Biomedical Engineering Reference
In-Depth Information
content by increasing the net positive charge on the lipoplex surface
and consequently amplifying the rate of electrostatic interactions
between the lipoplexes and endosomal membranes [44, 65, 102].
The efficacy of siRNA delivery by a commercially available lipid-
based transfection reagent JetSI was also enhanced after mixing it
with fusogenic lipids [61].
6.4.2 pH-SensitiveLipoplexes
A variety of modifications to lipid-based delivery carriers have been
designed to protect positively charged fusogenic lipoplexes from
interactions with serum proteins and macrophages while maintaining
the fusogenic character necessary for efficient endosomal escape
and intracellular trafficking of the siRNAs. One of the approaches
used to protect these carriers and their cargo is a modification of the
outer surface of the lipoplex with hydrophilic, pH-sensitive polymers
[57, 58, 131]. These polymer-liposome conjugates are stable in the
circulatory system. However, upon endocytosis and lowering the
pH inside the endosomal vesicle, the polymer molecules are rapidly
hydrolyzed exposing the underlying lipoplexes and promoting their
fusion with endosomal membranes and the release of their contents
into the cytosol. Coating the liposomal surface with PEG-polycation
block copolymers has been shown to be much more efficient at
targeted silencing when compared with a commercially available
transfection reagent (Oligofectamine TM ) [7].
In a similar manner, Carmona et al. developed liposomes
composed of DOPE lipid and an aminoxy cholesteryl lipid, which
enables covalent attachment of biocompatible polymers, such as
PEG [19]. This bioconjugation produces oxime bonds, which are
stable at neutral pH, but readily hydrolyze at pH 5.5 and lower. This
pH sensitivity of the siRNA carrier allows the PEG desorption that
leads to nanoparticle destabilization and, consequently, escape from
the early endosome.
6.4.3 pH-SensitivePolyplexes
A number of pH-sensitive, endosomal buff ering polymers have been
developed to improve gene knockdowns through more eff ective
siRNA delivery. The high efficiency of nucleic acid delivery by
protonable cationic polymers has been primarily attributed to their
 
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