Drug Targeting Organ-Specific Strategies

144 5 Delivery of Drugs and Antisense Oligonunucleotides to the Proximal Tubular Cell
drug conjugate. With respect to the administration route, the conjugate could possibly be administered
subcutaneously or intramuscularly. This is a common administration route for
polypeptide drugs such as insulin. If immunogenicity appears to be a serious limitation for
chronic treatment, a synthetic polymer may be used as the ‘reabsorptive’ carrier instead
[97,98].
For short-term clinical interventions with the aim of protecting the kidney during acute
reperfusion or preventing allograft rejection after transplantation, the prerequisite of parenteral
administration does not constitute a serious limitation.
5.4 Renal Delivery of Antisense Oligodeoxynucleotides
5.4.1 Introduction
Various macromolecular and pro-drug technologies designed to achieve selective renal drug
accumulation and action have been discussed in the previous sections of this chapter. In these
approaches, traditional drugs have been modified through coupling to carrier molecules. It is
generally accepted that, at least in theory, antisense oligodeoxynucleotides (AS-ODN) offer
a new approach for selective treatment [99,100].
In view of the preferential distribution of some AS-ODNs to the kidney the oligonucleotide
backbone could even be employed for renal-specific drug delivery because of both
their intrinsic activity and the potential of coupling of other agents to them.
Antisense refers to the use of single-stranded synthetic oligonucleotides to inhibit gene expression
[99,100].The striking advantage of the antisense approach in comparison to traditional
drugs is its potential for specificity. The binding affinity between the oligonucleotide
and its target receptor is many orders of magnitude higher compared to that at other binding
sites, as a result of the multiple interaction sites that exist on the target receptors [101]. Since
affinity is proportional to the number of interactions between a drug and its receptor, the
specificity of an AS-ODN depends on its length. The base pairing specificity of an AS-ODN
of about 15-17 nucleotides in length appeared to be sufficient to inhibit only one target gene
within the entire human genome [99]. For successful inhibition in vivo, the plasma and intracellular
stability and the pharmacokinetic profile of the antisense molecule along with the
turnover time of the inhibited gene are important determinants.
First, we will briefly review the different aspects that are of importance in the use of antisense
for in vivo therapy. Second, we will describe the effects of antisense targeting to the
proximal tubule of the kidney that have been obtained so far.
5.4.2 Mechanism of Action of Antisense Oligodeoxynucleotides
AS-ODN are designed to be complementary to the coding (sense) sequence of the mRNA in
the cell. After hybridization to target sequences, translational arrest occurs via one of several
putative mechanisms. The first mechanism is inhibition of transcription. Secondly, AS-
ODN can prevent the synthesis of fully mature mRNA in the cytosol at the level of splicing,