Strategies to target bioactive molecules to subcellular compartments. Focus on natural compounds

Many potential pharmacological targets are present in multiple subcellular compartments and have different pathophysiological roles depending on location. In these cases, selective targeting of a drug to the relevant subcellular domain(s) may help to sharpen its impact by providing topological specificity, thus limiting side effects, and to concentrate the compound where needed, thus increasing its effectiveness. We review here the state of the art in precision subcellular delivery. The major approaches confer "homing" properties to the active principle via permanent or reversible (in pro-drug fashion) modifications, or through the use of special-design nanoparticles or liposomes to ferry a drug(s) cargo to its desired destination. An assortment of peptides, substituents with delocalized positive charges, custom-blended lipid mixtures, pH- or enzyme-sensitive groups provide the main tools of the trade. Mitochondria, lysosomes and the cell membrane may be mentioned as the fronts on which the most significant advances have been made. Most of the examples presented here have to do with targeting natural compounds - in particular polyphenols, known as pleiotropic agents - to one or the other subcellular compartment.