The antiangiogenic efficacy of NGR-modified PEG–DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats

Abstract

Aminopeptidase N (APN), recognized by Asn-Gly-Arg (NGR) peptides, is expressed in the pericytes associated with the BBB, and the main objective of this study is to confirm the hypothesis that NGR-modified DSPE–PEG micelles containing paclitaxel (NGR-M-PTX) can bind to and kill brain tumor angiogenic blood vessels and penetrate into the brain tumor interstitial space, resulting in direct cell death. NGR-M-PTX is prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified micelles on BMEC (murine brain microvascular endothelial cells) were investigated. The effect of NGR-M-PTX on BMEC proliferation and the cytotoxicity of NGR-M-PTX in C6 glioma cells were also tested. The antitumor activity NGR-M-PTX was evaluated in C6 glioma tumor–bearing rats in vivo. The particle size of NGR-M-PTX was approximately 54.2 nm. The drug encapsulation efficiency of NGR-M-PTX was 82.11 ± 2.82%. The cellular coumarin-6 level of NGR-M-coumarin-6 in the BMEC was about 2.2-fold higher than that of M-coumarin-6. BMEC proliferation was significantly inhibited by NGR-M-PTX. NGR-M-PTX had a much lower IC₅₀ value than M-PTX and free drug. The growth of C6 glioma tumor was markedly inhibited by NGR-M-PTX compared with Taxol. In conclusion, our results show that antiangiogenic therapy using NGR-M-PTX exhibits potent in vivo antitumor activity in a C6 glioma–bearing animal model.

Keywords::

• Aminopeptidase N (APN)
• Asn-Gly-Arg (NGR)
• paclitaxel (PTX)
• DSPE-PEG micelles
• brain glioma–bearing rats
• antitumor efficacy.

Acknowledgement

The authors thank Dr. David Jack for correcting language.

Declaration of interest

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 30873170) and the National Basic Research Program of China (973 Program 2007CB935800 and 2009CB930300).