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Title

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

AuthorsDíaz Moscoso, Alejandro ; Gourriérec, Loïc le; Gómez García, Marta ; Benito, Juan M. ; Balbuena Olivia, Patricia ; Ortega-Caballero, Fernando; Guilloteau, Nicolas; Giorgo, Christophe di; Vierling, Pierre; Defaye, Jacques; Ortiz-Mellet, Carmen; García-Fernández, José Manuel
KeywordsAmphiphiles
Cyclodextrins
Gene delivery
Nanoparticles
Self-assembly
Issue Date15-Oct-2009
PublisherWiley-VCH
CitationChemistry - a European Journal 15(46): 12871-12888 (2009)
AbstractA 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 hydrogen-bonding 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.
Description18 páginas, 11 figuras, 4 esquemas
Publisher version (URL)http://dx.doi.org/10.1002/chem.200901149
URIhttp://hdl.handle.net/10261/36635
DOI10.1002/chem.200901149
ISSN0947-6539
E-ISSN1521-3765
Appears in Collections:(IIQ) Artículos
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