Vector-mediated drug delivery to the brain

https://doi.org/10.1016/S0169-409X(98)00087-8Get rights and content

Abstract

Vector-mediated drug delivery to the brain employs the chimeric peptide technology, wherein a non-transportable drug is conjugated to a blood–brain barrier (BBB) transport vector. The latter is a modified protein or receptor-specific monoclonal antibody that undergoes receptor-mediated transcytosis through the BBB in vivo. Conjugation of drug to transport vector is facilitated with either chemical linkers, avidin–biotin technology, polyethylene glycol linkers, or liposomes. Multiple classes of therapeutics have been delivered to the brain with the chimeric peptide technology, including peptide-based pharmaceuticals, such as a vasoactive intestinal peptide analog or neurotrophins such as brain-derived neurotrophic factor, antisense therapeutics including peptide nucleic acids, and small molecules incorporated within liposomes. The successful delivery of a drug through the BBB in vivo requires special molecular formulation of the drug. Therefore, it is important to merge central nervous system drug discovery and delivery as early as possible in the overall CNS drug development process.

Introduction

Drug delivery to the brain is made difficult by the presence of the blood–brain barrier (BBB), which is formed by tight junctions within the capillary endothelium of the vertebrate brain [1]. These tight junctions eliminate the normal porous transcellular or paracellular pathways for solute diffusion from plasma to organ interstitial space. Circulating drugs, with the exception of lipid-soluble small molecules with a molecular mass under a 400–600 threshold 2, 3, have restricted passage through the BBB, and do not enter the central nervous system (CNS) in pharmacologically significant amounts from the bloodstream. Traditional approaches to solving the brain drug delivery problem attempt to bypass the BBB and employ craniotomy-based drug delivery, including either intraventricular drug infusion or local intracerebral implants. In addition to being highly invasive, craniotomy-based drug delivery relies on diffusion from local depot sites. Since diffusion decreases with the square of the diffusion distance, the effective treatment volume is <1 mm3 from the local release site [4].

Craniotomy-based drug delivery to the brain is not needed if brain targeting strategies are used that take advantage of the normal endogenous transport pathways within the brain capillary endothelium. Fig. 1 illustrates that both carrier-mediated transport (CMT) and receptor-mediated transport (RMT) pathways are available for certain circulating nutrients or peptides. The availability of these endogenous CMT or RMT pathways means that portals of entry to the brain for circulating drugs are potentially available. Specific nutrient transport systems include the hexose carrier, which transports d-glucose, but not l-glucose, and also transports 2-deoxyglucose, 3-O-methylglucose, mannose or galactose [5]. The BBB monocarboxylic acid transporter (MCT) mediates BBB passage of lactate, pyruvate and ketone bodies and is inhibited by monocarboxylic acid drugs such as probenecid 6, 7, 8. The BBB neutral amino acid transporter (NAAT) transports phenylalanine and 13 other large or small neutral amino acids in plasma [9]. The BBB basic amino acid transporter (BAAT) transports arginine, lysine, and ornithine [9]. The BBB choline transporter transports choline and other quaternary ammonium drugs [10]. The BBB adenosine carrier mediates the brain uptake of purine nucleosides and some pyrimidine nucleosides such as uridine [11]. The BBB adenine carrier mediates the brain uptake of purine bases such as adenine or guanine but not pyrimidine bases [11]. The CMT pathways are reviewed in detail in other chapters of this volume. This chapter will review the RMT pathways and provide examples of how these endogenous transport systems within the BBB can be used to facilitate drug delivery to the brain.

Section snippets

Origin of the concept

The concept of receptor-mediated transcytosis (RMT) of peptides through the BBB originated in the mid-1980s with the observation that the human BBB insulin receptor mediated the endocytosis of insulin into the brain capillary endothelium in vitro and the transcytosis of insulin through the BBB in vivo [12]. Insulin was observed to bind in a saturable mechanism to capillaries isolated from both animal and human autopsy brains 13, 14. The saturation studies allowed for computation of the

Vector discovery

Ligands for the various RMT systems shown in Fig. 1 are potential vectors for delivering drugs across the BBB. The use of insulin as a vector is problematical because the administration of a drug–insulin conjugate, would cause hypoglycemia by triggering insulin receptors in peripheral tissues. The use of transferrin as a delivery vector may not be advantageous owing to the very high concentration of endogenous transferrin in the circulation, which competes for BBB transferrin binding sites. The

