A new short pH-responsive anticancer peptide derived by intramolecular charge shielding strategy

The pH-responsive anticancer peptides (ACPs) have been regarded as a new generation of prospective antitumor candidates due to their selectivity. However, the successful utilizations have been hampered by their narrow therapeutic index, poor stability and long sequence. Here, a new type of short pH-responsive ACPs was constructed by smart intramolecular charge shielding in histidine-rich peptide LH. This design would not depend on the introduction of additional anionic binding peptide, which might be an effective method for appreciably shortening the sequence of pH-responsive ACPs while improving their safety and stability. As expected, 2E-K stood out from the acquired peptides as it exhibited a considerable pH-dependent antitumor activity concomitant with remarkably improved therapeutic selectivity (14.5-fold increase) and extended serum half-life (3.6-fold enhancement) compared to LH. Experimental results showed that acid-activated 2E-K could efficiently induce tumor cell death by rapid membrane damage. Notably, the in vivo experiments further confirmed its excellent antitumor efficacy and low toxicity when compared with PTX, which demonstrating its superiority for in vivo application. In conclusion, our work opened a new avenue for developing short pH-responsive ACPs as promising alternative drugs in cancer treatment.