TY - JOUR
T1 - Rational design of acid-labile branched polycation with superior gene transfection capacity
AU - Wang, Rui
AU - Cheng, Jiumu
AU - Yan, Guoqing
AU - Wang, Chun
AU - Wang, Xin
AU - Wang, Jun
AU - Tang, Rupei
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/8/11
Y1 - 2017/8/11
N2 - There is much need in advancing rational design of synthetic cationic polymers as gene carriers. Inspired by the molecular blueprint of the famed branched polyethylenimine (bPEI), here we describe a new series of acid-labile branched poly(ortho ester amino alcohol)s (bPOEAAs) that embodies multiple design principles about polymer degradability, chain branching, and type of cationic amino groups. The bPOEAAs were facilely synthesized via expoxide-amine reaction of monomers with various ratios, allowing a range of branching degrees and amine compositions to be explored. A polymer (bPOEAA2) with an intermediate degree of branching and approximately equal fraction of secondary and tertiary amines was identified to be optimal in forming stable polyplexes with plasmid DNA. Rapid release of DNA from the polymer was achieved by accelerated backbone degradation at endosomal acidic pH. Together, these unique features of bPOEAA2 enabled markedly improved transfection efficiency in cells in physiological medium and much lower cytotoxicity than bPEI. Insights gained from the rational design and screening of bPOEAAs may contribute to deeper understanding of structure-activity relationship of polymeric gene carriers, which may ultimately lead to safer and more effective gene therapies.
AB - There is much need in advancing rational design of synthetic cationic polymers as gene carriers. Inspired by the molecular blueprint of the famed branched polyethylenimine (bPEI), here we describe a new series of acid-labile branched poly(ortho ester amino alcohol)s (bPOEAAs) that embodies multiple design principles about polymer degradability, chain branching, and type of cationic amino groups. The bPOEAAs were facilely synthesized via expoxide-amine reaction of monomers with various ratios, allowing a range of branching degrees and amine compositions to be explored. A polymer (bPOEAA2) with an intermediate degree of branching and approximately equal fraction of secondary and tertiary amines was identified to be optimal in forming stable polyplexes with plasmid DNA. Rapid release of DNA from the polymer was achieved by accelerated backbone degradation at endosomal acidic pH. Together, these unique features of bPOEAA2 enabled markedly improved transfection efficiency in cells in physiological medium and much lower cytotoxicity than bPEI. Insights gained from the rational design and screening of bPOEAAs may contribute to deeper understanding of structure-activity relationship of polymeric gene carriers, which may ultimately lead to safer and more effective gene therapies.
KW - Branched polyethylenmine
KW - Gene delivery
KW - Ortho ester
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U2 - 10.1016/j.polymer.2017.07.002
DO - 10.1016/j.polymer.2017.07.002
M3 - Article
AN - SCOPUS:85021805241
SN - 0032-3861
VL - 123
SP - 1
EP - 9
JO - Polymer
JF - Polymer
ER -