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Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges

Victor M. Pulgar

Frontiers in Neuroscience · 2019 · Review · CC BY

doi:10.3389/fnins.2018.01019 (opens in a new tab)

Abstract

The blood brain barrier (BBB) presents a formidable challenge to the delivery of drugs into the brain. Several strategies aim to overcome this obstacle and promote efficient and specific crossing through BBB of therapeutically relevant agents. One of those strategies uses the physiological process of receptor-mediated transcytosis (RMT) to transport cargo through the brain endothelial cells toward brain parenchyma. Recent developments in our understanding of intracellular trafficking and receptor binding as well as in protein engineering and nanotechnology have potentiated the opportunities for treatment of CNS diseases using RMT. In this mini-review, the current understanding of BBB structure is discussed, and recent findings exemplifying critical advances in RMT-mediated brain drug delivery are briefly presented.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Brain diseases are among the less understood and poorly treated conditions. In spite of the rapid growth in recent years in drug development, there is still a low success rate of effective therapies focused in diseases of the central nervous system. A main issue hindering therapeutic success is the tightly regulated extracellular environment of the brain tissue which makes reaching macromolecular targets into the brain a great challenge. The isolation of the brain tissue from the peripheral circulation is thought to arise from the existence of multi-level “barriers,” established in different compartments in the central nervous system of most vertebrates providing protection to the neural tissue. Key to those protective mechanisms is the regulation of the entry of macromolecules from the blood to the brain across the blood-brain barrier (BBB). The BBB regulates an extended surface of interaction between blood and brain. It is calculated that the brain capillary network in humans is approximately 600 km long with a surface of 15–25 m2.

The intimate association between neurons, glial cells, and brain microvessels in the neurovascular unit is being recognized as the functional point for regulation of cerebral blood flow. Among those cell types, the brain endothelial cells are the building blocks of the BBB impeding the entry of most molecules from blood to brain, with the exception of those small and lipophilic in nature. Several recent studies have focused on the functional interactions between endothelial, neuronal and glial cell types and their role on regulating BBB function. Since neurons rarely occur at long distance from a brain capillary, the BBB also plays a major role in controlling fast delivery of substances to the brain and the local neuronal environment. Due to its extended contact and exchange surface area, most research has focused on the brain endothelium as the therapeutic target to increase brain drug delivery.

Structure of the Bbb

Structurally, capillary networks can be divided into continuous non-fenestrated capillaries, continuous fenestrated and discontinuous capillaries. This division is based on their ability to regulate crossing of solutes from blood to tissues; thus continuous fenestrated capillaries are least permeable whereas discontinuous are the most permeable. In the BBB, continuous non-fenestrated capillaries, where tight junctions (TJs) connect endothelial cells, form a high-resistance para-cellular barrier limiting the crossing of molecules and ions. Transmembrane proteins are an important part of TJs, they bind the cytoskeleton and link adjacent endothelial cells in a close configuration, eliminating intercellular spaces. Some of the proteins important for TJs structure and function include integral membrane proteins such as members of the claudin family i.e., claudin 3, 5, and 12, ocludins, and junctional adhesion molecules. Evidences indicate that claudins are essential for the formation of the para-cellular barrier and the structure is stabilized by zona occludens ZO -1, -2, and -3 and additional proteins that link the TJs with the cytoskeleton. This structure is further reinforced by the basal lamina, a ∼40 nm thick matrix formed predominantly of collagen type 1V, laminin, and heparan sulfate proteoglycan. Metalloproteinases are other components that contribute to regulation of BBB function in health and disease.

Additionally, glial cells such as astrocytes play an important role in development and maintenance of the BBB. Up to 99% of the basal capillary membrane is covered by astrocytes “end feet” and glial-derived factors such as GDNF, angiopoietin-1 and angiotensin II all contribute to BBB integrity. Along with astrocytes “end feet,” pericytes are also lining the cerebral vasculature, surrounding brain endothelial cells and contributing to the barrier properties of the BBB. Recent advances on pericytes research indicate that this cell type is rather complex with more than one functional definition depending on their location along the arterio-venous capillaries. The fact that brain microvessels are enriched in pericytes, and pericyte-deficient mouse mutants showed increased BBB permeability exemplifies the importance of pericytes for BBB control. Pericytes seem to contribute in two ways to BBB integrity: downregulating trans-endothelial permeability and promoting astrocyte-endothelial cells contacts. Moreover, growing evidences point now to the importance of the interactions between pericytes and other cell types within the neurovascular unit in health and disease.

The multicellular organization occurring at the neurovascular unit involving endothelial cells and astrocytes among others cell types forms the framework where the highly regulated crossing of macromolecules from blood to brain occurs.

Crossing the Bbb

The existence of efflux transport systems in brain capillary endothelial cells reinforce the barrier properties of the BBB by removing undesirable substances from the brain to the systemic circulation. Multidrug resistance transporters, monocarboxylate transporters and organic anion transporters/organic anion transporting polypeptide have been implicated in the efflux of drugs from the brain. Consequently, the activity of these efflux transporters limits the effectiveness of CNS targeted drugs (; Figure 1C).

Most of the drug transporters belong to two major classes; adenosine triphosphate binding cassette (ABC) and solute carrier (SLC) transporters. ABC transporters are active transporters coupling efflux against concentration gradients to ATP hydrolysis with P-glycoprotein (P-gp) being the most extensively studied BBB transporter of the ABC family. P-gp is encoded by the multidrug resistance gene 1 (MDR1) and its function is regulated by intracellular factors and environmental toxins.

In order to facilitate the efficient delivery of drugs to the brain, the functional and structural tightness of the BBB needs to be overcome. Strategies used to cross BBB involve para-cellular as well as trans-cellular mechanisms.

