Send to

Choose Destination
Chem Biol Drug Des. 2019 May 6. doi: 10.1111/cbdd.13537. [Epub ahead of print]

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

Zhang Y1,2, Li L3, Chang L1,2, Liu H1,2, Song J2, Liu Y4, Bao H1, Liu B2, Wang R2, Ni J1,2.

Author information

School of Pharmacy, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Department of Pharmacy, Daping Hospital & Research Institute of Surgery, Army Medical University, Chongqin, China.
Department of Pharmacy, Lanzhou General Hospital of People's Liberation Army, Lanzhou, China.


Cell penetrating peptides (CPPs) were 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. This article is protected by copyright. All rights reserved.


Cell penetrating peptides; acid-activate; anticancer drug delivery; low cytotoxicity; pH-dependent antitumor activity


Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center