Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 350

7.7.3 Protein Binding
PS oligonucleotides have been reported to bind readily with plasma proteins such as
albumin and  2 -macroglobuline, inhibiting their rapid excretion from the body [145] .
This protein binding is a nonspecific electrostatic interaction dependent on salt type
and pH of the surrounding biological milieu. The PS oligonucleotides have been
reported to bind to  2 -macroglobuline with higher affinity than albumin. These oligo-
nucleotides have also been reported to bind to other plasma proteins as well, but with
lower affinity, and binding of the PS oligonucleotides to the thrombin-binding sites
of these plasma proteins results in severe hematological risks [146] . However, this
protein binding of PS oligonucleotides has been found to be reversible and to occur
both in plasma and tissues. Tissue distribution of these oligonucleotides has been
attributed to the protein binding within the organ and on the cell surface, constitut-
ing the organ resulting in higher tissue uptake of oligonucleotides. Thus, a decrease
in protein binding of oligonucleotides results in a decreased tissue disposition and
an increased urinary excretion. Certain drugs such as aspirin have been reported to
displace PS oligonucleotides from plasma proteins, increasing their rate of excretion
and decreasing the magnitude of their biological effect [147] .
7.7.4 Effect of Route of Administration
AS ODNs can be administered locally or systemically to elicit a biological effect.
Local delivery is advantageous over systemic administration as it avoids dis-
tribution into nontarget tissues, resulting in reduced side effects associated with
unwanted tissue distribution. The antisense agents can be administered through
oral, nasal, rectal vaginal, pulmonary, topical, intravenous, subcutaneous, intra-
dermal, or intrathecal routes [135,136,142,148-150] . Bioavailability of PS oligo-
nucleotides has been found to be very poor following oral administration because
of their large size, and hydrophilic and ionic nature [136,149] . PS oligonucleotides
are rapidly absorbed from the site of injection following intradermal or subcuta-
neous administration, but not following intrathecal or pulmonary administrations
[142,148,149] .
7.7.5 Pharmacodynamics
The cellular distribution of AS ODNs accounts for their pharmacodynamic effect.
This requires suborgan distribution of the oligonucleotides to the target cells and
subcellular distribution to the binding site in target mRNA. The onset and duration
of antisense activity decides the dose of AS ODN and its frequency of adminis-
tration. The dosing of AS ODNs is dependent on their structural chemistry, with
first-generation AS ODNs being administered three times a week and second-
generation AS ODNs being administered once a week. The therapeutic effect of
an AS ODN in an organ or tissue weakens in parallel to its elimination from that
organ or tissue [151,152] .