Tumor-specific pH-responsive peptide-modified pH-sensitive liposomes containing doxorubicin for enhancing glioma targeting and anti-tumor activity.

Abstract

The pH environment in gliomas is acidic. Therefore, in the present research, we selected our previously reported tumor-specific pH-responsive peptide H7K(R2)2 as a targeting ligand, which could respond to the acidic pH environment in gliomas, possessing CPP characteristics. The pH-sensitive liposomes were selected as carriers which could also respond to the acidic pH environment in gliomas triggering encapsulated drug release from these pH-sensitive liposomes. The H7K(R2)2-modified pH-sensitive liposomes containing doxorubicin (DOX-PSL-H7K(R2)2) were designed and prepared in order to evaluate their potential targeting of glioma tumor cells and their anti-tumor activity in mice with glioma tumor cells. DOX-PSL-H7K(R2)2 was prepared by the thin-film hydration method followed by remote loading using an ammonium sulfate gradient method. The in vitro release of DOX from pH-sensitive liposomes was tested and the in vitro targeting characteristics of H7K(R2)2-modified liposomes regarding C6 (rat C6 glioma cells) and U87-MG (human glioblastoma cells) were evaluated. The in vivo anti-tumor activity of DOX-PSL-H7K(R2)2 was also investigated in C6 tumor-bearing mice and in U87-MG orthotopic tumor-bearing nude mice. A specific targeting effect triggered by an acidic pH was observed in our in vitro experiments in C6 and U87-MG glioma cells. The pH-triggered DOX release from the pH-sensitive liposomes under acidic conditions was also confirmed in our in vitro experiment. Anti-tumor activity of DOX-PSL-H7K(R2)2 was found in C6 tumor-bearing mice and U87-MG orthotopic tumor-bearing nude mice in in vivo experiments. The antiangiogenic activity of DOX-PSL-H7K(R2)2 was confirmed in C6 tumor-bearing mice in the in vivo experiment. These H7K(R2)2-modified pH-sensitive liposomes containing anti-tumor drugs developed in this study are a promising delivery system involving the response stimuli at the acidic pH in the glioma tumor microenvironment and are suitable for anti-tumor therapy.

• Authors: Yang Zhao, Wei Ren, Ting Zhong, Shuang Zhang, Dan Huang, Yang Guo, Xin Yao, Chao Wang, Wei-Qiang Zhang, Xuan Zhang, Qiang Zhang
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 222 Pg. 56-66 (Jan 28 2016) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26682502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• H7K(R2)2 peptide
• Liposomes
• Peptides
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (administration & dosage, chemistry, pharmacology, therapeutic use)
• Drug Liberation
• Glioma (drug therapy)
• Humans
• Hydrogen-Ion Concentration
• Liposomes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Peptides (administration & dosage, chemistry, pharmacology, therapeutic use)
• Rats
• Tumor Microenvironment