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A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency

Authors Zhao M, Li J, Ji H, Chen D, Hu H

Received 10 May 2019

Accepted for publication 29 July 2019

Published 14 August 2019 Volume 2019:14 Pages 6519—6538

DOI https://doi.org/10.2147/IJN.S215250

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Jiang Yang

Peer reviewer comments 4

Editor who approved publication: Dr Lei Yang


Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang Hu

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

Background: 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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