A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang HuDepartment of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaBackground: Polycation carriers show great foreground in the developing efficient and safe gene delivery; neve...
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| Autores principales: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2019
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/52b25d38837443c8b7c943b7351fdd61 |
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| Sumario: | Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang HuDepartment of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaBackground: Polycation carriers show great foreground in the developing efficient and safe gene delivery; nevertheless, they are cytotoxic and unstable in vivo because of the excess cationic charge. PEGylation improves the biocompatibility and stability of polycation, whereas PEGylation restrains the endosomal escape to some extent.Materials and methods: To address this issue and promote the transfection in vivo, a pH-sensitive conjugate folate-polyethylene glycol-carboxylated chitosan (shorten as FA-PEG-CCTS) was designed and coated on the surface of PEI/NLS/pDNA (PNDs), forming a versatile gene carrier FA-PEG-CCTS/PEI/NLS/pDNA (FPCPNDs). The novel carrier exhibited a few picturesque characteristics, including (i) neutral surface charge to restrain nonspecific interactions; (ii) folate receptors (FR)-mediated endocytosis to augment cellular uptake; (iii) dual proton sponge effect to realize endosome escape, and (iv) nuclear localization sequences (NLS) to enhance the transfection of pDNA.Results: FPCPNDs could compress and protect pDNA from degradation. FPCPNDs energetically targeted tumor cells because of their high binding affinity between FA and highly expressed FR on the tumor surface, accordingly enhancing the cellular uptake. In the acidic endosomes, FA-PEG-CCTS segment dissociated from PNDs. Then, PNDs realized endosomal escape through the proton sponge effect of PEI. Furthermore, FPCPNDs showed admirable transfection efficiency with the aid of NLS peptides. What’s more, in vivo studies revealed that FPCPNDs had supreme antitumor activity among the whole preparations.Conclusion: In vitro and in vivo assays thus demonstrate that FPCPNDs is a hopeful strategy for gene delivery.Keywords: gene delivery, PEI, gene transfection, NLS, shell–core structure, CCTS |
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