Drug Targeting Organ-Specific Strategies

44 2 Brain-Specific Drug Targeting Strategies
Table 2.2. Pharmacologic effects obtained with chimeric peptides in animal models.
Chimeric peptide Dose Mode of Animal model Effect
administration
Biotinylated VIP 12 µg kg -1 Intracarotid infusion Rat; artificial ventilation Increase in CBF
analogue under nitrous oxide
linked to OX26-Av anesthesia
Biotinylated VIP 20 µg kg-1 or Single i.v. injection Rat; conscious Dose-dependent
analogue 100 µg kg-1 increase in
linked to OX26-SA CBF
NGF chemically 6.2 µg/ i.v. injection Rat; intraocular forebrain Survival of cholinconjugated
to OX26
injection 4× every 2 weeks transplant ergic neurons
NGF chemically 50 µg/ i.v. injection, twice Aged rat (24 months) Improvement of
conjugated injection weekly for 6 weeks spatial memory
to OX26 in impaired rats
NGF chemically 20 µg/ i.v. injection Rat; quinolinic acid Rescue of striatal
conjugated injection daily 3 days + lesion cholinergic
to OX26 every 2 days
6×
neurons
NGF chemically i.v. injection Non-human primate Upregulation of
conjugated p75 NGF-receptor
to anti primate
TfR mAb AK30
in striatum
GDNF chemically 5µg/ i.v. injection Rat; intraocular spinal Survival of motorconjugated
to OX26 injection 3× every 2 weeks cord transplant neurons
Biotinylated 250 µg kg-1 i.v. injection Rat; transient forebrain Rescue of CA1
PEG-BDNF daily for 7 days ischaemia hippocampal
linked to OX26-SA neurons
BDNF, brain derived neurotrophic factor; CBF, cerebral blood flow; GDNF, glial cell line derived
neurotrophic factor; NGF, nerve growth factor; TfR, transferrin receptor; VIP, vasoactive intestinal
polypeptide.
demonstration of a pharmacological effect with a vector-mediated drug delivery strategy, because
VIP-containing nerve fibres are abundant around intracerebral small arteries and arterioles.
This peptide acts as a potent vasodilator when applied topically to intracranial vessels
and plays an important role in the modulation of cerebral blood flow (CBF). However,
as its receptors are expressed on the vascular smooth muscle cells, which are beyond the
blood–brain barrier, no effects on CBF are usually seen after systemic administration of VIP.
A metabolically stabilized analogue of VIP was constructed which could be biotinylated at
a single site. Brain delivery of the biotinylated VIP analogue by the OX26–avidin vector resulted
in the desired pharmacological effect. A significant increase in CBF of 65% could be
demonstrated after systemic administration of the chimeric peptide.The effect was seen both
in anaesthetized rats under controlled respiration after intracarotid infusion as well as in conscious
animals after i.v. bolus injection. When an equal dose of the peptide alone without a
vector was injected (12 µg kg –1 for the intracarotid infusion or 20 µg kg –1 in the i.v. study)
there was no measurable effect on CBF compared to control animals. In contrast, the well established
peripheral effects of VIP on glandular blood flow in the thyroid gland or the sali-