A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrin αvβ3 for the treatment of melanoma.

Abstract

The use of pH-responsive cell-penetrating peptides (CPPs) is an attractive strategy for drug delivery in vivo, however, they still could not actively target to the desired sites. Here, we designed a pH-responsive CPP (TR) with the ability of active targeting to integrin αvβ3, which was a tandem peptide consisted of active targeting ligand peptide (c(RGDfK)) and pH-responsive CPP (TH). The targeting efficiency of TR with integrin was evaluated by molecular simulation and docking studies. The affinity assays of TR peptide modified liposomes (TR-Lip) at pH7.4 and pH6.5 demonstrated adequately the pH-responsive binding efficacy of TR-Lip with integrin αvβ3. The cellular uptake of CFPE-labeled TR-Lip on integrin αvβ3-overexpressing B16F10 cells was 41.67-, 30.67-, and 11.90-fold higher than that of CFPE-labeled PEG-, RGD-, and TH-modified liposomes at pH6.5, respectively, suggesting that TR-Lip could not only actively target to αvβ3-overexpressing cells compared to TH-Lip, but also significantly increased cellular uptake compared to RGD-Lip. At the concentration of 20μg/mL paclitaxel (PTX), the killing activity of PTX-loaded TR-Lip (PTX-TR-Lip) against B16F10 cells was 1.80-, 1.45-, 1.30-, 1.15-time higher than that of PTX-loaded PEG-, RGD-, TH-modified liposomes and free PTX at pH6.5, respectively. In vivo imaging displayed the maximum accumulation of DiD-labeled TR-Lip at tumor sites compared to the other groups. Tumor inhibition rate of B16F10 tumor-bearing mice treated with PTX-TR-Lip was 85.04%, relative to that of PBS. In B16F10 tumor-bearing mice, PTX-TR-Lip showed significantly higher survival rate compared with the other groups. Collectively, all the results in vitro and in vivo suggested that TR-Lip would be a potential delivery system for PTX to treat integrin αvβ3-overexpressing tumor-bearing mice.

• Authors: Kairong Shi, Jianping Li, Zhonglian Cao, Ping Yang, Yue Qiu, Bo Yang, Yang Wang, Yang Long, Yayuan Liu, Qianyu Zhang, Jun Qian, Zhirong Zhang, Huile Gao, Qin He
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 217 Pg. 138-50 (Nov 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26368312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cell-Penetrating Peptides
• Integrin alphaVbeta3
• Liposomes
• Phosphatidylethanolamines
• 1,2-distearoylphosphatidylethanolamine
• Polyethylene Glycols
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, blood, pharmacokinetics)
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cell-Penetrating Peptides (administration & dosage, chemistry, therapeutic use)
• Coculture Techniques
• Drug Liberation
• Female
• Humans
• Hydrogen-Ion Concentration
• Integrin alphaVbeta3 (metabolism)
• Liposomes
• Melanoma, Experimental (drug therapy, metabolism)
• Mice, Inbred C57BL
• Paclitaxel (administration & dosage, blood, pharmacokinetics)
• Phosphatidylethanolamines (chemistry)
• Polyethylene Glycols (chemistry)