About 25years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be reached in vivo.
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