Biomedical Engineering Reference
In-Depth Information
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Figure 7.5
pH-sensitive polymers can enhance siRNA endosomal escape. The initial
step is endocytosis of the polymeric micelle/siRNA complexes, followed
by acidic endosome buffering, which leads to increased osmotic pressure
and finally to lysis and release of siRNA into the cytosol.
counterion concentrations inside the endosome lead to osmotic swelling,
endosomal membrane rupture, and the eventual leakage of nucleic acids into
the cytosol.
89
Itaka et al. prepared PEG-polycation diblock copolymers possessing
diamine side chains with distinctive pK
a
values for siRNA encapsulation into
polyplex micelles with high endosomal escape ability. PEG-poly{3-[(3-
aminopropyl)amino]propylaspartamide} (PEG-DPT; PEG, 12 000 g mol
-1
;
polymerization degree of the DPT segment, 68), carrying a diamine side chain
with a distinctive pK
a
value, was newly synthesized by a side-chain aminolysis
reaction of PEG-poly(b-benzyl-
L
-aspartate) block copolymer (PEG-PBLA)
with dipropylenetriamine (DPT) (Figure 7.6). The unique feature of PEG-
DPT is the regulated location of primary and secondary amino groups in the
side chain. The former groups, with higher pK
a
values, are settled at the distal
end of the side chain to participate in ion complex formation with phosphate
groups in the siRNA molecule, whereas the latter groups, with lower pK
a
values, are located closer to the polymer backbone, where they are expected to
have a substantial fraction of the unprotonated form even in the complex,
presumably due to the lower protonation power and the spatial restriction,
