Nucleophile responsive charge-reversing polycations for pDNA transfection.
Polym Chem
; 14(14): 1591-1601, 2023 Apr 04.
Article
em En
| MEDLINE
| ID: mdl-37033743
ABSTRACT
Polycationic carriers promise low cost and scalable gene therapy treatments, however inefficient intracellular unpacking of the genetic cargo has limited transfection efficiency. Charge-reversing polycations, which transition from cationic to neutral or negative charge, can offer targeted intracellular DNA release. We describe a new class of charge-reversing polycation which undergoes a cationic-to-neutral conversion by a reaction with cellular nucleophiles. The deionization reaction is relatively slow with primary amines, and much faster with thiols. In mammalian cells, the intracellular environment has elevated concentrations of amino acids (â¼10×) and the thiol glutathione (â¼1000×). We propose this allows for decationization of the polymeric carrier slowly in the extracellular space and then rapidly in the intracellular milleu for DNA release. We demonstrate that in a lipopolyplex formulation this leads to both improved transfection and reduced cytotoxicity when compared to a non-responsive polycationic control.
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MEDLINE
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En
Ano de publicação:
2023
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Article