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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Cell-permeable peptides induce dose- and length-dependent cytotoxic effects.
Alessandra K Cardozo1, Valérie Buchillier, Marc Mathieu
1The Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium.
Biochimica Et Biophysica Acta
|July 14, 2007
Summary
Tat(48-57) and Antp(43-58) are cell-penetrating peptides used for drug delivery. Tat(48-57) showed low toxicity, while Antp(43-58) was more toxic. Peptide conjugates above 10 microM induced cytotoxicity, linked to stress pathways.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Cell-penetrating peptides (CPPs) like Tat(48-57) and Antp(43-58) facilitate intracellular delivery.
- Understanding CPPs' toxicity is crucial for effective drug delivery applications.
- Previous studies highlight the membrane translocation efficiency of Tat and Antp peptides.
Purpose of the Study:
- To determine the tolerance threshold of different cell types to peptides conjugated with Tat(48-57) and Antp(43-58) carriers.
- To investigate the relationship between peptide conjugate concentration, sequence length, and cytotoxicity.
- To identify intracellular pathways involved in CPP-induced toxicity.
Main Methods:
- Treatment of three distinct cell types with varying concentrations of Tat(48-57) and Antp(43-58) peptide conjugates.
- Monitoring intracellular peptide uptake using confocal laser scanning fluorescence microscopy.
- Assessing cytotoxicity and activation of stress signaling pathways (JNK, p38 MAPK).
Main Results:
- Tat(48-57) carriers were well-tolerated up to 100 microM, while Antp(43-58) exhibited higher toxicity.
- Peptide conjugates at concentrations >10 microM induced length-dependent cytotoxicity in most cell types, except 208F rat fibroblasts.
- Cytotoxicity correlated with increased JNK and p38 MAPK activation, with poor uptake in resistant 208F cells.
Conclusions:
- Tat(48-57) is a safer carrier than Antp(43-58) for intracellular peptide delivery.
- Optimizing effector molecule design (short sequence, high affinity) is essential to minimize cytotoxicity below 10 microM.
- The findings provide a general framework for designing CPPs for safe and effective intracellular delivery across various cell types.
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