Vector-mediated drug delivery to the brain
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.
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