title: Mannosyl-coated nanocomplexes from amphiphilic cyclodextrins and pDNA for site-specific gene delivery.
abstract: Fully homogeneous facial amphiphiles consisting in a cyclodextrin (CD) platform onto which a polycationic cluster and a multi-tail hydrophobic moiety have been installed (polycationic amphiphilic CDs; paCDs) self-organized in the presence of plasmid DNA to form nanometric complexes (CDplexes) which exhibit broad-range transfection capabilities. We hypothesized that biorecognizable moieties located at the hydrophilic rim in the CD scaffold would be exposed at the surface of the corresponding nanoparticles after DNA-promoted aggregation, endowing the system with molecular recognition abilities towards cell receptors. This concept has been demonstrated by developing an efficient synthetic strategy for the preparation of multivalent polycationic glyco-amphiphilic CDs (pGaCDs). Self-assembled nanoparticles obtained from mannosylated pGaCDs and pDNA (average hydrodynamic diameter 80 nm) have been shown to be specifically recognized by mannose-specific lectins, including concanavalin A (Con A) and the human macrophage mannose receptor (MMR). Further macrophage adhesion studies indicated that unspecific binding, probably due to electrostatic interactions with negatively charged cell membrane components, can also operate. The relative specific versus non-specific internalization is dependent on the pGaCD:pDNA proportion, being optimal at a protonable nitrogen/phosphate (N/P) ratio of 5. The resulting GlycoCDplexes were shown to specifically mediate transfection in Raw 264.7 (murine macrophage) cells expressing the mannose-fucose receptor in vitro. FACS experiments confirmed that transfection using these nanoparticles is mannose-dependent, supporting the potential of the approach towards vectorized gene delivery.
authors: Instituto de Investigaciones Químicas, CSIC-Universidad de Sevilla, Sevilla, Spain.
authors: Alejandro
authors: A
authors: Díaz-Moscoso
authors: Nicolas
authors: N
authors: Guilloteau
authors: Céline
authors: C
authors: Bienvenu
authors: Alejandro
authors: A
authors: Méndez-Ardoy
authors: José L Jiménez
authors: JL
authors: Blanco
authors: Juan M
authors: JM
authors: Benito
authors: Loïc
authors: L
authors: Le Gourriérec
authors: Christophe
authors: C
authors: Di Giorgio
authors: Pierre
authors: P
authors: Vierling
authors: Jacques
authors: J
authors: Defaye
authors: Carmen Ortiz
authors: CO
authors: Mellet
authors: José M García
authors: JM
authors: Fernández
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003208:Concanavalin A / Q000378:metabolism; D003505:Cyclodextrins / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008358:Mannose / Q000737:chemistry*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008422:Materials Testing; D051379:Mice; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010957:Plasmids / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D003505:Cyclodextrins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D003208:Concanavalin A; D004247:DNA; D008358:Mannose