Transport Across the Bbb

As part of its normal function, the endothelial cells allow the influx of nutrients and regulatory molecules into the brain via passive and active mechanisms. In normal conditions, some passive movement of solutes exists through small intercellular pores located in the TJs (Figure 1E). The molecular entities responsible for this transport are largely unknown, although recent evidences point to claudins as pore-forming structures in BBB TJs. Since early stage CNS diseases do not show evident BBB alterations, this pathway offers fewer opportunities than trans-cellular transport for drug delivery.

Transport of small molecules trough cells is common in polarized cells. Thus, in brain vascular endothelial cells, hydrophobic molecules with molecular weight lower than 500 Da once they escape the P-gp-type multidrug resistance efflux pumps may diffuse transcellularly from systemic circulation to brain parenchyma (Figure 1F). The transport of nutrients, however, requires specialized transporters (Figure 1D). Thus, large neutral aminoacid transporters (LAT1) transport aminoacids, nucleosides, and some drugs, while glucose uses the glucose transporter (GLUT1).

Transcytosis

Transcytosis is a phenomenon present in many different cell types, from neurons to intestinal cells, osteoclasts and endothelial cells. In polarized cells, unidirectional transcytosis refers to the transport of macromolecules from apical to basolateral plasma membranes. Steps along this pathway include endocytosis, intracellular vesicular trafficking and exocytosis. The first of these steps may involve adsorptive (charge dependent) or receptor-mediated internalization (Figures 1A,B). Positively charged molecules such as polymers, cationic lipids, albumin and nanoparticles may interact with the negatively charged cell membrane and internalize through adsorptive endocytosis. Although initially thought to be attenuated in brain endothelial cells, virtually all endothelial cells display receptor-mediated transcytosis (RMT). Recent applications of imaging techniques allowed for detailed analyses of transcytosis in brain endothelial cells. Several receptors capable of inducing RMT are present in the BBB, such as the insulin receptor, transferrin receptor, and receptors responsible for lipoprotein transport, while others such as albumin receptors are not expressed.

The intracellular transport of macromolecules is mediated by the vesicular system. In brain endothelial cells three types of endocytic vesicles have been identified: clathrin-coated pits involved in most of the RMT, caveolae that participate in adsorptive-mediated endocytosis of extracellular molecules and receptor trafficking, and macropinocytotic vesicles. Of these, clathrin-coated vesicles are involved in most of the internalization processes mediated by approximately 20 different receptors in brain endothelial cells.

Once a vesicle is internalized, the common intracellular pathway begins with the initial sorting station, the early endosome (;; Figure 2). In BBB endothelial cells endocytosis occurs at the apical and basolateral membranes with both processes generating its own early endosomes. In polarized cells, routing back to the plasma membrane can occur directly from EE or from recycling endosomes. Alternatively, vesicle components can be delivered to late endosomes and targeted for lysosomal degradation. This endosomal trafficking plays an important role in the efficiency of RMT in BBB.

Rmt for Drug Delivery to the Brain

In general, strategies using RMT for drug delivery to the brain involve the generation of a complex between the drug of interest and a receptor-targeting entity. This entity may be the endogenous receptor ligand, an antibody targeting the receptor or a mimetic peptide ligand. These two components can be chemically linked or the drug can be incorporated in liposomes or nanoparticles decorated with the RMT-targeting ligand. Among the most studied targets for RMT in brain endothelial cells are the transferrin receptor, low-density lipoprotein (LDL) receptor and insulin receptor, for reviews see. In the following section, some examples of the use of these systems are presented with focus in recent advances.

Transferrin Receptor

Iron delivery to the brain is accomplished via binding and intracellular trafficking of the iron binding protein transferrin (Tf). The Tf receptor (TfR) has been the target of numerous in vitro and in vivo studies aiming to deliver drugs to the brain (see Table 1). Approaches used include liposomes decorated with Tf used for delivery of imaging agents and DNA or the use of an iron-mimetic peptide as ligand. Since the presence of high blood levels of Tf requires competition with the endogenous ligand, alternative methods involving anti-TfR antibodies have been developed. Challenges using anti-TfR to deliver drugs to the brain via RMT include specificity to the brain tissue, potential lysosomal degradation and significant transport into the brain parenchyma. With the use of protein engineering it has been shown that reducing antibody’s affinity for Tf improves release of the antigen-antibody complex in the basolateral side of the BBB endothelial cells. A correlation has also been suggested between increased antibody’s affinity and lysosomal degradation supporting the idea that lower antibody’s affinity would help avoid intracellular degradation of the complexes being transported. Studies comparing the brain penetration of monovalent versus divalent antibodies indicate lower lysosomal colocalization of the monovalent form and better transcytosis. It appears that in addition to antibody’s affinity in physiological conditions, a lower affinity at pH5.5 (lysosomal) also promotes effective transcytosis as suggested by in vitro studies using immortalized human brain endothelial cells.

The recent successes using TfR in RMT strategies has prompted novel developments aiming to potentiate drug delivery to the brain. Thus, recent reports showed efficient BBB crossing of particles functionalized with anti-TfR antibodies and containing non-permeant drugs of interest for treating brain diseases. Some examples include liposomes containing the MYBE/4C1 antihuman TfR antibody and loaded with the anticancer drug doxorubicin displaying enhanced uptake in human brain endothelial cells, and liposomes containing Tf and docetaxel showing greater brain uptake after i.v., injection in rats compared to the drug alone. The use of nanoparticles formulated using the Tf system has shown that functionalization with anti-TfR antibodies enhances the delivery of particles carrying relevant drugs such as drugs able to inhibit beta amyloid aggregates. Nanoparticles carrying the chemotherapeutic agent temozolomide have also facilitated enhanced drug uptake by glioblastoma cells. This strategy also exemplifies some of the challenges remaining in the field since gold nanoparticles (AuNPs) coated with the 8D3 anti-TfR antibody injected in mouse are transported through the BBB with low efficiency and most of the particles remain sequestered intracellularly in the endothelial cells. Successful uptake by the BBB but low delivery to the brain parenchyma was also reported with quantum dots. The dual functionalization of particles with peptides targeting the TfR to cross the BBB and additional therapeutic agents opens opportunities to specifically modulate gene expression in brain cells as shown by studies of co-delivery of doxorubicin and RNAi targeting the VEGF, or siRNA targeting the EGFR to glioma cells. The significant reduction in expression of the pro vascularization factors VEGF and EGFR observed in these two studies supports this use of co-delivery systems.

