Potential use of glucuronylglucosyl-β-cyclodextrin/dendrimer conjugate (G2) as a siRNA carrier for the treatment of familial amyloidotic polyneuropathy

We previously reported that 6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-cyclodextrin (GUG-beta-CyD) conjugate with polyamidoamine dendrimer (dendrimer, generation 2; G2) (GUG-beta-CDE (G2)) is useful as a gene transfer carrier. In the present study, to investigate the potentials of GUG-beta-CDE (G2) as a siRNA carrier, we evaluated the RNAi effect of its complex with siRNA against transthyretin (TTR) mRNA (siTTR) for the treatment of familial amyloidotic polyneuropathy (FAP). Among the various GUG-beta-CDEs (G2) having the different degrees of substitution of GUG-beta-CyD (degree of substation (DS) 1.8, 2.5, 3.0 and 5.0), GUG-beta-CDE (G2, DS 1.8) showed the highest siTTR transfer activity. GUG-beta-CDE (G2, DS 1.8)/siTTR complex showed no cytotoxicity in HepG2 cells. After intravenous administration of GUG-beta-CDE (G2, DS 1.8)/siTTR complex to BALB/c mice, TTR mRNA expression was tended to reduce with negligible change of blood chemistry data. Particle size, zeta-potential and cellular association of the GUG-beta-CDE (G2, DS 1.8) complex were almost the same as those of the other CDEs complexes. Meanwhile, GUG-beta-CDE (G2, DS 1.8)/siTTR complex showed high endosomal escaping ability of siTTR in cytoplasm. These findings suggest the potential of GUG-beta-CDE (G2, DS 1.8) as a siRNA carrier for the FAP treatment.