14081696 - 15 Aug 2022

Cited by 3 | Viewed by 1902

Abstract

Our understanding of the pharmacokinetic principles governing the uptake of endogenous substances, xenobiotics, and biologicals across the blood–brain barrier (BBB) has advanced significantly over the past few decades. There is now a spectrum of experimental techniques available in experimental animals and humans which, [...] Read more.

Our understanding of the pharmacokinetic principles governing the uptake of endogenous substances, xenobiotics, and biologicals across the blood–brain barrier (BBB) has advanced significantly over the past few decades. There is now a spectrum of experimental techniques available in experimental animals and humans which, together with pharmacokinetic models of low to high complexity, can be applied to describe the transport processes at the BBB of low molecular weight agents and macromolecules. This review provides an overview of the models in current use, from initial rate uptake studies over compartmental models to physiologically based models and points out the advantages and shortcomings associated with the different methods. A comprehensive pharmacokinetic profile of a compound with respect to brain exposure requires the knowledge of BBB uptake clearance, intra-brain distribution, and extent of equilibration across the BBB. The application of proper pharmacokinetic analysis and suitable models is a requirement not only in the drug development process, but in all of the studies where the brain uptake of drugs or markers is used to make statements about the function or integrity of the BBB. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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27 pages, 2190 KiB

Open AccessEditor’s ChoiceReview

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

by Patrick T. Ronaldson and Thomas P. Davis

Pharmaceutics 2022, 14(7), 1501; https://doi.org/10.3390/pharmaceutics14071501 - 20 Jul 2022

Cited by 11 | Viewed by 3430

Abstract

Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have [...] Read more.

Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood–brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a “gateway” that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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28 pages, 4490 KiB

Open AccessEditor’s ChoiceReview

IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

by Ruben J. Boado

Pharmaceutics 2022, 14(7), 1476; https://doi.org/10.3390/pharmaceutics14071476 - 15 Jul 2022

Cited by 12 | Viewed by 3645

Abstract

The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood–brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and monoclonal antibodies (MAb), do not cross the BBB. These biotherapeutics can be re-engineered [...] Read more.

The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood–brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and monoclonal antibodies (MAb), do not cross the BBB. These biotherapeutics can be re-engineered as brain-penetrating bifunctional IgG fusion proteins. These recombinant proteins comprise two domains, the transport domain and the therapeutic domain, respectively. The transport domain is an MAb that acts as a molecular Trojan horse by targeting a BBB-specific endogenous receptor that induces receptor-mediated transcytosis into the brain, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The therapeutic domain of the IgG fusion protein exerts its pharmacological effect in the brain once across the BBB. A generation of bifunctional IgG fusion proteins has been engineered using genetically engineered MAbs directed to either the BBB HIR or TfR as the transport domain. These IgG fusion proteins were validated in animal models of lysosomal storage disorders; acute brain conditions, such as stroke; or chronic neurodegeneration, such as Parkinson’s disease and Alzheimer’s disease. Human phase I–III clinical trials were also completed for Hurler MPSI and Hunter MPSII using brain-penetrating IgG-iduronidase and -iduronate-2-sulfatase fusion protein, respectively. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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178 pages, 12752 KiB

Open AccessEditor’s ChoiceReview

A Historical Review of Brain Drug Delivery

by William M. Pardridge

Pharmaceutics 2022, 14(6), 1283; https://doi.org/10.3390/pharmaceutics14061283 - 16 Jun 2022

Cited by 63 | Viewed by 12715

Abstract

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved [...] Read more.

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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16 pages, 1148 KiB

Open AccessReview

Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis

by Hiroyuki Sonoda, Kenichi Takahashi, Kohtaro Minami, Toru Hirato, Tatsuyoshi Yamamoto, Sairei So, Kazunori Tanizawa, Mathias Schmidt and Yuji Sato

Pharmaceutics 2022, 14(6), 1240; https://doi.org/10.3390/pharmaceutics14061240 - 11 Jun 2022

Cited by 8 | Viewed by 3168

Abstract

Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood–brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious [...] Read more.

Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood–brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e.g., by fusing them with antibodies against innate receptors on the cerebrovascular endothelium) so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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42 pages, 7925 KiB

Open AccessEditor’s ChoiceReview

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

by Johanna Huttunen, Santosh Kumar Adla, Magdalena Markowicz-Piasecka and Kristiina M. Huttunen

Pharmaceutics 2022, 14(6), 1234; https://doi.org/10.3390/pharmaceutics14061234 - 10 Jun 2022

Cited by 2 | Viewed by 3122

Abstract

Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain [...] Read more.

Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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