Chemical linkers

The attachment of the drug, that normally does not undergo transport through the BBB, to a BBB transport vector such as the 83-14 MAb, results in the formation of a chimeric peptide, providing the bifunctionality of the conjugate is retained [38]. That is, the chimeric peptide must have not only a BBB transport function, but also a pharmaceutical function derived from the attached drug. Certain drugs may not be pharmacologically active following attachment to a BBB transport vector. In this

Vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) is a potent CNS vasodilator when the peptide is applied topically to pial vessels [58]. However, the intracarotid infusion of VIP does not increase cerebral blood flow owing to the failure of this peptide to cross the BBB in vivo [59]. Conversely, the systemic administration of VIP results in marked increases in blood flow in certain peripheral tissues, e.g., salivary gland [60], owing to the rapid transport of this 3000 Dalton peptide across the porous walls

Antisense therapeutics

Antisense oligodeoxynucleotides (ODN) are potential neuropharmaceuticals with high degrees of specificity since these molecules, in theory, should react in a sequence specific mechanism with target messenger RNA (mRNA) molecules in the cell cytosol. The first generation antisense ODNs were phosphodiester (PO)–ODNs and these molecules had dual sites of action: (i) RNA degradation via activation of RNase H through formation of DNA–RNA heteroduplexes, and (ii) arrest of RNA translation by

Liposome delivery through the blood–brain barrier

The strategies for linking drugs to transport vectors shown in Table 2 all involve an approximate 1:1 stoichiometry of vector to drug. However, the carrying capacity of the vector could be greatly expanded by incorporation of the non-transportable drug in liposomes, followed by subsequent conjugation of the liposome to a BBB drug delivery vector. Liposomes, even small unilamellar vesicles, do not undergo significant transport through the BBB in the absence of vector-mediated drug delivery [86].

Conclusions

The chimeric peptide technology involves conjugation of a non-transportable drug to a BBB transport vector, and has been applied to peptide pharmaceuticals, nucleic acid therapeutics, and small molecules (Fig. 9). Present-day vectors achieve levels of brain uptake of a non-transportable pharmaceutical that exceed the brain uptake of morphine by 1–10 fold. The availability of the 83-14 HIRMAb allows for extension of the chimeric peptide technology to Old World primates such as Rhesus monkeys,

Acknowledgements

This work was supported by Department of Energy grant DE-FG03-98ER62655.

References (89)

  • E.A. Bayer et al.

    Protein biotinylation

    Methods Enzymol.

    (1990)
  • S.L. Morrison et al.

    Genetically engineered antibodies and their application to brain delivery

    Adv. Drug Deliv. Rev.

    (1995)
  • Y. Suzuki et al.

    Characterization of the relaxant effects of vasoactive intestinal peptide (VIP) and PHI on isolated brain arteries

    Brain Res.

    (1984)
  • M. O'Donnell et al.

    Structure-activity studies of vasoactive intestinal polypeptide

    J. Biol. Chem.

    (1991)
  • D.A. Brown et al.

    Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding

    J. Biol. Chem.

    (1994)
  • R.L. Juliano et al.

    Pharmacokinetics of liposomes-encapsulated anti-tumor drugs. Studies with vinblastine, actinomycin D, cytosine arabinoside, and daunomycin

    Bioch. Pharmacol.

    (1978)
  • M.W. Brightman, T.S. Reese, N. Feder, Assessment with the electron-microscope of the permeability to peroxidase of...
  • V.A. Levin

    Relationship of octanol–water partition coefficient and molecular weight to rat brain capillary permeability

    J. Med. Chem.

    (1980)
  • W.M. Pardridge

    CNS drug design based on principles of blood–brain barrier transport

    J. Neurochem.

    (1998)
  • M. Mak et al.

    Distribution of drugs following controlled delivery to the brain interstitium

    J. Neuro-Oncol.

    (1995)
  • W.H. Oldendorf

    Carrier-mediated blood–brain barrier transport of short-chain monocarboxylic organic acids

    Am. J. Physiol.

    (1973)
  • W.M. Pardridge et al.

    Permeability changes in the blood–brain barrier: Causes and consequences

    CRC Crit. Rev. Toxicol.

    (1975)
  • W.H. Oldendorf

    Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection

    Am. J. Physiol.

    (1971)
  • E.M. Cornford et al.

    Carrier mediated blood–brain barrier transport of choline and certain choline analogs

    J. Neurochem.

    (1978)
  • W.M. Pardridge

    Receptor-mediated peptide transport through the blood–brain barrier

    Endocrine Rev.

