Ternary complexes of folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugate, siRNA and low-molecular-weight polysaccharide sacran as a novel tumor-selective siRNA delivery system

We previously developed a tumor-selective siRNA carrier by preparing polyamidoamine dendrimer (generation 4, G4) conjugates with alpha-cyclodextrin and folate-polyethylene glycol (Fol-P alpha C (G4)). In the present study, we developed ternary complexes of Fol-P alpha C (G4)/siRNA with low-molecular-weight-sacrans to achieve more effective siRNA transfer activity. Among the different molecular-weight sacrans, i.e. sacran 100, 1000 and 10,000 (MW 44,889 Da, 943,692 Da and 1,488,281 Da, respectively), sacran 100 significantly increased the cellular uptake and the RNAi effects of Fol-P alpha C (G4)/siRNA binary complex with negligible cytotoxicity in KB cells (folate receptor-a positive cells). In addition, the zeta-potential and particle size of Fol-P alpha C (G4)/siRNA complex were decreased by the ternary complexation with sacran 100. Importantly, the in vivo RNAi effect of the ternary complex after the intravenous administration to tumor-bearing BALB/c mice was significantly higher than that of the binary complex. In conclusion, Fol-P alpha C (G4)/siRNA/sacran 100 ternary complex has a potential as a novel tumor-selective siRNA delivery system. (C) 2017 Elsevier B.V. All rights reserved.