Drug Targeting Organ-Specific Strategies

10 1 Drug Targeting: Basic Concepts and Novel Advances
overcome the final obstacle, finding the nucleus, application of knowledge of viral infection
processes have led to the application of viral nuclear localization signals. Furthermore, the
aforementioned viral tegument protein VP22 also localizes in the nuclear compartment. In
the early stages of cell mitosis, VP22 translocates into the nucleus, binds to the condensing
chromatin and remains bound [44]. It will be interesting to see whether these principles of
nuclear targeting can be exploited for the targeted delivery of DNA to the cell type of choice.
By assembling polypeptides that can code for all the necessary cellular transport tasks on
a scaffold, Sheldon and colleagues developed so-called ‘loligomers’, branched squid-like peptides
that can self-localize in the cytoplasm or nucleus [45]. In vitro application revealed good
transfection properties of one of the nuclear localizing loligomers [46]. Its potential for application
in drug targeting, i.e. the ability to combine cell specificity of DNA delivery with
loligomer-orchestrated intracellular routing capacity, needs to be established.
1.3.5 Mitochondrial Targeting
Mitochondria are the ATP suppliers of the cells and have an important role in modulating intracellular
calcium levels and cellular apoptosis. The mitochondrial respiratory chain is furthermore
an important supplier of damaging free radicals. Evidence increases that mitochondria
are heavily involved in numerous diseases and therefore they may become important
targets for the development of new drugs and therapies [47].
Both the large membrane potential across the inner membrane and the protein import
machinery of the mitochondria may be exploited for selectively delivering drugs to this cellular
organelle. Lipophilic cations in particular, have been studied for mitochondrial targeting
purposes based on their mitochondrial accumulation potential. Using triphenylphosphonium
as a carrier, Smith et al. were able to selectively deliver antioxidant activity into the mitochondrial
compartment of cells [48]. Similar to proteins that require nuclear localization
sequences for homing to this compartment, cellular proteins that need to be targeted to mitochondria
require mitochondrial localization sequences [49]. Fusion of these signal sequences
with (model) proteins of interest redirects the proteins into the mitochondrial compartments.
Whether these intracellular targeting entities can be combined with other targeting
entities that specifically direct them into the desired cell type in the body, is however
questionable. One option may be to package the mitochondrial targeting system in immunoliposomes
that provide the cell specificity [47], but further research is awaited to provide insight
into the potential and limitations of this approach.
1.4 Drug Targeting Strategies in the Clinic
Most of the drug delivery systems that have been studied for clinical application are capable
of rate- and/or time-controlled drug release.The therapeutic advantages in these approaches
lie in the in vivo predictability of release rate, minimized peak plasma levels, predictable and
extended duration of action and reduced inconvenience of frequent re-dosing and hence, improved
patient compliance [1].