Print Email Facebook Twitter Nucleophile responsive charge-reversing polycations for pDNA transfection Title Nucleophile responsive charge-reversing polycations for pDNA transfection Author Lewis, R.W. (TU Delft ChemE/Advanced Soft Matter) Muralidharan, A. (TU Delft BN/Bionanoscience; TU Delft BN/Stan Brouns Lab; Kavli institute of nanoscience Delft) Klemm, B. (TU Delft ChemE/Advanced Soft Matter) Boukany, P. (TU Delft ChemE/Product and Process Engineering) Eelkema, R. (TU Delft ChemE/Advanced Soft Matter) Department BN/Bionanoscience Date 2023 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 (∼10×) and the thiol glutathione (∼1000×). 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. To reference this document use: http://resolver.tudelft.nl/uuid:69617da3-ecd7-4a48-81d2-26e613330bd7 DOI https://doi.org/10.1039/d3py00075c ISSN 1759-9954 Source Polymer Chemistry, 14 (14), 1591-1601 Part of collection Institutional Repository Document type journal article Rights © 2023 R.W. Lewis, A. Muralidharan, B. Klemm, P. Boukany, R. Eelkema Files PDF d3py00075c.pdf 2.57 MB Close viewer /islandora/object/uuid:69617da3-ecd7-4a48-81d2-26e613330bd7/datastream/OBJ/view