New designed pH-responsive histidine-rich peptides with antitumor activity.

Anticancer peptides have received widespread attention as alternative antitumor therapeutics due to their unique action mode. However, the systemic toxicity hampers their successful utilisation in tumour therapy. Here, the tumour acidic environment was used as a trigger to design a series of histidine-rich peptides by optimising the distribution of histidine and leucine based on the amphiphilic peptide LK, in hoping to achieve desirable acid-activate anticancer peptides. Among all the obtained peptides, L9H5-1 showed enhanced antitumor activity at acidic pH concomitant with low toxicity at normal pH, exhibiting excellent pH-response. At acidic pH, protonated L9H5-1 could rapidly kill tumour cells by efficient membrane disruption as evidenced by experiments, including increasing intracellular PI uptake and LDH release, dramatic membrane damage and increase of later apoptotic/necrotic cells. Moreover, no cell cycle arrest was observed after treated with L9H5-1. Interestingly, this study found that the new peptides with the same number of histidines and leucines displayed different pH-dependent antitumor activity, indicating that the position of amino acid alteration is extremely important for the design of acid-activated histidine-rich peptides. In short, our work provides a new avenue to develop new acid-activated anticancer peptides as promising antitumor drugs with high efficiency and good selectivity.