About 25 years 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.

大约25年前，已证明某些肽具有穿越质膜的能力。这导致了细胞穿透肽（CPP）的发展，作为媒介来介导自身不显示细胞进入的（大分子）分子的细胞进入。尽管如此，尽管有前期的有希望的临床前研究开始盛行，但尚未批准任何一种基于CPP的药物。CPP研究的一个范例是，肽几乎被所有细胞吸收。在探索性研究和早期临床前开发中，该假设指导治疗目标的选择。然而，尽管对于组织培养实验来说，这种无差别的摄取可能是这种情况，但是在生物体中，事实并非如此。生物分布分析表明，CPP仅靶向非常有限的细胞，而几乎几乎无法达到许多组织。在这里，我们回顾了CPPs和基于CPP的药物递送系统的生物分布分析。基于此分析，我们提出了向CPP研究中的机会主义方法转变的范例。CPP的应用应侧重于已证明可达到相关靶细胞的那些病理生理学体内。