TfR has been used extensively as a model for brain transcytosis, although initial reports came from just one laboratory, later reports supported reproducibility of its use in different settings. Outstanding issues remaining such as brain specificity and low drug uptake will promote further research of this important RMT system.

Insulin Receptor

Insulin is transported into the brain by the insulin receptor (IR). Similarly to the TfR, anti-IR antibodies have been developed and used in strategies to drug delivery into the brain (see Table 1). Following the development of humanized anti-IR antibodies (HIRMAb) that showed good internalization and transport to the brain after intravenous administration in monkeys, fusion proteins were developed to deliver relevant enzymes as therapies for genetic disorders. One of those examples is a fusion protein between the HIRMAb and α-L-idorunidase (IDUA) an enzyme missing in Hurler’s Syndrome, Mucopolysaccharidosis Type I (MSPI), a disorder of brain lysosomal storage. In pre-clinical studies, HIRMAb-IDUA showed good safety, adequate plasma glucose control, and limited antidrug antibody production. Of great interest are recent reports describing clinical studies with HIRMAb-IDUA. In MSPI pediatric and adult patients intravenous infusion of HIRMAb-IDUA describes the first clinical use of RMT to drug delivery into the brain. Although some adverse events reported include reaction at the infusion site, and transient hypoglycemia, the positive neurocognitive and somatic effects observed in pediatric patients represents a significant advancement on the translational aspects of RMT.

LDL Receptor

Low-density lipoprotein receptor (LDLR), a single transmembrane glycoprotein able to recognize LDL particles and promote their endocytosis, as well as LDLR-related proteins (LRPs), are present in the BBB and mediate transport of lipoproteins and other ligands through RMT (;; Table 1). Recent in vitro studies showed that LDLR is preferentially located in apical rather than basolateral membranes in brain endothelial cells supporting a role for ligand uptake from the circulation. To date no antibodies have been developed targeting the LDLR system, however, LDLR and LRP ligands have been used for drug delivery into the brain. One of those ligands is melanotransferrin, which displays a greater rate of brain transport compared to Tf. In spite of structural homology to Tf, melanotransferrin uses the LDLR and not the TfR to cross the BBB. Interestingly, recent reports showed melanotrasferrin delivery and in vivo effectiveness of a fusion protein with an interleukin-1 receptor antagonist in a model of neuropathic pain. Lipoproteins have also been used to target LDLR for effective brain delivery, as described in glioblastoma cells. Recent developments include functionalization of solid nanoparticles with ApoE, these 160 nm nanoparticles showed efficient clathrin-dependent endocytosis and transcellular transport in human brain endothelial cells. Other targeting members of the LDLR family include “angiopeps.” For example, Angiopep-2 was identified by studying a series of 19 amino acid peptides with the ability to bind the LPR-1 receptor. Angiopep-2 was shown to mediate efficient delivery of a conjugate Angiopep-2-placlitaxel to gliomas, and more recently antinociceptive properties were demonstrated for an Angiopep-2-neurotensin fusion protein. These studies provide evidence of successful delivery of therapeutically relevant agents to the brain via RMT targeting the LDLR family.

Single Domain Llama Antibodies

Single domain antibodies (sdAbs) are naturally occurring fragments of the antibody’s heavy chain that lack the light chain. Among them, sdAbs from camelids specifically FC5 and FC44 have been studied for brain transcytosis of cargo in animal models and their potential warrants further developments (see Table 1). FC5 and FC44 recognize α(2,3)-sialoglycoprotein expressed in the luminal side of brain endothelial cells and display advantages over other antibodies such as small size, greater specificity and stability, and low immunogenicity.

Conclusion

Recent advances using RMT are providing alternatives to overcome the barrier properties of the BBB and develop more efficient drug delivery to the brain. Future developments based the TfR, IR, and LDLR and other RMT systems will offer new opportunities in this growing field. However, in spite of clear therapeutic advances shown in animal studies, outstanding challenges remain for the development of efficient and specific RMT-based drug delivery. Although the mechanisms mediating efficient transcytosis through the brain endothelium are still incompletely understood, details about the specific targeting to brain endothelial cells are being revealed. Similarly, the limited brain specific versus systemic drug uptake may explain the lack of success of some potential therapies in non-human primates models of brain diseases.

In addition to increasing knowledge about the factors modulating intracellular trafficking, the generation of fusion proteins with RMT-targeting antibodies as well as functionalization of Nano carriers, an improved understanding of BBB transport, pharmacokinetics, and protein engineering will be needed to potentiate the clinical applicability of RMT.

Author Contributions

VP was responsible for the design of this review, the literature searches, writing and interpretations presented.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 104

  1. 1.

    Abbott N. J. (2013 ). Blood-brain barrier structure and function and the challenges for CNS drug delivery. J. Inherit. Metab. Dis. 36 437–449.

    Not in our library10.1007/s10545-013-9608-0 (opens in a new tab)

  2. 2.

