Tuning the Topological Landscape of DNA–Cyclodextrin Nanocomplexes by Molecular Design |
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Authors: | Dr. Tania Neva Ana I. Carbajo-Gordillo Dr. Juan M. Benito Hugo Lana Dr. Gema Marcelo Prof. Carmen Ortiz Mellet Prof. Conchita Tros de Ilarduya Prof. Francisco Mendicuti Prof. José M. García Fernández |
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Affiliation: | 1. Institute for Chemical Research, IIQ, CSIC-Univ. Sevilla, C/ Américo Vespucio 49, 41092 Sevilla, Spain;2. Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, 31080 Pamplona, Spain;3. Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Instituto de Investigación Química, “Andrés M. del Rio” (IQAR), University of Alcalá, Campus Universitario Ctra. Madrid-Barcelona, Km 33.600, 28871 Alcalá de Henares, Spain;4. Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/ Prof García González 1, 41012 Sevilla, Spain |
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Abstract: | Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes. |
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Keywords: | computational methods cyclodextrins nanocomplex topology nonviral gene delivery self-assembly |
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