    (1986)
  • H.J.L. Frank et al.

    A direct in vitro demonstration of insulin binding to isolated brain microvessels

    Diabetes

    (1981)
  • W.M. Pardridge et al.

    Human blood–brain barrier insulin receptor

    J. Neurochem.

    (1985)
  • R.D. Broadwell et al.

    Transcytotic pathway for blood- borne protein through the blood–brain barrier

    Proc. Natl. Acad. Sci. USA

    (1988)
  • U. Bickel et al.

    In vivo demonstration of subcellular localization of anti-transferrin receptor monoclonal antibody–colloidal gold conjugate within brain capillary endothelium

    J. Histochem. Cytochem.

    (1994)
  • R.R. Reinhardt et al.

    Insulin-like growth factors cross the blood–brain barrier

    Endocrinology

    (1994)
  • P.L. Golden et al.

    Human blood–brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels

    J. Clin. Invest.

    (1997)
  • J.B. Fishman et al.

    Receptor-mediated transcytosis of transferrin across the blood–brain barrier

    J. Neurosci. Res.

    (1987)
  • M.W.B. Bradbury

    Transport of iron in the blood–brain–cerebrospinal fluid system

    J. Neurochem.

    (1997)
  • C.M. Morris et al.

    Uptake and distribution of iron and transferrin in the adult rat brain

    J. Neurochem.

    (1992)
  • R.L. Roberts et al.

    Receptor-mediated endocytosis of transferrin at the blood–brain barrier

    J. Cell. Sci.

    (1993)
  • R. Roberts et al.

    Studies of the mechanism of iron transport across the blood–brain barrier

    Ann. Neurol.

    (1992)
  • D. Wu et al.

    Drug targeting of a peptide radiopharmaceutical through the primate blood–brain barrier in vivo with a monoclonal antibody to the human insulin receptor

    J. Clin. Invest.

    (1997)
  • A.W. Vorbrodt

    Ultracytochemical characterization of anionic sites in the wall of brain capillaries

    J. Neurocytol.

    (1989)
  • J. Huwyler et al.

    Examination of blood–brain barrier transferrin receptor by confocal fluorescent microscopy of unfixed isolated rat brain capillaries

    J. Neurochem.

    (1998)
  • L. Descamps et al.

    Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells

    Am. J. Physiol.

    (1996)
  • Y. Shechter et al.

    Autoantibodies to insulin receptor spontaneously develop as anti-idiotypes in mice immunized with insulin

    Science

    (1982)
  • W.A. Jefferies et al.

    Transferrin receptor on endothelium of brain capillaries

    Nature

    (1984)
  • L.R. Walus et al.

    Enhanced uptake of rsCD4 across the rodent and primate blood–brain barrier following conjugation to anti- transferrin receptor antibodies

    J. Pharmacol. Exp. Ther.

    (1996)
  • W.M. Pardridge et al.

    Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood–brain barrier in vivo in the primate

    Pharm. Res.

    (1995)
  • Cited by (129)

    • Recent advances in siRNA delivery mediated by lipid-based nanoparticles

      2020, Advanced Drug Delivery Reviews
      Citation Excerpt :

      Recent studies focused on brain delivery have offered a novel strategy for the treatment of neurological disorders. In addition to reducing drug size, delivering drugs to the brain via carrier-mediated transport involved in uptake such as that of glucose can be a very attractive strategy [204,205]. In 2013, it was reported that ionizable cationic lipid-LNP containing siRNA spread widely in the brain and showed significant knockdown of target mRNA (GRIN1, coding GluN1 subunit of NMDA [N-methyl-d-aspartate] receptor) in the brain after intracortical or intracerebroventricular injection without an immune response [206].

    • Liposomes for drug delivery in stroke

      2019, Brain Research Bulletin
    • Applications of nanotechnology in drug delivery to the central nervous system

      2019, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      The ligands or antibodies coupling to the surfaces are well suited for cancer therapies. The HER2/neu ligand is an instance of small-molecule proteins and is applied for targeting poly (lactide-coglycolide) NPs with docetaxel, which has been investigated in vitro with HER2+ breast cancer cells [172–174]. Monoclonal antibodies are frequently used for targeting.

    • Drug delivery to the brain

      2019, Nanomaterials for Drug Delivery and Therapy
    View all citing articles on Scopus
    View full text