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Fig. 8.6 Formation of inorganic/organic hybrid nanoparticles by the use of PEG-SS-siRNA and
calcium phosphate. Reprinted with permission from [ 52 ] . Copyright 2009 Wiley
siRNA in a controlled manner. Furthermore, using a similar strategy to form poly-
meric nanoparticles, the same authors employed the polyanion PEG-block-
poly(methacrylic acid) (PEG-PMA). The strategy was to incorporate the molecular
units facilitating endosomal escape directly into the block copolymer structure trig-
gered by PMA conformational transition at pH 4-6 which approximately corre-
sponds to the endosomal pH [ 70 ]. Finally, the use of PEG-polyanion was essential
to the formation of stable hybrid nanoparticles that showed an appreciable silencing
of the reporter gene in vitro.
Interestingly, other reports have proposed the use of different strategies to obtain
stable hybrid nanoparticles through inorganic/organic interactions. Zhang et al.
hypothesized that the integration of siRNA into block copolymers via a cleavable
disulfide bond to form PEG-ss-siRNA conjugate could be useful to form the cal-
cium phosphate hybrid nanoparticles and obtain a high loading efficiency (Fig. 8.6 )
[ 52 ]. Theoretically, an increased efficacy of siRNA entrapment is a trade-off rela-
tionship in the regulated crystal growth since siRNA and PEG- block -polyanion
compete for binding with the positive charges on the CaP crystal [ 71 ] . Indeed, using
PEG and siRNA bound via disulfide, the authors obtained nanoparticles of size
between 90 and 120 nm with very narrow particle size distribution (polydispersity
index <0.1). Nanoparticles were confirmed to be spherical and exhibited well-
defined core-shell architecture, with up to 86% siRNA incorporation efficiency.
8.6
Designing Polymeric Nanocarriers for Cytoplasmic
Delivery
A great advantage of using synthetic polymers in nanocarrier systems is the possi-
bility to include blocks or segments with distinct functions to overcome a specific
delivery barrier. Hence, it is of great importance to understand the pathways and
environments in which the nanocarriers undergo, and the physical, chemical or bio-
logical changes in the microenvironment that are related to the disease to be treated
or tissue to be reached.
Many block copolymers with smart functions, such as chemical [ 72- 74 ] or physi-
cal [ 75 ] stimuli-sensitivity, and the targetability to specific tissues [ 38, 39 ] have
already been designed for drug or gene delivery. These functions utilize the stimuli
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