Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 94, Issue 5, Pages 1884-1893Publisher
WILEY
DOI: 10.1111/cbdd.13537
Keywords
acid-activated; anticancer drug delivery; cell-penetrating peptides; low cytotoxicity; pH-dependent antitumor activity
Funding
- the Fundamental Research Funds for the Central Universities [lzujbky-2017-204] Funding Source: Medline
- the National Natural Science Foundation of China [81273440, 81773564] Funding Source: Medline
- the Specialized Research Fund for the Doctoral Program of Higher Education [20130211130005] Funding Source: Medline
- the Key Science & Technology Program of Gansu Province [17YF1FA125] Funding Source: Medline
- the Science & Technology Program of Chengguan District [2016-1-2] Funding Source: Medline
- the Natural Science Foundation of Gansu Province [17JR5RA204] Funding Source: Medline
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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.
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