Biomedical Engineering Reference
In-Depth Information
or electromagnetic radiations, which helps in the opening of tight junc-
tions. Because the tight junctions act as a tightly bound wall, one method
for the penetration of the BBB is by disruption. The disruption of the BBB
must be transient and reversible in order to have any role in the delivery of
therapeutic molecules. Disruption of the BBB can be achieved by infusion
of hypertonic solutions [23]. Hypertonic solutions cause opening of tight
junctions due to higher osmotic pressure, which leads to a shrinking of
endothelial cells, by which disarrangement of extracellular proteins occurs,
and finally entry of the drug which takes place paracellularly [23]. Various
osmotic substances have already been tested, and amongst these mannitol
has been found to be effective and safe. Mannitol has been used for several
years for treating brain tumors, where the barrier is opened for 30 min
when a 25% solution of the drug is allowed for 30s [220]. Lysophosphatidic
acid increases TJ permeability in cultured brain endothelial cells via the
activation of PKC-alpha channels, which reduces caudin-5 expression
and F-actin recombination [221]. These substances show a rapid, dose-
dependent and reversible action, where the effect can be attenuated by
activation of protein kinase C. Cyclodextrins (CDs) are cyclic oligosac-
charides composed glucose units, namely a-, b-, g-CD. Monnaert and col-
leagues [222] studied the endothelial permeability and toxicity of native,
methylated, and hydroxypropylated a-, b-, g-CD in an in vitro cell model.
Native a-, b-CD elicited a rapid increase in sucrose permeability of ce-
rebral endothelial cell monolayers, which correlated with their ability to
extract phospholipids [222]. High concentrations of hydroxypropyl g-CD
and g-CD increased doxorubicin passage through the brain endothelial cell
monolayers, but at the expense of a loss of the BBB integrity and decreased
junctional staining of occludin. This finding suggests that oligosaccharide
units are likely to be responsible for the toxicity of CDs in the brain, because
of their extraction of lipophilic components of the BBB, phospholipids and
cholesterol, which may break down the brain endothelial cell monolayers
[223]. Biologically active vasoactive agents such as bradykinin, angiotensin
peptides, leukotrienes, histamine and VEGF are also capable, under some
circumstances, of disrupting the BBB, suggesting that they may play a role
in modulating the BBB permeability. Bradykinin is a plasma kinin pro-
duced from a plasma globulin kininogen by the action of specific enzyme
kalikreins. This is found to permeate the BBB by action on B2 receptors
expressed on the endothelium of luminal membrane. It can modulate in-
tercellular tight junctions by elevating the calcium level of the membrane
which activates actin/myosin fibres leading to leaching out of junctional
proteins and loosening of the tight junction. In the case of brain gliomas,
microvascular permeability in tumour tissue is more sensitive to the ef-
fects of these biological compounds than the normal brain endothelia cells.
Therefore, these stimuli when used in combination with imaging materials,
gene or anticancer drugs, can potentially boost the preferential delivery of
