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Mannosyl-coated nanocomplexes from amphiphilic cyclodextrins and pDNA for site-specific gene delivery


Alejandro Díaz-Moscoso, Nicolas Guilloteau, Céline Bienvenu, Alejandro Méndez-Ardoy, José L. Jiménez Blanco, Juan M. Benito, Loïc Le Gourriérec, Christophe Di Giorgio, Pierre Vierling, Jacques Defaye, Carmen Ortiz Mellet, José M. García Fernández Biomaterials 2011, Vol. 32, 7263-7273

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 specific mannose-specific lectins, including concanvalin 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 specificversus non-specific internalization is dependent on thepGaCD: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 trasfection using these nanoparticles is mannose-dependent, supporting the potential of the approach towards vectorized gene delivery.