    Abbott N. J. Ronnback L. Hansson E. (2006 ). Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7 41–53.

    Not in our library10.1038/nrn1824 (opens in a new tab)

  3. 3.

    Abulrob A. Sprong H. Van Bergen En Henegouwen P. Stanimirovic D. (2005 ). The blood-brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J. Neurochem. 95 1201–1214.

    Not in our library10.1111/j.1471-4159.2005.03463.x (opens in a new tab)

  4. 4.

    Aird W. C. (2007a ). Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100 158–173.

    Not in our library10.1161/01.res.0000255691.76142.4a (opens in a new tab)

  5. 5.

    Aird W. C. (2007b ). Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ. Res. 100 174–190.

    Not in our library10.1161/01.res.0000255690.03436.ae (opens in a new tab)

  6. 6.

    Anderson J. M. Van Itallie C. M. (2009 ). Physiology and function of the tight junction. Cold Spring Harb. Perspect. Biol. 1:a002584.

    Not in our library10.1101/cshperspect.a002584 (opens in a new tab)

  7. 7.
    Camelid Single-Domain Antibodies: Historical Perspective and Future Outlook · 2017
    No notice
  8. 8.

    Armulik A. Genove G. Mae M. Nisancioglu M. H. Wallgard E. Niaudet C. (2010 ). Pericytes regulate the blood-brain barrier. Nature 468 557–561.

    Not in our library10.1038/nature09522 (opens in a new tab)

  9. 9.

    Attwell D. Mishra A. Hall C. N. O’farrell F. M. Dalkara T. (2016 ). What is a pericyte? J. Cereb. Blood Flow Metab. 36 451–455.

    Not in our library10.1177/0271678x15610340 (opens in a new tab)

  10. 10.

    Barar J. Rafi M. A. Pourseif M. M. Omidi Y. (2016 ). Blood-brain barrier transport machineries and targeted therapy of brain diseases. Bioimpacts 6 225–248.

    Not in our library10.15171/bi.2016.30 (opens in a new tab)

  11. 11.

    Bien-Ly N. Yu Y. J. Bumbaca D. Elstrott J. Boswell C. A. Zhang Y. (2014 ). Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 211 233–244.

    Not in our library10.1084/jem.20131660 (opens in a new tab)

  12. 12.

    Boado R. J. Hui E. K. Lu J. Z. Pardridge W. M. (2009 ). AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys. J. Biotechnol. 144 135–141.

    Not in our library10.1016/j.jbiotec.2009.08.019 (opens in a new tab)

  13. 13.

    Boado R. J. Hui E. K. Lu J. Z. Pardridge W. M. (2011 ). CHO cell expression, long-term stability, and primate pharmacokinetics and brain uptake of an IgG-paroxonase-1 fusion protein. Biotechnol. Bioeng. 108 186–196.

    Not in our library10.1002/bit.22907 (opens in a new tab)

  14. 14.

    Boado R. J. Hui E. K. Lu J. Z. Pardridge W. M. (2012 ). Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metab. Dispos. 40 2021–2025.

    Not in our library10.1124/dmd.112.046375 (opens in a new tab)

  15. 15.

    Boado R. J. Ka-Wai Hui E. Zhiqiang Lu J. Pardridge W. M. (2014a ). Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol. Bioeng. 111 2317–2325.

    Not in our library10.1002/bit.25289 (opens in a new tab)

  16. 16.

    Boado R. J. Lu J. Z. Hui E. K. Pardridge W. M. (2014b ). Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol. Pharm. 11 2928–2934.

    Not in our library10.1021/mp500258p (opens in a new tab)

  17. 17.

    Boado R. J. Lu J. Z. Hui E. K. Pardridge W. M. (2010 ). IgG-single chain Fv fusion protein therapeutic for Alzheimer’s disease: expression in CHO cells and pharmacokinetics and brain delivery in the rhesus monkey. Biotechnol. Bioeng. 105 627–635.

    Not in our library10.1002/bit.22576 (opens in a new tab)

  18. 18.

    Boado R. J. Lu J. Z. Hui E. K. Pardridge W. M. (2018 ). Reduction in Brain heparan sulfate with systemic administration of an IgG trojan horse-sulfamidase fusion protein in the mucopolysaccharidosis Type IIIA mouse. Mol. Pharm. 15 602–608.

    Not in our library10.1021/acs.molpharmaceut.7b00958 (opens in a new tab)

  19. 19.

    Boado R. J. Lu J. Z. Hui E. K. Sumbria R. K. Pardridge W. M. (2013 ). Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor. Biotechnol. Bioeng. 110 1456–1465.

    Not in our library10.1002/bit.24795 (opens in a new tab)

  20. 20.

    Boado R. J. Zhang Y. Zhang Y. Pardridge W. M. (2007 ). Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol. Bioeng. 96 381–391.

    Not in our library10.1002/bit.21120 (opens in a new tab)

  21. 21.

    Boado R. J. Zhang Y. Zhang Y. Xia C. F. Wang Y. Pardridge W. M. (2008 ). Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrier. Biotechnol. Bioeng. 99 475–484.

    Not in our library10.1002/bit.21602 (opens in a new tab)

  22. 22.

    Brooks D. A. (2009 ). The endosomal network. Int. J. Clin. Pharmacol. Ther. 47(Suppl. 1), S9–S17.

    Not in our library10.5414/cpp47009 (opens in a new tab)

  23. 23.

    Cabezon I. Manich G. Martin-Venegas R. Camins A. Pelegri C. Vilaplana J. (2015 ). Trafficking of gold nanoparticles coated with the 8D3 anti-transferrin receptor antibody at the mouse blood-brain barrier. Mol. Pharm. 12 4137–4145.

