Cell‐penetrating peptides (CPPs) are still an interesting and viable alternative for drug delivery applications. CPPs contain considerably high amounts of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an enhanced anionic nature of their membrane surface, a property that could be used by CPPs to target these cells. We recently identified a branched CPP that displays a high internalization capacity while exhibiting selectivity for certain tumor cell types. In this study we elucidated this observation in greater detail by investigating the underlying mechanism behind the cellular uptake of this peptide. An additional cytotoxicity screen against several cancer cell lines indeed demonstrates high cytotoxic activity against cancer cells over normal fibroblasts. Furthermore, we show that this feature can be used for delivering the anticancer drug actinomycin D with high efficiency in the MCF‐7 cancer cell line.

Within this study, we report about the design and biological characterization of novel cell-penetrating peptides (CPPs) with selective suborganelle-targeting properties. The nuclear localization sequence N50, as well as the nucleoli-targeting sequence NrTP, respectively, were fused to a shortened version of the cell-penetrating peptide sC18. We examined cellular uptake, subcellular fate and cytotoxicity of these novel peptides, N50-sC18* and NrTP-sC18*, and found that they are nontoxic up to a concentration of 50 or 100 µM depending on the cell lines used. Moreover, detailed cellular uptake studies revealed that both peptides enter cells via energy-independent uptake, although endocytotic processes cannot completely excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide–drug conjugates.

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The back cover picture shows how the branched cell‐penetrating peptide (CPP), namely (sC18)2, effectively enters cancerous cells. Owing to its structural properties, different interactions between cancerous and noncancerous cells occur, leading to obvious different entry pathways. As a result, (sC18)2 strongly affects cancerous cells and exhibits significant toxic activity to a wide range of different cancer cell types. Moreover, synergistic effects were obtained when combining the CPP with the cytostatic drug actinomycin D. More information can be found in the Full Paper by Ines Neundorf et al. on page 42 in Issue 1, 2017 (DOI:10.1002/cmdc.201600498).