Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells

Cell‐penetrating peptides (CPPs) have been considered as potential drug delivery vectors due to their remarkable membrane translocation capacity. However, lack of specificity and extreme systemic toxicity hamper their successful application for drug delivery. Here, we designed a new pH‐activatable CPP, LHHLLHHLHHLLHH‐NH₂ (LH), by substitution of all lysines and two leucines of LKKLLKLLKKLLKL‐NH₂ (LK) with histidines. As expected, histidine‐rich LH could be activated and penetrate into cells at pH 6.0, whereas its membrane transduction activity could be shielded at pH 7.4. In contrast, LK showed no obviously different cellular uptake at both pH conditions. Importantly, LH was significantly less cytotoxicity compared with LK at both pH values, suggesting a better safety for further application. In addition, after conjugation of camptothecin (CPT) with LH, this conjugate displayed remarkably pH‐dependent antitumor activity than free CPT and LK‐CPT. This study provides a new tumor pH‐responsive CPP with low toxicity for selective anticancer drug delivery.