Bioreducible crosslinked cationic nanopolyplexes from clickable polyethylenimines enabling robust cancer gene therapy

Kangkang An; Huizhi Fengyan; Xinting Xu; Rong Jin; Xiaoxin Hu; Peng Zhao; Chao Lin

doi:10.1016/j.nano.2019.102144

Bioreducible crosslinked cationic nanopolyplexes from clickable polyethylenimines enabling robust cancer gene therapy

Nanomedicine. 2020 Feb:24:102144. doi: 10.1016/j.nano.2019.102144. Epub 2019 Dec 12.

Authors

Kangkang An¹, Huizhi Fengyan¹, Xinting Xu², Rong Jin³, Xiaoxin Hu², Peng Zhao², Chao Lin⁴

Affiliations

¹ Department of Periodontology, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China.
² Institute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, PR China.
³ Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai, PR China.
⁴ Department of Periodontology, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China; Institute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, PR China. Electronic address: chaolin@tongji.edu.cn.

PMID: 31838150
DOI: 10.1016/j.nano.2019.102144

Abstract

Bioreducible crosslinked polyplexes from branched polyethylenimine (BPEI, 10 kDa) were successfully constructed through DNA neutralization by disulfide-linked azidated BPEI (PAZ) and subsequent DNA condensation by azadibenzocyclooctyne-modified BPEI (PDB), following their self-crosslinking via azide-azadibenzocyclooctyne click chemistry. Click-crosslinked cationic polyplexes (c-polyplexes) revealed high extracellular colloidal stability against negative heparin and ions while intracellular bioreducible degradability for efficient gene unpacking. In vitro gene transfection in cancer cells indicated that the c-polyplexes produced markedly higher transfection efficiency than non-crosslinked counterparts in the serum. The c-polyplexes also had prolonged circulation kinetics, elevated gene accumulation level in SKOV-3 tumor xenografted in a mouse model and in turn superior transgene expression in the tumor. By small hairpin RNA for VEGF silencing, the c-polyplexes exerted significant tumor growth inhibition following with low systemic toxicity in the mouse. This study highlights the design of clickable polycations to construct crosslinked cationic nanopolyplexes for intravenous gene delivery against cancer.

Keywords: Click chemistry; Clickable polycation; Crosslinked polyplexes; Non-viral gene therapy; Polyethylenimine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cations / chemistry*
Click Chemistry / methods*
Genetic Therapy / methods*
Kinetics
Polyethyleneimine / chemistry*
Vascular Endothelial Growth Factor A / chemistry

Substances

Cations
Vascular Endothelial Growth Factor A
Polyethyleneimine