Biomedical Engineering Reference
In-Depth Information
insertion of a small-caliber catheter into the brain parenchyma. Through
this catheter, the drug is actively pumped into the brain parenchyma and
penetrates into the interstitial space. Because infusion is delivered directly
into the brain parenchyma via a cannula, the BBB is bypassed and specific
regions can be targeted for treatment [235]. This method has demonstrated
in laboratory experiments to deliver high molecular weight proteins 2 cm
from the injection site in the brain parenchyma [236]. The success of CED
relies on precise placement of the catheters and other infusion parameters
for delivery into the correct location in the brain parenchyma.
Implants are made up of biodegradable/non-biodegradable polymeric
materials encapsulating drugs inside them. The basic mechanism behind
drug release from these devices is diffusion. These implants are placed inside
the brain surgically, where they release the drug for a predetermined level
of time. Polymer depots have been used for the delivery of drugs into the
cerebral environment in the tumor cavity of the brain, with the drug being
present inside the polymer matrix as a core material. It offers sustained re-
lease of drugs by the biodegradation of polymer. Similarly Gliadel® wafer
(MGI Pharma, Bloomington, USA), a polymer depot containing carmus-
tine showed its release over a period of 5 days when placed in the tumor
resection cavity [237]. This system was composed of a lipophilic anticancer
agent, carmustine, incorporated into a poly(carboxypropane)-sebacic acid
(PCPP-SA) belonging to the series of polyanhydrides. The therapeutic effect
of the Gliadels wafer was tested in two phase III clinical trials [238-239].
The median survival time obtained with treated patients was significantly
prolonged in comparison with untreated patients (2-month increase).
However, with the application of this system, infections and cerebral edemas
due to the high concentration of carmustine and obstructive hydrocephalus
resulting from the dislodgment of the wafer, were also demonstrated.
6.1.4 Drug modifications and prodrugs
Physicochemical properties of drugs, such as lipophilicity, lack of ionization
at physiological pH, and molecular weight, determine the extent to which
drugs can cross the BBB. Various attempts have been made to overcome the
limited access of drugs to the brain by chemical modification of the drug.
One strategy for modification of the drug is lipidization, which involves the
addition of lipid-like molecules through modification of the hydrophilic
moieties on the drug structure. Lipid-soluble molecules are believed to be
transported through the barrier, by accessing small pores that form tran-
siently within the lipid bilayer. The addition of hydrophobic groups to a
molecule may enhance its brain transfer by passive diffusion. Consecutive
addition of methyl groups, in a series of barbiturates, increased lipophilic-
ity and brain penetration in animals. This strategy has been frequently em-
ployed, but the results have often been disappointing. The best examples of
such attempts are the series of lipophilic analogues of nitrosoureas, where
