Biomedical Engineering Reference
In-Depth Information
these materials to the brain tumour to achieve tumour diagnosis, tumour
gene therapy or chemotherapeutic treatment. Cereport, a synthetic pep-
tide analogue of bradykinin, increases the permeability of the BBB by tran-
siently disrupting the TJ and shows specific time, dose and size dependent
actions on human brain microvascular endothelial cells [224]. Studies have
shown that Cereport is capable of enhancing the BBB transport of a num-
ber of drugs, including carboplatin, loperamide, and acyclovir in different
types of diseased animal models [225]. Because Cereport has no toxicity
by itself, it can selectively increase drug uptake in the brain tumour and
shows less effect in a non-permeable normal brain. When attached to the
surface of a liposome, Cereport is even more effective in facilitating Evans
blue transport into the brain compared to free Cereport with liposome
[226]. This study also demonstrated that Cereport attached liposomes can
be potentially used for transporting different types of drugs, including P-gp
substrates, via transient TJ opening.
Several modulators with the capacity to temporarily open a TJ to en-
hance the transport of drugs and traces have been evaluated. 45 kDa bio-
logical molecule zonula occludens toxin (Zot), an active TJ modulator at the
BBB, can induce a reversible, concentration-dependent TJ opening, which
increases the paracellular transport of sucrose and inulin (permeability
markers) without detectable short-term toxicity, in cultured bovine brain
capillary endothelia cells [227]. In addition, it also permits an enhanced
transport of the therapeutic agents doxorubicin and paclitaxel that would
normally have very low transportation across the BBB.
Viruses can also act as stimuli and open the TJ via upregulation of
chemokines as a precursor for infiltration of inflammatory cells into
the CNS. Immunohistochemical analysis of CNS tissue, from HIV-1-
seronegative and HIV-1-infected patients revealed significant tight junction
disruption in patients who died with HIV encephalitis, as shown by frag-
mentation or absence of immunoreactivity for occluding and ZO-1 [228].
These phenomena were associated with accumulation of activated HIV-1-
infected brain macrophages, fibrinogen leakage, and marked astrocytosis,
suggesting that the main route of HIV-1-infected monocyte entry into the
CNS could be the disrupted BBB structure.
The capacity of energy-based physical methods, such as ultrasound,
microwave or electromagnetic fields, to open the BBB has been also inves-
tigated. The important advantage of this approach is its specificity for tar-
geting to a specific area of brain. Focused ultrasound techniques concentrate
acoustic energy in a focal spot deep in the body with minimal effect to tis-
sues outside the field of focus. This allows it to non-invasively induce local
biological effects deep inside the body. Hynynen et al. [229] showed that
the introduction of a preformed gas bubble before focused ultrasound expo-
sure would allow transient opening of the BBB locally without causing acute
damage to the neurons. The gas bubble not only confines the ultrasound
