Biomedical Engineering Reference
In-Depth Information
cholesterol formulation (LIP) in vitro and in vivo. These data suggested
that adsorptive transcytosis could be one of the mechanisms for TAT-LIP
transport across the BBB, and the positive charge of the TAT-LIP played
an important role in enhancing this transport. AMT enables many poorly
brain-penetrating drugs to cross the BBB, and holds potential for promoting
drug delivery into the brain. However, because it is a non-specific process, the
adsorptive process also occurs in the blood vessels and in other organs. This
poses a challenge for both achieving therapeutic concentration in the brain
and limiting the drug distribution in non-target organs.
6.1.2.3 Efflux pump inhibition
Passive diffusion of substances across the BBB may depend on their lipo-
philicity and molecular weight. However, a large number of compounds are
rapidly effluxed from the brain into the blood by extremely effective efflux
pumps expressed in the BBB. These efflux systems include Pglycoprotein
(Pgp) and multidrug resistance proteins (MRPs). There exists also, an enzy-
matic barrier to drug transport in the BBB. Specifically, the activity of many
enzymes that participate in the metabolism and inactivation of endogenous
compounds, such as g-glutamyl transpeptidase, alkaline phosphatase, and
aromatic acid decarboxylase is elevated in cerebral microvessels. To circum-
vent this obstacle, it is possible to administer the drug with a pharmaco-
logical modulator, which inhibits efflux transport systems in brain capillary
endothelial cells. One promising example of such pharmacological modula-
tors is represented by a class of Pluronic® block copolymers. These block
copolymers consist of hydrophilic ethylene oxide (EO), and hydrophobic
propylene oxide (PO) blocks arranged in a basic A-B-A tri-block structure
EO
n/2
-PO
m
-EO
n/2
. The block copolymers with various numbers of hy-
drophilic EO (
n
) and hydrophobic PO (
m
) units, are characterized by a
distinct hydrophilic-lipophilic balance (HLB). Due to their amphiphilic
character these copolymers display surfactant properties including the ability
to interact with hydrophobic surfaces and biological membranes. Extensive
studies have confirmed that Pluronic® P85, a Pluronic® block copolymer,
can be used not only as an effective efflux pump inhibitor, but also as a drug
delivery vehicle [216]. Studies in multidrug resistant cancer cells, polarized
intestinal epithelial cells, Caco-2, and polarized BBB monolayers provided
compelling evidence that selected Pluronic® block copolymers can inhibit
drug efflux transport systems [217]. The most studied Pluronic® P85
showed the ability to enhance the BBB permeability for a wide range of
drugs, including doxorubicin, etoposide, taxol, 3¢-azido-3¢-deoxythymidine,
valproic acid, and loperamide in the bovine brain microvessel. Evidence sug-
gests that the inhibition mechanisms of Pluronic® block copolymers on
P-gp activity in the BBB involve three effects, namely copolymer interaction
with the cell membrane, inhibition of P-gp ATPase activity, and depletion
of cellular ATP [216].
