Drug Targeting Organ-Specific Strategies

40 2 Brain-Specific Drug Targeting Strategies
Morphological studies in rats, where the induction of neuropathological changes by osmotic
opening was examined, provided evidence of uptake of macromolecules by the brain.
The extravasation of plasma proteins such as fibrinogen and albumin was shown immunohistochemically
at the light microscopic level. Electron microscopy revealed ultrastructural
changes such as swelling of astrocytic processes and severe mitochondrial damage in neurons
[73]. There was also evidence of prolonged (24 h) cellular stress or injury in neurons and glia
as expressed by the induction of heat shock protein (HSP-70).While the nonspecific opening
of the BBB to plasma proteins harbours a risk of eliciting neuropathological changes, osmotic
disruption has been tested for its potential as a delivery method for macromolecular drugs
such as monoclonal antibodies against various tumour antigens or their Fab fragments. In
other studies, uptake after intracarotid administration of nanoparticles (20-nm iron oxide
particles) by normal brain, and uptake of recombinant adenovirus or herpes virus by normal
brain tissue and brain tumour xenografts in nude rats was postulated [74,75].
Compared to small molecules, barrier opening for high molecular weight compounds is of
shorter duration [72]. Furthermore, a characteristic difference exists in the degree of barrier
opening in tumour versus normal brain tissue. Barrier disruption was consistently found to
be more pronounced for the normal BBB, which may limit the clinical applicability of hyperosmolar
barrier opening, at least for cytotoxic drugs [76].
BBB opening may also be achieved by receptor-mediated mechanisms. The vasoactive
compounds prostaglandins, histamine, serotonin, leukotriene C 4 (LTC 4), and bradykinin
have all been shown to increase BBB permeability [16]. The effects of LTC 4 and bradykinin
are more pronounced on the blood–tumour barrier than on the normal BBB. In the case of
LTC 4 this effect is ascribed to the presence of an enzymatic barrier in normal brain tissue due
to the endothelial expression of γ-GTP. The enzyme metabolizes and inactivates LTC 4 to
LTD 4. In contrast, tumour vessels are unable to express equivalent activities of γ-GTP, a fact
that may be exploited for selective opening of the tumour barrier by intracarotid administration
of LTC 4. However, the effect is restricted to small molecules, as there was no increase
in the tumour accumulation of a dextran tracer of molecular weight 70 kDa. On the other
hand, bradykinin also opens the barrier for the high molecular weight range. It acts on endothelial
cells through B 2-receptors located on the abluminal side. Normal brain tissue is protected
from barrier opening by bradykinin in the vascular lumen because the peptide cannot
access these receptors. In tumour vessels the barrier integrity is sufficiently compromised to
allow for additional bradykinin-mediated opening at low peptide concentrations. While
bradykinin itself requires intracarotid administration, an analogue with prolonged half-life
(RMP-7) is effective after intracarotid or intravenous application. A 4–5-fold increase in the
delivery of the cytokines interferon-γ , tumour necrosis factor α and interleukin-2 to experimental
RG2 glioma in rats was demonstrated after intracarotid infusion of RMP-7 [77]. The
drug is currently being evaluated in the therapy of human malignant gliomas to enhance delivery
of carboplatin to the tumour [78].
2.4.2.5 Vector-mediated Delivery
In this approach,‘chimeric peptides’ [79] are generated as transportable drug derivatives targeting
the receptor-mediated mechanism. Chimeric peptides are formed by linking a drug