A Glutathione-Specific and Intracellularly Labile Polymeric Nanocarrier for Efficient and Safe Cancer Gene Delivery.
2020
Cationic
polymers condense nucleic acids into nanosized complexes
(polyplexes) that are widely explored for nonviral gene delivery,
but their strong electrostatic binding with DNA causes inefficient
intracellular gene release and translation and thereby unsatisfactory
gene transfection efficiencies. Facilitated intracellular dissociation
of polyplexes by making the polymer undergo positive-to-negative/neutral
charge reversal can effectively solve these problems, but they must
be sufficiently stable during the delivery. Herein, we report the
first glutathione (GSH)-specific intracellular labile polyplexes for
cancer-targeted gene delivery. The polymers are made from p-(2,4-dinitrophenyloxybenzyl)-ammonium cationic moieties,
whose p-2,4-dinitrophenyl ether is cleaved specifically
by GSH, rather than other biological thiols, triggering the conversion
of the ammonium cation into the carboxylate anion and thus the fast
intracellular DNA release of the polyplexes. Furthermore, the polyplexes
coated with PEG-functionalized lipids are stable in biological fluids
to gain long blood circulation for tumor accumulation. Thus, the efficient
tumor accumulation and cell transfection of the polyplexes loaded
with the tumor suicide gene tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) give rise to potent antitumor activity similar to that
of the first-line chemotherapy drug paclitaxel but with much less
adverse effects.
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