RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 169

delivery nanoparticles within the tumor microenvironment by the
EPR eff ect may not correlate well with the therapeutic outcome.
One of the first approaches used to systemically deliver siRNAs
involved rapid injection of siRNAs in a large volume of physiological
buff er, termed hydrodynamic injection [11, 101, 108, 136, 163].
The rapid injection of large fluid volumes leads to right-sided heart
failure resulting in an elevated venous pressure and the transient
disruption of the plasma membrane of cells in highly vascular tissues,
including lung, liver, spleen, and pancreas. This transient disruption
of the plasma membrane facilitates the uptake of the siRNAs and
the concomitant targeted silencing of gene expression. The ease of
delivery to the liver and the susceptibility of the liver to variety of
agents that induce acute or chronic liver injury (for example, viral
infections, autoimmune hepatitis, toxins, and liver transplantation)
has made the liver an attractive target for siRNA-mediated therapeutic
gene silencing [15, 127, 136, 162]. The targeted silencing of Fas by
hydrodynamic delivery of siRNAs protected mice from fulminant
hepatitis induced by the intraperitoneal injection of a fas agonist
antibody [136]. Although eff ective, this approach requires a high
dose of siRNAs to achieve eff ective silencing with only a relatively
small fraction of the siRNAs actually entering the target tissue. In
addition, systemic hydrodynamic injection is too risky for human
therapeutic applications.

6.2 Cell-Type Specific Delivery

Eff ective systemic delivery requires agents that facilitate the transport
of siRNAs to specific cell type(s) (Figure 6.3). Cell type-specific
delivery approaches reduce potential toxicities to neighboring
bystander cells, promote the accumulation of the siRNA at the target
tissue, and lower the therapeutic dose necessary to achieve eff ective
silencing in the cells of interest. Typically, these approaches take
advantage of molecules that recognize specific surface antigens
expressed on distinct cells or tissues. These antigens can define
a very narrow or broad spectrum of cell types depending on the
breadth of their distribution. Several diff erent types of molecules,
including antibodies, ligands, and aptamers, have been successfully
used for cell type-specific siRNA delivery [30, 31].