Journal
MACROMOLECULAR BIOSCIENCE
Volume 14, Issue 4, Pages 546-556Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/mabi.201300422
Keywords
gene vectors; pH-sensitive; reduction-sensitive; three-armed peptides
Funding
- National Key Basic Research Program of China [2011CB606202]
- National Natural Science Foundation of China [51125014, 51233003, 21004046]
- Ministry of Education of China [5052012203003]
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To address the inherent barriers of gene transfection, two reduction-sensitive branched polypeptides (RBPs) are synthesized and explored as novel non-viral gene vectors. The introduced disulfide linkages in RBPs facilitate glutathione-triggered intracellular gene release and reduce polymer degradation-induced cytotoxicity. Furthermore, the highly branched architecture concurrently realizes multivalency for strong DNA binding and elicits conformational flexibility for tight DNA compacting, which are beneficial for cellular entry. To increase the endosomal escape of plasmid DNA, pH-sensitive histidyl residues are incorporated into RBPs to improve buffer capacity in an acidic environment. In vitro study demonstrates that RBPs can efficiently mediate the DNA transfection and avoid apparent cytotoxicity in HeLa and COS7. The present gene delivery system offers a simple and flexible approach to fabricate microenvironment-specific branched gene vectors for gene therapy.
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