cicCartuja Centro de Investigaciones Científicas de la cartuja

Polycationic Amphiphilic Cyclodextrins for Gene Delivery: Synthesis and Effect of Structural Modifications on Plasmid DNA Complex Stability, Cytotoxicity, and Gene Expression

IIQ

Alejandro Díaz-Moscoso, Lçic Le Gourriérec, Marta Gómez-García, Juan M. Benito, Patricia Balbuena,Fernando Ortega-aballero, Nicolas Guilloteau,Christophe Di Giorgio, Pierre Vierling, Jacques Defaye, Carmen Ortiz Mellet, and José M. García Fernández Chem. Eur. J. 2009, Vol. 15, 12871-12888

A molecular-diversity-oriented approach for the preparation of well-defined polycationic amphiphilic cyclodextrins paCDs) as gene-delivery systems is reported. The synthetic strategy takes advantage of the differential reactivity of primary versus secondary hydroxyl groups on the CD torus to regioselectively decorate each rim with cationic elements and lipophilic tails, respectively. Both the charge density and the hydrophobic–hydrophilic balance can be finely tuned in a highly symmetrical architecture that is reminiscent of both cationic lipids and cationic polymers, the two most prominent types of nonviral gene vectors. The monodisperse nature of paCDs and the modularity of the synthetic scheme are particularly well suited for structure–activity relationship studies. Gel electrophoresis revealed that paCDs self-assemble in the presence of plasmid DNA (pDNA) to provide homogeneous, stable nanoparticles (CDplexes) of 70–150 nm that fully protect pDNA from the environment. The transfection efficiency of the resulting CDplexes has been investigated in vitro on BNL-CL2 and COS-7 cell lines in the absence and presence of serum and found to be intimately dependent on architectural features. Facial amphiphilicity and the presence of a cluster of cationic and hydrogenbonding centers for cooperative and reversible complexation of the polyanionic DNA chain is crucial to attain high transgene expression levels with very low toxicity profiles. Further enhancement of gene expression, eventually overcoming that of polyplexes from commercial polyethyleneimine (PEI) polymers (22 kDa), is achieved by building up space-oriented dendritic polycationic constructs.

• Improved non-covalent biofunctionalization of Multi-Walled Carbon... IIQ Mohyeddin Assali et al.
• Versatility and multifunctionality of highly reflecting Bragg mirrors... ICMS Olalla Sánchez-Sobrado et al.
• Nitration of tyrosine 74 prevents human cytochrome c... IBVF/IIQ José M. García-Heredia et al.
• Organocatalytic Asymmetric Cyanosilylation of Nitroalkenes IIQ Pablo Bernal et al.
• Inhibition of Target of Rapamycin signaling and stress activate... IBVF María Esther Pérez-Pérez et al.
• Fra proteins influencing filament integrity, diazotrophy... IBVF Victoria Merino-Puerto et al.
• Oxidation state and local structure of Ti-based additives... ICMS Emilie Deprez et al.
• Arabidopsis S-Sulfocysteine Synthase Activity Is Essential for Chloroplast... IBVF María Ángeles Bermúdez et al.
• Cyclometallation and Hydrogen/Deuterium Exchange Reactions... IIQ Jesús Campos et al.
• An O-Acetylserine(thiol)lyase Homolg with L-Cysteine... IBVF Consolación Álvarez et al.
• Ionic liquid templated TiO₂ nanoparticles as a support in gold ... ICMS Rafael S. Avellaneda et al.
• Polycationic Amphiphilic Cyclodextrins for Gene Delivery ... IIQ Alejandro Díaz-Moscoso et al.