Zn-Promoted gene transfection efficiency for non-viral vectors: a mechanism study

The development of cationic non-viral gene vectors that may overcome obstacles in gene delivery is of great significance to the gene therapy. Metallic complexes with high affinity to nucleic acids are ideal new options for delivery systems. In this report, a 1,4,7,10-tetraazacyclododecane (cyclen)-b...

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Bibliographic Details
Published inNew journal of chemistry Vol. 45; no. 3; pp. 13549 - 13557
Main Authors Zhao, Rui-Mo, Guo, Yu, Yang, Hui-Zhen, Zhang, Ji, Yu, Xiao-Qi
Format Journal Article
LanguageEnglish
Published Cambridge Royal Society of Chemistry 14.08.2021
Subjects
Biocompatibility
Cations
Cell membranes
Efficiency
Flow cytometry
Gene therapy
Nucleic acids
Polymers
Scanning microscopy
Titration
Toxicity
Zinc compounds
Zinc coordination
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Summary:The development of cationic non-viral gene vectors that may overcome obstacles in gene delivery is of great significance to the gene therapy. Metallic complexes with high affinity to nucleic acids are ideal new options for delivery systems. In this report, a 1,4,7,10-tetraazacyclododecane (cyclen)-based polymer and its Zn( ii ) complex were prepared as a non-viral gene delivery vector. It was found that a Zn-coordination improved the gene transfection efficiency while slightly reducing the cytotoxicity of the polymer. This study focused on the mechanism of such improvement. Acid-base titration results revealed that Zn-coordination significantly increased the pH buffering capacity of the cationic material and the enhanced "proton sponge effect" might facilitate the endosomal escape, which was confirmed by confocal laser scanning microscopy. Flow cytometry showed that Zn-coordination improved the cellular uptake, which might be attributed to the higher zeta-potential of the Zn-complex and the resulting stronger interaction between the Zn ion and cell membrane. Moreover, chloroquine/nigericin experiments further demonstrated that the higher transfection efficiency of the zinc complex was due to its better endosomal escape ability. These results may provide clues for the development of novel non-viral gene vectors with high endosomal escape ability and biocompatibility. Mechanism studies revealed that a Zn coordination to cyclen-based cationic polymer may effectively improve the buffering capacity and endosomal escape ability.
Bibliography:Electronic supplementary information (ESI) available. See DOI
10.1039/d1nj02115j
ISSN:1144-0546
1369-9261
DOI:10.1039/d1nj02115j