Biomedical Engineering Reference
In-Depth Information
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Figure 7.1
Barriers to siRNA uptake following systemic administration. siRNAs
may be degraded in the blood, removed by renal excretion or by
macrophages. siRNAs may not reach their target cells because of
electrostatic repulsion. Following internalization, siRNAs may be
prevented from reaching their intracellular targeted mRNA due to an
inability to escape from the endosome-lysosome pathway.
enzymatic degradation by endogenous nucleases.
22
One of the first biological
barriers encountered by administered siRNAs is presented by the nuclease
activity in plasma and tissues. The major activity in plasma is a 39-exonuclease;
however, cleavage of internucleotide bonds can also take place. The reported
half-life for unmodified siRNAs in serum ranges from several minutes to
around an hour.
23-25
In addition, the kidney plays a key role in siRNA
clearance and several studies in animals have reported that the biodistribution
of siRNA shows the highest uptake in the kidney.
26-28
In addition to
circulating nuclease degradation and renal clearance, a major barrier to in vivo
delivery of siRNAs is uptake by the reticuloendothelial system (RES). The
RES is composed of phagocytic cells, including circulating monocytes and
