RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 176

high buff ering capacity that is thought to act as a 'proton sponge' and
mediate endosomal release. In this approach, proton absorbance by
buff ering polymers prevents acidification of endosomal vesicles,
thereby increasing the ATPase-mediated influx of protons as well as
counterions (which enter the vesicles to balance the proton flux).
Increased concentration of the counterions inside the endosome
leads to osmotic swelling, followed by endosomal membrane rupture,
and eventually to the leakage of the polyplex and its contents into
the cytosol [134]. Polyethyleneimine (PEI) is one of the most widely
investigated cationic polymers for nucleic acid delivery [124, 125,
144]. Positively charged amine groups of PEI both facilitate their
interaction with negatively charged nucleic acid molecules and enable
endosomal release through their action as proton sponges. However,
treatment with PEI has toxic side eff ects that directly correlate to
the size of the polymer and this has impeded its application for
therapeutic drug delivery.
Polyethyleneimine and polyamidoamine dendrimers
(symmetrically and repeatedly branched polymers) have also
been utilized for siRNA delivery owing to their excellent proton-
absorbing properties [119, 120]. This excellent buff ering capacity of
dendrimers is attributed to the high density of readily protonable
tertiary amine groups. However, maintaining the neutral character
of the outer surface of these cationic dendrimers is important for
controlling morphology of the polyplexes and protection of the
concentrated siRNA molecules inside. In addition, the presence of
dense modifiable peripheral groups facilitates attachment of target
recognition elements for cell specific delivery [120].
More sophisticated polymeric siRNA carriers with tunable pH
sensitivities have been developed by Wang and colleagues [150].
They have developed a multifunctional polymeric siRNA carriers
composed of a proton-sponge domain, a hydrophobic domain, and a
domain of polymerizable cysteine residues. The presence of various
protonable amino groups with diff ering p K a values increases the
buff ering capacity of the complex. The hydrophobic portion of the
particle improves the overall stability of the carrier allowing the
formation of a compact structure enclosing the siRNA molecules. The
presence of disulfide bonds formed between the cysteine residues
stabilizes the nanoparticles even further. After endosomal release,
disulfide bonds are reduced by cytosolic glutathione resulting in
dissociation of the nanoparticles and release of siRNA into the