Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 359

selected neucleotide binding aptamers for the treatment of prostate cancer. In addition
to that, repeated branched dendritic structures, specifically polycationic dendrimers,
can bind strongly with oligonucleotides/siRNA for better nuclease resistance and effi-
cient gene silencing. Also, human mesenchymal stem cells are inevitable as a viable
nonimmunogenic cellular delivery system [194] . Moreover, many pharma companies
are licensing their FDA-approved delivery platforms to the specialized players of anti-
sense technology in the market: ALZET pumps [195] , Minicircle DNA technology,
DiLA2 platform, PRINT nanoparticle technologies, to name a few ( Table 7.1 ).
7.8.3 Route of Administration
The first step in developing vectors for antisense drug delivery is to choose an effec-
tive route of administration, depending on the intended use of the antisense agent,
that is, whether local or systemic. The potential of AS ODNs and siRNA has been
investigated for applications through different routes, for example, the skin, lungs,
and mucosal membranes like intravaginal, ocular, and nasal, and various systemic
delivery routes [10,126,141] . Furthermore, there are some recent papers reporting the
study of siRNA delivery through oral route for targeting macrophages [121] .
7.8.3.1 Local Applications
Local delivery of antisense drugs, such as by electroporation or hydrodynamic intra-
venous injection, can reduce general problems associated with systemic administra-
tion, for example, clearance from the body, toxicity due to unwanted tissue distribution,
and reduced transfection due to low cellular uptake; but they suffer from limitations
like cytotoxicity at the application site and the requirement of large injection volume
[157,162] . PEI-associated siRNA has been delivered via electroporation in rodents for
the treatment of collagen-induced arthritis [196] . Further, intrathecal injection of anti-
sense agents have been explored for CNS delivery for a number of applications like
knockdown of serotonin transporters in mice brain, treatment of various diseases like
chronic neuropathic pain, and formalin-induced nociception [197,198] . Some ocular
diseases can be treated by intravitreal injection of antisense agents to treat eye diseases
like AMD, inhibition of ocular neurovascularization, and angiogenesis [199-202] . An
AS ODN formulation, Vitravene, is available in the market for the treatment of retinitis.
siRNA is also being evaluated as an inhalation therapy for lung disorders and systemic
applications [203] . Moreover, intranasal administration of siRNA has been investigated
in rodents for targeting heme oxygenase-1 to enhance ischemia-reperfusion-induced
lung apoptosis and for the treatment of respiratory virus infection [8] . However, many
diseases require systemic administration, and hence a special consideration should be
given to the rational design of an antisense agent and development of its delivery vector.
7.8.3.2 Systemic Applications
As discussed earlier, systemic administration of siRNA and AS ODNs is a big chal-
lenge, because they have to cross many obstacles on the way to the target. Many