    Not in our library10.1021/acs.molpharmaceut.5b00597 (opens in a new tab)

  24. 24.

    Candela P. Gosselet F. Miller F. Buee-Scherrer V. Torpier G. Cecchelli R. (2008 ). Physiological pathway for low-density lipoproteins across the blood-brain barrier: transcytosis through brain capillary endothelial cells in vitro. Endothelium 15 254–264.

    Not in our library10.1080/10623320802487759 (opens in a new tab)

  25. 25.

    Chow B. W. Gu C. (2015 ). The molecular constituents of the blood-brain barrier. Trends Neurosci. 38 598–608.

    Not in our library10.1016/j.tins.2015.08.003 (opens in a new tab)

  26. 26.

    Cserr H. F. Bundgaard M. (1984 ). Blood-brain interfaces in vertebrates: a comparative approach. Am. J. Physiol. 246 R277–R288.

    Not in our library10.1152/ajpregu.1984.246.3.r277 (opens in a new tab)

  27. 27.

    Dauchy S. Miller F. Couraud P. O. Weaver R. J. Weksler B. Romero I. A. (2009 ). Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem. Pharmacol. 77 897–909.

    Not in our library10.1016/j.bcp.2008.11.001 (opens in a new tab)

  28. 28.

    Demeule M. Beaudet N. Regina A. Besserer-Offroy E. Murza A. Tetreault P. (2014 ). Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties. J. Clin. Invest. 124 1199–1213.

    Not in our library10.1172/jci70647 (opens in a new tab)

  29. 29.

    Demeule M. Currie J. C. Bertrand Y. Che C. Nguyen T. Regina A. (2008 ). Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J. Neurochem. 106 1534–1544.

    Not in our library10.1111/j.1471-4159.2008.05492.x (opens in a new tab)

  30. 30.

    Demeule M. Poirier J. Jodoin J. Bertrand Y. Desrosiers R. R. Dagenais C. (2002 ). High transcytosis of melanotransferrin (P97) across the blood-brain barrier. J. Neurochem. 83 924–933.

    Not in our library10.1046/j.1471-4159.2002.01201.x (opens in a new tab)

  31. 31.

    Drappatz J. Brenner A. Wong E. T. Eichler A. Schiff D. Groves M. D. (2013 ). Phase I study of GRN1005 in recurrent malignant glioma. Clin. Cancer Res. 19 1567–1576.

    Not in our library10.1158/1078-0432.ccr-12-2481 (opens in a new tab)

  32. 32.

    ElAli A. Theriault P. Rivest S. (2014 ). The role of pericytes in neurovascular unit remodeling in brain disorders. Int. J. Mol. Sci. 15 6453–6474.

    Not in our library10.3390/ijms15046453 (opens in a new tab)

  33. 33.
    Vascular, glial, and lymphatic immune gateways of the central nervous system · 2016
    No notice
  34. 34.

    Engelhardt B. Vajkoczy P. Weller R. O. (2017 ). The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18 123–131.

    Not in our library10.1038/ni.3666 (opens in a new tab)

  35. 35.

    Fu A. Zhou Q. H. Hui E. K. Lu J. Z. Boado R. J. Pardridge W. M. (2010 ). Intravenous treatment of experimental Parkinson’s disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier. Brain Res. 1352 208–213.

    Not in our library10.1016/j.brainres.2010.06.059 (opens in a new tab)

  36. 36.

    Furuse M. (2010 ). Molecular basis of the core structure of tight junctions. Cold Spring Harb. Perspect. Biol. 2:a002907.

    Not in our library10.1101/cshperspect.a002907 (opens in a new tab)

  37. 37.
    Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial · 2018
    No notice
  38. 38.

    Gleitz H. F. Liao A. Y. Cook J. R. Rowlston S. F. Forte G. M. D’souza Z. (2018 ). Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms. EMBO Mol. Med. 10:e8730.

    Not in our library10.15252/emmm.201708730 (opens in a new tab)

  39. 39.

    Gregori M. Orlando A. Re F. Sesana S. Nardo L. Salerno D. (2016 ). Novel antitransferrin receptor antibodies improve the blood-brain barrier crossing efficacy of immunoliposomes. J. Pharm. Sci. 105 276–283.

    Not in our library10.1016/j.xphs.2015.11.009 (opens in a new tab)

  40. 40.

    Haqqani A. S. Caram-Salas N. Ding W. Brunette E. Delaney C. E. Baumann E. (2013 ). Multiplexed evaluation of serum and CSF pharmacokinetics of brain-targeting single-domain antibodies using a NanoLC-SRM-ILIS method. Mol. Pharm. 10 1542–1556.

    Not in our library10.1021/mp3004995 (opens in a new tab)

  41. 41.

    Haqqani A. S. Delaney C. E. Brunette E. Baumann E. Farrington G. K. Sisk W. (2018 ). Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier. J. Cereb. Blood Flow Metab. 38 727–740.

    Not in our library10.1177/0271678x17740031 (opens in a new tab)

  42. 42.

    Hori S. Ohtsuki S. Hosoya K. Nakashima E. Terasaki T. (2004 ). A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J. Neurochem. 89 503–513.

    Not in our library10.1111/j.1471-4159.2004.02343.x (opens in a new tab)

  43. 43.

    Hussain M. M. Strickland D. K. Bakillah A. (1999 ). The mammalian low-density lipoprotein receptor family. Annu. Rev. Nutr. 19 141–172.

    Not in our library10.1146/annurev.nutr.19.1.141 (opens in a new tab)

  44. 44.

    Irudayanathan F. J. Wang N. Wang X. Nangia S. (2017 ). Architecture of the paracellular channels formed by claudins of the blood-brain barrier tight junctions. Ann. N. Y. Acad. Sci. 1405 131–146.

