کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1945747 | 1053273 | 2007 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Cell-permeable peptides induce dose- and length-dependent cytotoxic effects Cell-permeable peptides induce dose- and length-dependent cytotoxic effects](/preview/png/1945747.png)
We have explored the threshold of tolerance of three unrelated cell types to treatments with potential cytoprotective peptides bound to Tat48–57 and Antp43–58 cell-permeable peptide carriers. Both Tat48–57 and Antp43–58 are well known for their good efficacy at crossing membranes of different cell types, their overall low toxicity, and their absence of leakage once internalised. Here, we show that concentrations of up to 100 μM of Tat48–57 were essentially harmless in all cells tested, whereas Antp43–58 was significantly more toxic. Moreover, all peptides bound to Tat48–57 and Antp43–58 triggered significant and length-dependent cytotoxicity when used at concentrations above 10 μM in all but one cell types (208F rat fibroblasts), irrespective of the sequence of the cargo. Absence of cytotoxicity in 208F fibroblasts correlated with poor intracellular peptide uptake, as monitored by confocal laser scanning fluorescence microscopy. Our data further suggest that the onset of cytotoxicity correlates with the activation of two intracellular stress signalling pathways, namely those involving JNK, and to a lesser extent p38 mitogen-activated protein kinases. These responses are of particular concern for cells that are especially sensitive to the activation of stress kinases. Collectively, these results indicate that in order to avoid unwanted and unspecific cytotoxicity, effector molecules bound to Tat48–57 should be designed with the shortest possible sequence and the highest possible affinity for their binding partners or targets, so that concentrations below 10 μM can be successfully applied to cells without harm. Considering that cytotoxicity associated to Tat48–57- and Antp43–58 bound peptide conjugates was not restricted to a particular type of cells, our data provide a general framework for the design of cell-penetrating peptides that may apply to broader uses of intracellular peptide and drug delivery.
Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes - Volume 1768, Issue 9, September 2007, Pages 2222–2234