RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 178

where they can associate with the RISC. To that end, Rozema and
colleagues developed a multifunctional polymer-based 'device'
designed to maximize each step in the delivery process — from target
cell recognition (by using the targeting ligand N- acetylgalactosamine)
to endosomal escape (by using the amphipatic poly(vinyl ether),
PBAVE, which acts as an endosomolytic agent) and silencing (by
using appropriate siRNAs) (Figure 6.2) [127]. They referred to this
system as a dynamic polyconjugate because each component is
revealed in a systematic manner. N- acetylgalactosamine is present
for delivery of the siRNA to hepatocytes, but it is released from the
polymer in the acidic environment of the endosome. At the same
time, the endosomolytic agent (PBAVE) is revealed through the
dissociation of a PEG shielding group, facilitating the translocation
of the siRNA from the endosomal compartment to the cytoplasm.
The siRNA molecules are attached to PBAVE through a disulfide
linkage that is cleaved in the reducing environment of the cytosol,
releasing the siRNA, which is free to interact with RISC and direct
target mRNA cleavage. These multifunctional delivery reagents will
become more important as RNAi-based gene-silencing technologies
make their way into the clinic.
Figure 6.2 Barriers to siRNA delivery in vivo . To be eff ective, systemic
delivery approaches need to protect siRNAs from degradation by serum
nucleases, avoid clearance from the circulatory system by renal filtration,
transport across the vascular endothelial barrier, facilitate eff ective
biodistribution and accumulation at the appropriate tissue, and promote
efficient siRNA uptake and endosomal escape into the cytoplasm of the
target cells where they can associated with RISC and guide the cleavage of
target mRNA.