    Not in our library10.1111/nyas.13378 (opens in a new tab)

  45. 45.

    Johnsen K. B. Bak M. Kempen P. J. Melander F. Burkhart A. Thomsen M. S. (2018 ). Antibody affinity and valency impact brain uptake of transferrin receptor-targeted gold nanoparticles. Theranostics 8 3416–3436.

    Not in our library10.7150/thno.25228 (opens in a new tab)

  46. 46.

    Jones A. R. Shusta E. V. (2007 ). Blood-brain barrier transport of therapeutics via receptor-mediation. Pharm. Res. 24 1759–1771.

    Not in our library10.1007/s11095-007-9379-0 (opens in a new tab)

  47. 47.

    Karatas H. Aktas Y. Gursoy-Ozdemir Y. Bodur E. Yemisci M. Caban S. (2009 ). A nanomedicine transports a peptide caspase-3 inhibitor across the blood-brain barrier and provides neuroprotection. J. Neurosci. 29 13761–13769.

    Not in our library10.1523/jneurosci.4246-09.2009 (opens in a new tab)

  48. 48.

    Kuang Y. Jiang X. Zhang Y. Lu Y. Ma H. Guo Y. (2016 ). Dual functional peptide-driven nanoparticles for highly efficient glioma-targeting and drug codelivery. Mol. Pharm. 13 1599–1607.

    Not in our library10.1021/acs.molpharmaceut.6b00051 (opens in a new tab)

  49. 49.

    Lajoie J. M. Shusta E. V. (2015 ). Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu. Rev. Pharmacol. Toxicol. 55 613–631.

    Not in our library10.1146/annurev-pharmtox-010814-124852 (opens in a new tab)

  50. 50.
    Functional morphology of the blood–brain barrier in health and disease · 2018
    No notice
  51. 51.

    Loscher W. Potschka H. (2005 ). Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog. Neurobiol. 76 22–76.

    Not in our library10.1016/j.pneurobio.2005.04.006 (opens in a new tab)

  52. 52.

    Loureiro J. A. Gomes B. Fricker G. Coelho M. A. N. Rocha S. Pereira M. C. (2016 ). Cellular uptake of PLGA nanoparticles targeted with anti-amyloid and anti-transferrin receptor antibodies for Alzheimer’s disease treatment. Colloids Surf. B Biointerfaces 145 8–13.

    Not in our library10.1016/j.colsurfb.2016.04.041 (opens in a new tab)

  53. 53.

    Lu J. Z. Boado R. J. Hui E. K. Zhou Q. H. Pardridge W. M. (2011 ). Expression in CHO cells and pharmacokinetics and brain uptake in the Rhesus monkey of an IgG-iduronate-2-sulfatase fusion protein. Biotechnol. Bioeng. 108 1954–1964.

    Not in our library10.1002/bit.23118 (opens in a new tab)

  54. 54.

    Lu W. (2012 ). Adsorptive-mediated brain delivery systems. Curr. Pharm. Biotechnol. 13 2340–2348.

    Not in our library10.2174/138920112803341851 (opens in a new tab)

  55. 55.

    Mahringer A. Fricker G. (2016 ). ABC transporters at the blood-brain barrier. Expert Opin. Drug Metab. Toxicol. 12 499–508.

    Not in our library10.1517/17425255.2016.1168804 (opens in a new tab)

  56. 56.

    Mayor S. Pagano R. E. (2007 ). Pathways of clathrin-independent endocytosis. Nat. Rev. Mol. Cell Biol. 8 603–612.

    Not in our library10.1038/nrm2216 (opens in a new tab)

  57. 57.

    Molino Y. David M. Varini K. Jabes F. Gaudin N. Fortoul A. (2017 ). Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. FASEB J. 31 1807–1827.

    Not in our library10.1096/fj.201600827r (opens in a new tab)

  58. 58.

    Neves A. R. Queiroz J. F. Lima S. A. C. Reis S. (2017 ). Apo E-functionalization of solid lipid nanoparticles enhances brain drug delivery: uptake mechanism and transport pathways. Bioconjug. Chem. 28 995–1004.

    Not in our library10.1021/acs.bioconjchem.6b00705 (opens in a new tab)

  59. 59.

    Niewoehner J. Bohrmann B. Collin L. Urich E. Sade H. Maier P. (2014 ). Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 81 49–60.

    Not in our library10.1016/j.neuron.2013.10.061 (opens in a new tab)

  60. 60.

    Nikanjam M. Blakely E. A. Bjornstad K. A. Shu X. Budinger T. F. Forte T. M. (2007 ). Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme. Int. J. Pharm. 328 86–94.

    Not in our library10.1016/j.ijpharm.2006.07.046 (opens in a new tab)

  61. 61.
    A monoclonal antibody-GDNF fusion protein is not neuroprotective and is associated with proliferative pancreatic lesions in parkinsonian monkeys. · 2012
    Not checked
  62. 62.

    Ohtsuki S. Terasaki T. (2007 ). Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm. Res. 24 1745–1758.

    Not in our library10.1007/s11095-007-9374-5 (opens in a new tab)

  63. 63.

    O’Sullivan C. C. Lindenberg M. Bryla C. Patronas N. Peer C. J. Amiri-Kordestani L. (2016 ). ANG1005 for breast cancer brain metastases: correlation between (18)F-FLT-PET after first cycle and MRI in response assessment. Breast Cancer Res. Treat. 160 51–59.

    Not in our library10.1007/s10549-016-3972-z (opens in a new tab)

  64. 64.

    Pardridge W. M. (2005 ). The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2 3–14.

    Not in our library10.1602/neurorx.2.1.3 (opens in a new tab)

  65. 65.

