Base invaders. Coupling experiments and multiscale modeling of dendrimer-based siRNA delivery agents

Posocco, Paola and Pavan, Giovanni Maria and Scocchi, Giulio and Handgraaf, Jan-Willem and Malek, Anastasia and Maly, Marek and Fermeglia, Maurizio and Fraaije, Johannes GEM and Catapano, Carlo V and Danani, Andrea (2008) Base invaders. Coupling experiments and multiscale modeling of dendrimer-based siRNA delivery agents. Advances in Science and Technology, 57. pp. 154-159. ISSN 1662-0356

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Injected, nano-scale drug delivery systems, or nanovectors, are ideal candidates to provide breakthrough solutions to the time-honored problem of optimizing therapeutic index for a treatment. Even modest amounts of progress towards this goal have historically engendered substantial benefits across multiple fields of medicine, with the translability, for example, from oncology to infectious diseases being granted by the fact that the progresses had a single common denominator in the underlying technological platform. In this work we combine multiscale molecular modeling and experimental approaches to define the mode and the molecular requirements of the interaction of oligonucleotide-based therapeutics (e.g., small interfering (si)RNA)and dendrimeric delivery reagents. In details, by mimicking in silico the experiments performed in vitro, information at the molecular level(e.g., interaction forces, mechanisms, structures, free energies of binding, self-assembly, etc.), which cannot be accessed by other experimental techniques, are obtained. Thus, critical molecular parameters for optimizing and de novo designing nanocargos for tissues and tumor specific uptake can be determined. This would provide valuable information to devise optimal delivery modalities that would increase the efficacy of siRNA therapeutics in cells and laboratory animals and move them toward clinical applications.

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