Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 537

A murine monoclonal antibody (OX26) to the transferrin receptor and insulin frag-
ments have been successfully used to deliver therapeutic P/P in animal studies [72-74] .
Large peptides, such as BDNF [75] and NGF, can be vector delivered to the brain,
and because neuronal growth and regeneration may require only trace quantities of
the latter protein, this biotechnology has potential clinical use in the treatment of neu-
ronal degeneration or the stimulation of brain repair.
BDNF activates the receptor tropomyosin-related kinase B (TrkB) with high
potency and specificity, promoting neuronal survival, differentiation, and synaptic
function in the ischemic hippocampus if the neurotrophin is injected directly into the
brain. This is not feasible in the case of human stroke, and the efficacy of BDNF
via peripheral (intravenous) administration is limited by the lack of transport of the
neurotrophin through the brain capillary wall in vivo . In one study, BDNF chime-
ric peptide was prepared by the conjugation of BDNF-PEG 2000 (BDNF pegylated
to improve the pharmacokinetics of BDNF) either to streptavidin or OX26 to the
BBB transferrin receptor. Avidin-biotin technology is used to link the BDNF and the
MAb. Conjugation of MAb to the BDNF was explored to ferry the BDNF across
the BBB via the transferrin receptor more effectively, resulting in a high degree of
neuroprotection in ischemia. Chimeric BDNF was administered via an intravenous
route. Figure 11.2 represents the BDNF chimeric peptide [75] .
In the treatment of infectious diseases of the CNS, there may be situations when pas-
sive immunization through the delivery of specific antisera may be clinically appropri-
ate. One technique for achieving this goal involves using the cationized albumin receptor
to deliver immunoglobulins across the BBB. This has been successfully executed by
Triguero et al. [76] , who demonstrated enhanced brain delivery of cationized immuno-
globulin compared to native protein in rats. IgG has been cationized by covalent cou-
pling of hexamethylenediaminie, resulting in increased transport of these plasma proteins
through the BBB in vivo . An alternate, but related, approach involves the conjugation of
Figure 11.2 Schematic representation of PEGylated BDNF chimeric peptide brain drug
targeting technology.