    Pardridge W. M. Boado R. J. Giugliani R. Schmidt M. (2018 ). Plasma pharmacokinetics of valanafusp alpha, a human insulin receptor antibody-iduronidase fusion protein, in patients with mucopolysaccharidosis type I. BioDrugs 32 169–176.

    Not in our library10.1007/s40259-018-0264-7 (opens in a new tab)

  66. 66.

    Pardridge W. M. Eisenberg J. Cefalu W. T. (1985 ). Absence of albumin receptor on brain capillaries in vivo or in vitro. Am. J. Physiol. 249 E264–E267.

    Not in our library10.1152/ajpendo.1985.249.3.e264 (opens in a new tab)

  67. 67.

    Paris-Robidas S. Brouard D. Emond V. Parent M. Calon F. (2016 ). Internalization of targeted quantum dots by brain capillary endothelial cells in vivo. J. Cereb. Blood Flow Metab. 36 731–742.

    Not in our library10.1177/0271678x15608201 (opens in a new tab)

  68. 68.

    Parkar N. S. Akpa B. S. Nitsche L. C. Wedgewood L. E. Place A. T. Sverdlov M. S. (2009 ). Vesicle formation and endocytosis: function, machinery, mechanisms, and modeling. Antioxid. Redox. Signal. 11 1301–1312.

    Not in our library10.1089/ars.2008.2397 (opens in a new tab)

  69. 69.

    Paterson J. Webster C. I. (2016 ). Exploiting transferrin receptor for delivering drugs across the blood-brain barrier. Drug Discov. Today Technol. 20 49–52.

    Not in our library10.1016/j.ddtec.2016.07.009 (opens in a new tab)

  70. 70.

    Perlmutter L. S. Chui H. C. (1990 ). Microangiopathy, the vascular basement membrane and Alzheimer’s disease: a review. Brain Res. Bull. 24 677–686.

    Not in our library10.1016/0361-9230(90)90007-m (opens in a new tab)

  71. 71.

    Persidsky Y. Ramirez S. H. Haorah J. Kanmogne G. D. (2006 ). Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J. Neuroimmune Pharmacol. 1 223–236.

    Not in our library10.1007/s11481-006-9025-3 (opens in a new tab)

  72. 72.

    Qian Z. M. Li H. Sun H. Ho K. (2002 ). Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol. Rev. 54 561–587.

    Not in our library10.1124/pr.54.4.561 (opens in a new tab)

  73. 73.

    Ramalho M. J. Sevin E. Gosselet F. Lima J. Coelho M. A. N. Loureiro J. A. (2018 ). Receptor-mediated PLGA nanoparticles for glioblastoma multiforme treatment. Int. J. Pharm. 545 84–92.

    Not in our library10.1016/j.ijpharm.2018.04.062 (opens in a new tab)

  74. 74.

    Rodriguez-Boulan E. Kreitzer G. Musch A. (2005 ). Organization of vesicular trafficking in epithelia. Nat. Rev. Mol. Cell Biol. 6 233–247.

    Not in our library10.1038/nrm1593 (opens in a new tab)

  75. 75.
    A Human Blood-Brain Barrier Transcytosis Assay Reveals Antibody Transcytosis Influenced by pH-Dependent Receptor Binding · 2014
    No notice
  76. 76.

    Schlageter K. E. Molnar P. Lapin G. D. Groothuis D. R. (1999 ). Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc. Res. 58 312–328.

    Not in our library10.1006/mvre.1999.2188 (opens in a new tab)

  77. 77.

    Sharma G. Modgil A. Layek B. Arora K. Sun C. Law B. (2013 ). Cell penetrating peptide tethered bi-ligand liposomes for delivery to brain in vivo: biodistribution and transfection. J. Control. Release 167 1–10.

    Not in our library10.1016/j.jconrel.2013.01.016 (opens in a new tab)

  78. 78.

    Sonali Singh R. P. Singh N. Sharma G. Vijayakumar M. R. Koch B. (2016 ). Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics. Drug Deliv. 23 1261–1271.

    Not in our library10.3109/10717544.2016.1162878 (opens in a new tab)

  79. 79.

    Sonoda H. Morimoto H. Yoden E. Koshimura Y. Kinoshita M. Golovina G. (2018 ). A blood-brain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Mol. Ther. 26 1366–1374.

    Not in our library10.1016/j.ymthe.2018.02.032 (opens in a new tab)

  80. 80.

    Sorrentino N. C. D’orsi L. Sambri I. Nusco E. Monaco C. Spampanato C. (2013 ). A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA. EMBO Mol. Med. 5 675–690.

    Not in our library10.1002/emmm.201202083 (opens in a new tab)

  81. 81.

    Spencer B. Marr R. A. Gindi R. Potkar R. Michael S. Adame A. (2011 ). Peripheral delivery of a CNS targeted, metalo-protease reduces abeta toxicity in a mouse model of Alzheimer’s disease. PLoS One 6:e16575.

    Not in our library10.1371/journal.pone.0016575 (opens in a new tab)

  82. 82.

    Staquicini F. I. Ozawa M. G. Moya C. A. Driessen W. H. Barbu E. M. Nishimori H. (2011 ). Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma. J. Clin. Invest. 121 161–173.

    Not in our library10.1172/jci44798 (opens in a new tab)

  83. 83.

    Stewart P. A. (2000 ). Endothelial vesicles in the blood-brain barrier: are they related to permeability? Cell Mol. Neurobiol. 20 149–163.

    Not in our library10.1023/a:1007026504843 (opens in a new tab)

  84. 84.

    Sumbria R. K. Hui E. K. Lu J. Z. Boado R. J. Pardridge W. M. (2013 ). Disaggregation of amyloid plaque in brain of Alzheimer’s disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide. Mol. Pharm. 10 3507–3513.

