title: Host-Guest-Mediated DNA Templation of Polycationic Supramolecules for Hierarchical Nanocondensation and the Delivery of Gene Material.
abstract: Only a few examples of monodisperse molecular entities that can compact exogenous nucleic acids into nanocomplexes, protect the cargo from the biological environment, facilitate cell internalization, and promote safe transfection have been reported up to date. Although these species open new venues for fundamental studies on the structural requirements that govern the intervening processes and their application in nonviral gene-vector design, the synthesis of these moieties generally requires a relatively sophisticated chemistry, which hampers further development in gene therapy. Herein, we report an original strategy for the reversible complexation and delivery of DNA based on the supramolecular preorganization of a β-cyclodextrin-scaffolded polycationic cluster facilitated by bisadamantane guests. The resulting gemini-type, dual-cluster supramolecules can then undergo DNA-templated self-assembly at neutral pH value by bridging parallel DNA oligonucleotide fragments. This hierarchical DNA condensation mechanism affords transfectious nanoparticles with buffering capabilities, thus facilitating endosomal escape following cell internalization. Protonation also destabilizes the supramolecular dimers and consequently the whole supramolecular edifice, thus assisting DNA release. Our advanced hypotheses are supported by isothermal titration calorimetry, NMR and circular dichroism spectroscopic analysis, gel electrophoresis, dynamic light scattering, TEM, molecular mechanics, molecular dynamics, and transfection studies conducted in vitro and in vivo.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, c/Prof. García González 1, 41012 Sevilla (Spain).
authors.forename: Laura
authors.initials: L
authors.lastname: Gallego-Yerga
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080, Pamplona (Spain).
authors.forename: Laura
authors.initials: L
authors.lastname: Blanco-Fernández
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080, Pamplona (Spain).
authors.forename: Koldo
authors.initials: K
authors.lastname: Urbiola
authors.affiliation: Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Universidad de Alcalá, Edificio de Farmacia, Campus Universitario, Ctra, Madrid-Barcelona Km 33.600, 28871 Alcalá de Henares, Madrid (Spain).
authors.forename: Thais
authors.initials: T
authors.lastname: Carmona
authors.affiliation: Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Universidad de Alcalá, Edificio de Farmacia, Campus Universitario, Ctra, Madrid-Barcelona Km 33.600, 28871 Alcalá de Henares, Madrid (Spain).
authors.forename: Gema
authors.initials: G
authors.lastname: Marcelo
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC - University of Sevilla, Avda. Americo Vespucio 49, 41092 Sevilla (Spain).
authors.forename: Juan M
authors.initials: JM
authors.lastname: Benito
authors.affiliation: Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Universidad de Alcalá, Edificio de Farmacia, Campus Universitario, Ctra, Madrid-Barcelona Km 33.600, 28871 Alcalá de Henares, Madrid (Spain). francisco.mendicuti@uah.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Mendicuti
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080, Pamplona (Spain). ctros@unav.es.
authors.forename: Conchita
authors.initials: C
authors.lastname: Tros de Ilarduya
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, c/Prof. García González 1, 41012 Sevilla (Spain). mellet@us.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.affiliation: Instituto de Investigaciones Químicas (IIQ), CSIC - University of Sevilla, Avda. Americo Vespucio 49, 41092 Sevilla (Spain). jogarcia@iiq.csic.es.
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
mesh_terms: D002460:Cell Line; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry*; D000071228:Polyelectrolytes; D014162:Transfection; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D004247:DNA; D009841:Oligonucleotides; D010446:Peptide Fragments; D011073:Polyamines; D000071228:Polyelectrolytes; D047392:beta-Cyclodextrins
keywords: cyclodextrins; gene delivery; nanocomplexes; self-assembly; supramolecular chemistry