title: Engineering buffering and hydrolytic or photolabile charge shifting in a polycarboxybetaine ester gene delivery platform.
abstract: Polycarboxybetaine esters (PCB-esters) can condense plasmid DNA into nanosized polyplexes for highly effective gene delivery with low toxicity. The design and characterization of tertiary CB-ester monomers and PCB-ester polymers are presented here to study the effects of molecular variation on functions important to nonviral gene transfer. Both buffering capacity and charge-shifting behavior can be tuned by modifying the distance between the charged groups and the ester size or type. A carbon spacer length (CSL) of one was found to bring the pKa of the tertiary amine into the optimal range for proton buffering. Ester hydrolytic degradation switches this polymer from cationic (DNA binding) to zwitterionic (DNA releasing) form while conferring nontoxicity. To allow rapid and externally controlled degradation, the effect of this charge-switching behavior on DNA release from polyplexes was directly studied with a novel photolabile PCB-nitrobenzyl ester (PCB-NBE). Photoinitiated ester degradation precipitated the rapid release of 72±5% of complexed DNA from PCB-NBE polyplexes. These insights reveal the key parameters important for the PCB-ester platform and the significance of charge switching to an effective and nontoxic nonviral gene delivery platform.
authors.affiliation: Department of Chemical Engineering, University of Washington, Seattle, Washington 98195, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.forename: Louisa R
authors.initials: LR
authors.lastname: Carr
authors.forename: Jean-Rene
authors.initials: JR
authors.lastname: Ella-Menye
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D002021:Buffers; D019556:COS Cells; D002412:Cations; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004952:Esters; D005456:Fluorescent Dyes; D006868:Hydrolysis; D008027:Light; D008156:Luciferases; D009930:Organic Chemicals; D010782:Photolysis; D010957:Plasmids; D011522:Protons; D055672:Static Electricity; D014162:Transfection / Q000379:methods*
chemical_list: D002021:Buffers; D002412:Cations; D004952:Esters; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C099476:PicoGreen; D011522:Protons; D001622:Betaine; D004247:DNA; D008156:Luciferases