title: Gene delivery properties of end-modified poly(beta-amino ester)s.
abstract: Here, we present the synthesis of a library of end-modified poly(beta-amino ester)s and assess their utility as gene delivery vehicles. Polymers were synthesized using a rapid, two-step approach that involves initial preparation of an acrylate-terminated polymer followed by a postpolymerization amine-capping step to generate end-functionalized polymers. Using a highly efficient poly(beta-amino ester), C32, we show that the terminal amine can greatly affect and improve polymer properties relevant to gene delivery. Specifically, the in vitro transfection levels can be increased by 30% and the optimal polymer:DNA ratio lowered 5-fold by conjugation of the appropriate end group. The most effective modifications were made by grafting primary diamine molecules to the chain termini. The added charge and hydrophobicity of some derivatives enhanced DNA binding and resulted in the formation of polymer-DNA complexes less than 100 nm in diameter. In addition, cellular uptake was improved 5-fold over unmodified C32. The end-modified poly(beta-amino ester)s presented here are some of the most effective gene-delivery polycations, superior to polyethylenimine and previously reported poly(beta-amino ester)s. These results show that the end-modification of poly(beta-amino ester)s is a general strategy to alter functionality and improve the delivery performance of these materials.
authors.affiliation: Department of Chemical Engineering, Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Zugates
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Tedford
authors.forename: Andreas
authors.initials: A
authors.lastname: Zumbuehl
authors.forename: Siddharth
authors.initials: S
authors.lastname: Jhunjhunwala
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kang
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018014:Gene Transfer Techniques; D015394:Molecular Structure; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D004952:Esters; D011108:Polymers; C507253:poly(beta-amino ester); D004247:DNA