Drug Targeting Organ-Specific Strategies

2.4 Drug Delivery Strategies 41
that is unable to cross the BBB to a vector (see Figure 2.8). Binding of the vector at the luminal
membrane of brain capillary endothelial cells initiates receptor-mediated or adsorptive-mediated
transcytosis (Figure 2.3c). Size and structure of the cargo may vary as long as
binding and cellular uptake of the vector is not inhibited by the drug moiety, and may only be
limited by the size of the endocytotic vesicles.
Initial studies of brain delivery based on the chimeric peptide strategy used the absorptivemediated
uptake of cationized albumin which was chemically coupled to the opioid peptide
β-endorphin [80] or its metabolically stabilized analogue [D-Ala 2 ]β-endorphin. Tracer experiments
in which the chimeric peptide was labelled in the endorphin moiety provided evidence
of internalization by isolated brain capillaries and transport into brain tissue in vivo
[81].
Endogenous ligands for receptor-mediated systems may be unsuitable as vectors due to
competition for transport or undesirable pharmacological effects. For example, plasma concentrations
of transferrin are in the range of 25 µM. Insulin as a vector would cause hypoglycaemia.
A logical alternative as vectors are monoclonal antibodies specific to the extracellular
domain of a peptide or protein receptor at the BBB. These antibodies can be designed as
non-competitive, i.e. they bind to the receptors at a site distinct from the ligand binding site
and do not interfere with the endocytosis process.
Brain uptake data for some vectors are compared in Table 2.1. Quantitative comparisons
within the same species are possible for the rat with vectors derived from the anti-TfR monoclonal
antibody OX26 and from cationized human serum albumin. To put the efficiency of
brain delivery into perspective, the comparison to a classical neuroactive drug may be informative.
In the rat, brain concentrations of morphine following systemic administration never
exceed 0.08% of injected dose per gram [%ID g –1 ] [82]. In contrast, OX26 easily reaches concentrations
in rat brain that are three to four times higher. Vectors based on cationized hu-
Vector Linker Drug
OX26
84-15
cHSA
(Strept)avidin -
Biotin
Peptides
VIP
DALDA
Proteins
NGF
BDNF
Oligonucleotides
PNA
Genes
luciferase
-Gal
Liposome
encapsulated drugs
Figure 2.8. Scheme of a chimeric peptide with examples for each of the distinct domains. OX26, anti-rat
transferrin receptor monoclonal antibody (mAb); 84-15, anti-human insulin receptor mAb; cHSA,
cationized human serum albumin; VIP, vasoactive intestinal polypeptide; DALDA, dermorphin
analogue; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; PNA, peptide nucleic
acid; β-gal, β-galactosidase.