Novel reduction-responsive cross-linked polyethylenimine derivatives by click chemistry for nonviral gene delivery.
Novel reducible disulfide-containing cross-linked polyethylenimines (PEI-SS-CLs) were synthesized via click chemistry and evaluated as nonviral gene delivery vectors. First, about four azide pendant groups were introduced into a low-molecular-weight (LMW) PEI (1.8 kDa) to get an azide-terminated PEI. Then, click reaction between a disulfide-containing dialkyne cross-linker and the azide functionalized LMW PEI resulted in a high-molecular-weight disulfide-containing cross-linked PEI composed of LMW constitute via a reducible cross-linker. The synthesized polymers were characterized by (1)H NMR, FTIR, and size-exclusion chromatography (SEC). It was shown that the obtained disulfide-containing cross-linked PEIs were able to condense plasmid DNA into positively charged nanoparticles. The degradation of the disulfide cross-linked polymers PEI-SS-CLs induced by DTT was confirmed by a gel retardation assay and SEC analysis. In vitro experiments revealed that the reducible PEI-SS-CLs were less cytotoxic and more effective in gene transfection (in both the presence and absence of serum) than the control nondegradable 25-kDa PEI. This study demonstrates that a reducibly degradable cationic polymer composed of LMW PEI cross-linked via a disulfide-containing linker possesses both higher gene transfection efficiency and lower cytotoxicity than PEI (25 kDa). These polymers are therefore attractive candidates for further in vivo evaluations.
Liu
Jia
J
Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, P R China.
Jiang
Xulin
X
Xu
Li
L
Wang
Xianmiao
X
Hennink
Wim E
WE
Zhuo
Renxi
R
D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D057930:Click Chemistry; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008970:Molecular Weight; D010084:Oxidation-Reduction; D011094:Polyethyleneimine / Q000737:chemistry*; D014162:Transfection / Q000379:methods*
D000480:Alkynes; D001386:Azides; D004220:Disulfides; D004337:Drug Carriers; D011094:Polyethyleneimine