Novel pH-responsive anticancer lipopeptide exhibiting superior antitumor performance by the smart intramolecular...

The pH-responsive anticancer peptides (ACPs) have gained increasing attention as a new generation of promising candidates for cancer therapy due to the better selectivity and low toxicity. Developing an effective strategy to improve the therapeutic potential of pH-responsive ACPs is crucial in facilitating their successful applications. Herein, an interesting design strategy was proposed by utilizing the combination of intramolecular charge shielding and lipidation modification to improve the antitumor efficacy of pH-responsive ACPs while maintaining low toxicity. A series of new short pH-responsive ACPs were designed and synthesized based on the histidine-rich peptide L7H7. The results showed that the intramolecular charge shielding peptide KLHE had higher pH-activated killing effect and selectivity index than L7H7. Notably, the smart co-modified peptides had a better ability to improve the pH-activated antitumor activity and reduce the toxicity of pH-responsive ACPs. Among them, the new pH-responsive lipopeptide ¹C6-KLHE derived from the optimal 1th site stood out as an alternative candidate, exhibiting excellent pH-dependent antitumor activity (2-fold increase) concomitant with significantly elevated therapeutic selectivity (11.1-fold increase) and enhanced serum stability 4.03-fold higher than KLHE. After acid activation, ¹C6-KLHE exerted antitumor effect by pH-dependent membrane disruption and cell apoptosis. Furthermore, the new peptide ¹C6-KLHE displayed the preferable antitumor efficacy and low toxicity in vivo compared to KLHE and PTX, which demonstrating its apparent superiority for in vivo application. In summary, our work reveals that the smart combination of intramolecular charge shielding and lipidation modification is an effective approach to develop prospective pH-responsive ACPs with better potential for tumor treatment.