    Not in our library10.1021/mp400348n (opens in a new tab)

  85. 85.

    Thom G. Tian M. M. Hatcher J. P. Rodrigo N. Burrell M. Gurrell I. (2018 ). A peptide derived from melanotransferrin delivers a protein-based interleukin 1 receptor antagonist across the BBB and ameliorates neuropathic pain in a preclinical model. J. Cereb. Blood Flow Metab. [Epub ahead of print],.

    Not in our library10.1177/0271678x18772998 (opens in a new tab)

  86. 86.

    Thomas F. C. Taskar K. Rudraraju V. Goda S. Thorsheim H. R. Gaasch J. A. (2009 ). Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm. Res. 26 2486–2494.

    Not in our library10.1007/s11095-009-9964-5 (opens in a new tab)

  87. 87.

    Thompson A. Nessler R. Wisco D. Anderson E. Winckler B. Sheff D. (2007 ). Recycling endosomes of polarized epithelial cells actively sort apical and basolateral cargos into separate subdomains. Mol. Biol. Cell 18 2687–2697.

    Not in our library10.1091/mbc.e05-09-0873 (opens in a new tab)

  88. 88.

    Tsai P. S. Kaufhold J. P. Blinder P. Friedman B. Drew P. J. Karten H. J. (2009 ). Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels. J. Neurosci. 29 14553–14570.

    Not in our library10.1523/jneurosci.3287-09.2009 (opens in a new tab)

  89. 89.

    Villasenor R. Collin L. (2017 ). High-resolution Confocal imaging of the blood-brain barrier: imaging, 3D reconstruction, and quantification of transcytosis. J. Vis. Exp. 129:e59407.

    Not in our library10.3791/56407 (opens in a new tab)

  90. 90.
    Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model · 2012
    No notice
  91. 91.

    Weber F. Bohrmann B. Niewoehner J. Fischer J. A. A. Rueger P. Tiefenthaler G. (2018 ). Brain shuttle antibody for Alzheimer’s disease with attenuated peripheral effector function due to an inverted binding mode. Cell Rep. 22 149–162.

    Not in our library10.1016/j.celrep.2017.12.019 (opens in a new tab)

  92. 92.

    Webster C. I. Caram-Salas N. Haqqani A. S. Thom G. Brown L. Rennie K. (2016 ). Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. FASEB J. 30 1927–1940.

    Not in our library10.1096/fj.201500078 (opens in a new tab)

  93. 93.

    Webster C. I. Hatcher J. Burrell M. Thom G. Thornton P. Gurrell I. (2017 ). Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti-transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity. Pain 158 660–668.

    Not in our library10.1097/j.pain.0000000000000810 (opens in a new tab)

  94. 94.

    Wei L. Guo X. Y. Yang T. Yu M. Z. Chen D. W. Wang J. C. (2016 ). Brain tumor-targeted therapy by systemic delivery of siRNA with Transferrin receptor-mediated core-shell nanoparticles. Int. J. Pharm. 510 394–405.

    Not in our library10.1016/j.ijpharm.2016.06.127 (opens in a new tab)

  95. 95.

    Willis C. L. (2012 ). Imaging in vivo astrocyte/endothelial cell interactions at the blood-brain barrier. Methods Mol. Biol. 814 515–529.

    Not in our library10.1007/978-1-61779-452-0_34 (opens in a new tab)

  96. 96.
    The blood-brain barrier: an engineering perspective · 2013
    No notice
  97. 97.

    Wosik K. Cayrol R. Dodelet-Devillers A. Berthelet F. Bernard M. Moumdjian R. (2007 ). Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27 9032–9042.

    Not in our library10.1523/jneurosci.2088-07.2007 (opens in a new tab)

  98. 98.

    Yemisci M. Caban S. Fernandez-Megia E. Capan Y. Couvreur P. Dalkara T. (2018 ). Preparation and characterization of biocompatible chitosan nanoparticles for targeted brain delivery of peptides. Methods Mol. Biol. 1727 443–454.

    Not in our library10.1007/978-1-4939-7571-6_36 (opens in a new tab)

  99. 99.

    Yong V. W. (2005 ). Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat. Rev. Neurosci. 6 931–944.

    Not in our library10.1038/nrn1807 (opens in a new tab)

  100. 100.

    Yu Y. J. Zhang Y. Kenrick M. Hoyte K. Luk W. Lu Y. (2011 ). Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Transl. Med. 3:84ra44.

    Not in our library10.1126/scitranslmed.3002230 (opens in a new tab)

  101. 101.

    Zhang Y. Pardridge W. M. (2009 ). Near complete rescue of experimental Parkinson’s disease with intravenous, non-viral GDNF gene therapy. Pharm. Res. 26 1059–1063.

    Not in our library10.1007/s11095-008-9815-9 (opens in a new tab)

  102. 102.

    Zhang Y. Wang Y. Boado R. J. Pardridge W. M. (2008 ). Lysosomal enzyme replacement of the brain with intravenous non-viral gene transfer. Pharm. Res. 25 400–406.

    Not in our library10.1007/s11095-007-9357-6 (opens in a new tab)

  103. 103.

    Zhou Q. H. Boado R. J. Hui E. K. Lu J. Z. Pardridge W. M. (2011a ). Brain-penetrating tumor necrosis factor decoy receptor in the mouse. Drug Metab. Dispos. 39 71–76.

    Not in our library10.1124/dmd.110.036012 (opens in a new tab)

  104. 104.

    Zhou Q. H. Boado R. J. Hui E. K. Lu J. Z. Pardridge W. M. (2011b ). Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion protein. Drug Metab. Dispos. 39 1149–1154.

    Not in our library10.1124/dmd.111.038349 (opens in a new tab)

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