Glutathione-Specific and Intracellularly Labile Polymeric Nanocarrier for Efficient and Safe Cancer Gene Delivery.
Guowei WangDingcheng ZhuXiaoxuan ZhouYing PiaoJianbin TangYou-Qing ShenPublished in: ACS applied materials & interfaces (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.
Keyphrases
- drug delivery
- ionic liquid
- papillary thyroid
- cancer therapy
- copy number
- genome wide
- reactive oxygen species
- circulating tumor
- squamous cell
- mental health
- genome wide identification
- cell therapy
- single molecule
- gene expression
- emergency department
- oxidative stress
- fluorescent probe
- locally advanced
- cell death
- single cell
- mass spectrometry
- lymph node metastasis
- radiation therapy
- transcription factor
- mesenchymal stem cells
- cell proliferation
- signaling pathway
- fatty acid
- pi k akt
- liquid chromatography
- tandem mass spectrometry