Glutathione-Specific and Intracellularly Labile Polymeric Nanocarrier for Efficient and Safe Cancer Gene Delivery
Guowei Wang1, Dingcheng Zhu1, Zhuxian Zhou1
1Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
Abstract:
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.
Insights
Researchers developed novel cationic polymers that form glutathione-specific polyplexes for targeted cancer gene delivery. These polyplexes release DNA inside cells, improving gene transfection and showing potent antitumor activity with fewer side effects.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Gene Therapy
Background:
- Cationic polymers form polyplexes for nonviral gene delivery, but inefficient DNA release limits transfection.
- Charge-reversal polymers enhance intracellular DNA release but require stability during delivery.
- Targeted gene delivery aims to improve therapeutic efficacy and reduce side effects.
Purpose of the Study:
- To develop glutathione (GSH)-specific, charge-reversing polyplexes for targeted cancer gene delivery.
- To enhance intracellular DNA release and improve gene transfection efficiency.
- To evaluate the antitumor efficacy and safety of TRAIL-loaded polyplexes.
Main Methods:
- Synthesized polymers with GSH-cleavable dinitrophenyloxybenzyl ammonium moieties.
- Formulated PEG-lipid coated polyplexes for stability and tumor accumulation.
- Loaded polyplexes with the tumor suicide gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
- Assessed polyplex stability, cellular uptake, DNA release, and in vivo antitumor activity.
Main Results:
- GSH cleavage specifically triggered cationic polymer to anionic conversion, enabling rapid intracellular DNA release.
- PEG-lipid coating ensured polyplex stability in biological fluids and prolonged circulation for tumor accumulation.
- TRAIL-loaded polyplexes demonstrated efficient tumor accumulation and cell transfection.
- Achieved potent antitumor activity comparable to paclitaxel with significantly reduced adverse effects.
Conclusions:
- Developed the first GSH-specific intracellular labile polyplexes for targeted cancer gene therapy.
- Charge-reversal mechanism effectively overcomes intracellular DNA release barriers.
- These polyplexes offer a promising strategy for effective and safe cancer treatment.
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