Journal
JOURNAL OF CONTROLLED RELEASE
Volume 222, Issue -, Pages 56-66Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2015.12.006
Keywords
Tumor-specific pH-responsive peptide; pH-sensitive liposomes; Targeting; Glioma; Anti-tumor activity
Funding
- Specialized Research Fund for the Doctoral Program of Higher Education [20120001110012]
- National Basic Research Program of China (973 Program) [2013CB932501]
- National Natural Science Foundation of China [81172992]
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The pH environment in gliomas is acidic. Therefore, in the present research, we selected our previously reported tumor-specific pH-responsive peptide H7K(R-2)(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(R-2)(2)-modified pH-sensitive liposomes containing doxorubicin (DOX-PSL-H7K(R-2)(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(R-2)(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(R-2)(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(R-2)(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(R-2)(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(R-2)(2) was confirmed in C6 tumor-bearing mice in the in vivo experiment. These H7K(R-2)(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. (C) 2015 Elsevier B.V. All rights reserved.
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