Biomedical Engineering Reference
In-Depth Information
selectivity and is very different from the concept of targeting from a military per-
spective where the term arguably first originated. Consider the firing of a bullet
from a gun as an example. The object the bullet is intended to hit is the target, while
targeting is associated with the act of aiming the gun so the bullet hits the target.
The action that the bullet produces is destruction of the target. This action is indis-
criminate in that if the bullet hits an object other than the target, that object will be
destroyed as well. Using the gunshot analogy to illustrate the drug discovery per-
spective on targeting would involve firing bullets that only destroy the target but
leave the non-targets unharmed. Most approaches to disease therapy have followed
such an argument: finding such selective molecules has been relatively easy when
there were significant differences between the disease causing process and normal
human biochemical pathways. Not surprisingly, infectious diseases are relatively
easier to treat than inherent disorders. The selectivity is however dose dependent
and most drugs that are considered to be selectively toxic to invading pathogens are
in fact toxic to human cells as well, but at higher doses.
The current challenges in drug therapy lie in the treatment of diseases associated
with malfunctions of normal human biochemical pathways in certain tissues. More
often that not, even dose dependent selectivity is hard to achieve. Therefore the
concept of targeting is becoming more and more associated with selective delivery.
The term 'targeting' should ideally imply that the molecule is in some way able to
selectively accumulate at an intended site of action and that the selective accumula-
tion is associated with its selective action. This distinction is particularly important
in developing targeted therapy for a disease like cancer. Unless unique molecular
targets found exclusively (or at sufficiently higher levels) in the diseased state and
not in normal state are discovered, selective accumulation at the disease site is
crucial to the improvement of therapy. In summary, it can be said that there appear
to be two distinct approaches to targeting in the context of drug therapy. The first
involves selective action on the target while the second involves selective accumu-
lation at the target. Most if not all examples of targeting seem to end up being the
combination of some degree of selective action on the target and some degree of
selective accumulation at the site of the target. Improving the degree of selective
accumulation has the added advantage, even for molecules with high target selec-
tive action, of reducing the required dose and hence should be a major focus of all
targeting approaches.
In the context of drug molecules the properties of selective accumulation are
associated with the concept of bioavailability and biodistribution that are related
to the physico-chemical properties of the molecule. To overcome the limitations
that a compound's physico-chemical properties can impose on its potential phar-
maceutical application, the process of large-scale screening of chemical libraries
has been extended beyond identifying desired bioactivity. Screening approaches
routinely incorporate selection for physico-chemical properties that are known to
confer high bioavailability as well. Unfortunately, this approach often leads to
many potent molecules being excluded from further development. These mole-
cules often have a potent pharmacological action at a desired molecular target but
aren't able to find their way exclusively to that target. It is almost certain that there
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