Drug Targeting Organ-Specific Strategies

SALINE
n=8
VECTOR
n=5
VIP
n=7
VIP/VECTOR
n=8
Organ blood flow (µL / min / g)
BRAIN BLOOD FLOW
SALIVARY GLAND BLOOD FLOW
VECTOR = OX26 / SA without VIPa
VIP = VIPa without VECTOR
VIP/VECTOR = BIO-xx-VIPa / OX26-SA
2.4 Drug Delivery Strategies 45
Figure 2.9. Differential pharmacological effect elicited
by vector-mediated delivery of a VIP analogue. The
organ blood flow in brain and salivary gland was
measured in conscious rats after i.v. administration of
vehicle (saline), the brain delivery vector OX26-SA,
the VIP peptide alone, or the chimeric peptide. While
cerebral blood flow increased in the chimeric peptide
group by 60% compared to the saline control, the
increase in salivary gland blood flow seen with the
peptide alone was abolished by coupling to the vector.
The VIP analogue was biotinylated with a noncleavable
14-atom spacer (biotin-XX) for coupling to
the vector. Data from reference [95].
vary gland were readily detectable [89,95], as shown in Figure 2.9. Notably, the effect on salivary
gland blood flow was attenuated in animals treated with the chimeric peptide delivery
system.Taking salivary gland blood flow in that respect as a potential adverse drug effect, the
delivery strategy of the VIP analogue to the brain not only resulted in the desired pharmacological
response at the target site, but it also diminished the effect at non-target sites and
therefore increased the therapeutic index [95].
Demonstrations of pharmacological effects of chimeric peptides have been achieved with
different neurotrophic factors in models of neurodegenerative diseases and ischaemia. The
initial report by Friden et al. utilized an ocular graft model of fetal midbrain placed into the
anterior eye chamber of adult rats [85].The vasculature of the grafted tissue retained its BBB
properties. Nerve growth factor was chemically coupled to the vector OX26 via a disulfide
linker. Repeated i.v. administration (four times bi-weekly) of the chimeric peptide promoted
survival of the cholinergic neurons within the graft. Further proof of pharmacological effect
of the same conjugate was obtained in aged rats with spatial learning deficits. They responded
to a 6-week treatment with twice weekly i.v. injections with improved performance in the
so-called Morris water maze learning task and immunohistochemistry showed increased cell
size of cholinergic neurons in the medial septal area of these rats [96]. The NGF-OX26
chimeric peptide was also effective in a quinolinic acid lesioning model of Huntington’s disease
[97].Treatment for 2 weeks significantly reduced the loss of intrastriatal cholinergic neurons
induced by stereotaxic injection of quinolinic acid.
Animal models of Parkinson’s disease suggest that Glial Cell-Line Derived Neurotrophic
Factor (GDNF) may be a suitable treatment modality for degenerative processes involving
dopaminergic midbrain neurons, and traumatic injury of spinal motor neurons.Therefore, the
effect of a GDNF-OX26 chimeric peptide was studied in another neural graft model [98].The
vector-mediated delivery of small i.v. doses equivalent to 5 µg of GDNF significantly promoted
the survival of ocular implants of fetal spinal cord motor neurons in rats.
The potential therapeutic benefit of brain-derived neurotrophic factor BDNF for rescuing
neurons after stroke was demonstrated in a forebrain ischaemia model [93]. In that study,