2010 Volume 25 Issue 6 Pages 598-606
Gene and oligonucleotide therapies are emerging as a potential strategy for the treatment of genetic diseases, cancers, cardiovascular diseases and infectious diseases. We have evaluated the potential use of various polyamidoamine (PAMAM) dendrimer (dendrimer, generation (G) 2-4) conjugates with cyclodextrins (CyDs) as novel DNA and RNA carriers. Among the various dendrimer conjugates with CyDs, the dendrimer (G3) conjugate with α-CyD having an average degree of substitution (DS) of 2.4 (α-CDE (G3, DS2.4)) displayed remarkable properties as DNA, shRNA and siRNA delivery carriers through the sensor function of α-CDEs toward nucleic acid drugs, cell surface and endosomal membranes. In an attempt to develop cell-specific gene transfer carriers, we prepared sugar-appended α-CDEs. Of the various sugar-appended α-CDEs prepared, galactose- or mannose-appended α-CDEs provided superior gene transfer activity to α-CDE in various cells, but not cell-specific gene delivery ability. However, lactose-appended α-CDE (Lac-α-CDE (G2)) was found to possess asialoglycoprotein receptor (AgpR)-mediated hepatocyte-selective gene and siRNA transfer activity both in vitro and in vivo. Most recently, we prepared folate-poly(ethylene glycol)-appended α-CDE (Fol-PαC (G3)) and revealed that Fol-PαC (G3) imparted folate receptor (FR)-mediated cancer cell-selective gene transfer activity. Consequently, α-CDEs bearing integrated, multifunctional molecules may possess the potential for DNA, shRNA and siRNA carriers.
