title: Low-generation asymmetric dendrimers exhibit minimal toxicity and effectively complex DNA.
abstract: Conventional dendrimers are spherical symmetrically branched polymers ending with active surface functional groups. Polyamidoamine (PAMAM) dendrimers have been widely studied as gene delivery vectors and have proven effective at delivering DNA to cells in vitro. However, higher-generation (G4-G8) PAMAM dendrimers exhibit toxicity due to their high cationic charge density and this has limited their application in vitro and in vivo. Another limitation arises when attempts are made to functionalize spherical dendrimers as targeting moieties cannot be site-specifically attached. Therefore, we propose that lower-generation asymmetric dendrimers, which are likely devoid of toxicity and to which site-specific attachment of targeting ligands can be achieved, would be a viable alternative to currently available dendrimers. We synthesized and characterized a series of peptide-based asymmetric dendrimers and compared their toxicity profile and ability to condense DNA to spherical PAMAM G1 dendrimers. We show that asymmetric dendrimers are minimally toxic and condense DNA into stable toroids which have been reported necessary for efficient cell transfection. This paves the way for these systems to be conjugated with targeting ligands for gene delivery in vitro and in vivo.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Neha
authors.initials: N
authors.lastname: Shah
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Harendra S
authors.initials: HS
authors.lastname: Parekh
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004270:DNA, Circular / Q000737:chemistry*; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008968:Molecular Conformation; D010957:Plasmids
chemical_list: D004270:DNA, Circular; D050091:Dendrimers; C104700:PAMAM Starburst