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Insights in cellular uptake mechanisms of pDNA– polycationic amphiphilic...

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Alejandro Díaz-Moscoso, Dries Vercauteren, Joanna Rejman, Juan M. Benito, Carmen Ortiz Mellet, Stefaan C. De Smedt, José M. García Fernández

Journal of Controlled Release 2010, Vol. 143, 318-325

IIQ

It is generally recognized that the major obstacle to afford an efficient gene delivery is cellular internalization and endosomal escape of the DNA. Recently, we have developed a modular strategy for the preparation of well defined polycationic amphiphilic cyclodextrins (paCDs) capable of complex and compact DNA into homogeneous nanoparticles (~70 nm). Since paCDs resemble both cationic polymers and cationic lipids, it is conceivable that the corresponding pDNA–paCD nanoparticles (CDplexes) might be internalized by the cell internalization mechanisms described for both lipoplexes and polyplexes. To verify this hypothesis, we have now investigated the uptake and transfection efficiencies of CDplexes in the presence of inhibitors of several endocytotic mechanisms, namely chlorpromazine, genistein, dynasore and methylated β-cyclodextrin (MbCD). Our data show that CDplexes are internalized by both clathrin-dependent (CDE) and clathrin-independent endocytosis (CIE). However, though the largest fraction of gene complexes is taken up via CDE, only the fraction internalized via the CIE pathway achieve gene expression.

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