Molecular characterization of the interaction between siRNA and PAMAM G7 dendrimers by SAXS, ITC, and molecular dynamics simultations

TY - JOUR

T1 - Molecular characterization of the interaction between siRNA and PAMAM G7 dendrimers by SAXS, ITC, and molecular dynamics simultations

AU - Jensen, Linda Boye

AU - Mortensen, Kell

AU - Pavan, Giovanni M.

AU - Kasimova, Marina Robertovna

AU - Jensen, Ditte K.

AU - Gadzhyeva, Veronika

AU - Nielsen, Hanne Mørck

AU - Foged, Camilla

PY - 2010/12/13

Y1 - 2010/12/13

N2 - A prerequisite for the use of dendrimers as drug delivery vehicles is the detailed molecular understanding of the drug interaction. The purpose of this study was to characterize the self-assembly process between siRNA and generation 7 poly(amidoamine) dendrimers and the resulting dendriplexes in aqueous solution using structural and calorimetric methods combined with molecular dynamics simulations. Complexes with a length scale of 150 nm showed a decreasing size with increasing amine-to-phosphate ratio by dynamic light scattering. At the molecular level, individual dendrimers studied by small-angle X-ray scattering (SAXS) showed no change in size upon siRNA binding, suggesting a rigid sphere behavior. Isothermal titration calorimetry (ITC) demonstrated exothermic binding with a concentration-dependent collapse of complexes. Both the experimentally determined δHbind and size were in close accordance with molecular dynamics simulations. This study demonstrates the unique complementarity of SAXS, ITC, and modeling for the detailed description of the molecular interactions between dendrimers and siRNA during dendriplex formation.

AB - A prerequisite for the use of dendrimers as drug delivery vehicles is the detailed molecular understanding of the drug interaction. The purpose of this study was to characterize the self-assembly process between siRNA and generation 7 poly(amidoamine) dendrimers and the resulting dendriplexes in aqueous solution using structural and calorimetric methods combined with molecular dynamics simulations. Complexes with a length scale of 150 nm showed a decreasing size with increasing amine-to-phosphate ratio by dynamic light scattering. At the molecular level, individual dendrimers studied by small-angle X-ray scattering (SAXS) showed no change in size upon siRNA binding, suggesting a rigid sphere behavior. Isothermal titration calorimetry (ITC) demonstrated exothermic binding with a concentration-dependent collapse of complexes. Both the experimentally determined δHbind and size were in close accordance with molecular dynamics simulations. This study demonstrates the unique complementarity of SAXS, ITC, and modeling for the detailed description of the molecular interactions between dendrimers and siRNA during dendriplex formation.

U2 - 10.1021/bm101033g

DO - 10.1021/bm101033g

M3 - Journal article

C2 - 21067145

SN - 1525-7797

VL - 11

SP - 3571

EP - 3577

JO - Biomacromolecules

JF - Biomacromolecules

IS - 12

ER -