Protamine-oligonucleotide-nanoparticles: Recent advances in drug delivery and drug targeting.

Application of oligonucleotides as active compounds has become a crucial field of pharmaceutical research in recent years. In order to improve inadequate transfection rate and to avoid rapid enzymatic degradation of antisense oligonucleotides (AS-ODNs) a novel nanoparticulate delivery system was reported by our group at the beginning of 2000. AS-ODNs are condensed by the polycationic peptide protamine into solid particles in the size range of 100-200nm. Nanoparticle formation is driven by a self-assembling process based on electrostatic interactions between the oppositely charged biomolecules. This new delivery system was named "proticles" and showed very efficient protection against enzymatic digestion, high transfection rates and significant antisense effects in vitro. Throughout broader research, this promising approach was enlarged, and AS-ODNs were replaced by siRNA or CpG-oligonucleotides to address the aspect of immune-modulation and vaccination. More recent studies on proticles verified upscaling of the self-assembling process as well as the potential of proticle formulations for active drug targeting, like tumor- or atherosclerotic plaque targeting. Thereby also the application for diagnostic purposes was emphasized. This review will focus on the characterization of the nucleoprotein protamine as well as on the variety of possible nucleotides/peptides which were already assembled into the proticle matrix. Furthermore it will provide an insight into the broad area of application where proticles can present a valuable tool for successful oligonucleotide delivery.