Biomedical Engineering Reference
In-Depth Information
Fig. 1 Bioresponsive polyplexes. (
a
) Systemic circulation of shielded polyplexes in blood stream
and attachment to cell surface receptor; (
b
) endocytosis into endosomes, deshielding by cleavage
of PEG linkers and activation of membrane-destabilizing component by acidic pH or other means;
(
c
) endosomal escape into cytosol; (
d
) siRNA transfer to form a cytosolic RNA-induced silencing
complex complex; (
e
) cytosolic migration and intranuclear import of pDNA; (
f
) presentation of
pDNA in accessible form to the transcription machinery
3.1 Bioresponsive Polyplex Shielding
In the blood circulation, polyplexes need to be shielded against numerous possible
biological interactions, but they should actively interact with the target cell surface
by electrostatic or ligand receptor interactions. In this regard, shielding with PEG or
other hydrophilic polymers provides many benefits (see Sect.
2.1
). Irreversible,
stable surface shielding, however, may also be disadvantageous for the transfection
efficiency in at least two aspects: it may block interactions of the polyplex with the
target cell surface, and it may also prevent lipid membrane-destabilizing interaction
within endosomes. Targeting ligands can restore the cell surface-polyplex inter-
action in a receptor-specific manner [
68
,
75
,
82
], but it cannot restore cationic
polymer interactions with the cellular lipid membranes involved in endosomal
escape. As a solution for this problem, bioresponsive deshielding strategies (i.e.,
removal of the shielding molecules) have been developed (see Fig.
2
). Location-
specific changes such as in pH [
55
,
56
,
69
,
76
,
195
-
197
], enzymatic activity [
198
],
or disulfide reducing potential [
83
] have been applied for timely removal of the
hydrophilic shield after nucleic acid nanoparticles have reached their target tissue.
pH-triggered deshielding strategies [
199
] include pH-labile acetal linkages
[
172
,
196
,
200
], and dialkylmaleic acid [
56
] or pyridylhydrazone [
69
,
76
] bonds
