The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats.
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 IC(50) 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.
Zhao
Bo-Jun
BJ
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Ke
Xi-Yu
XY
Huang
Yue
Y
Chen
Xiao-Mei
XM
Zhao
Xin
X
Zhao
Bing-Xiang
BX
Lu
Wan-liang
WL
Lou
Jin-Ning
JN
Zhang
Xuan
X
Zhang
Qiang
Q
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects; D005434:Flow Cytometry; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D043384:Glutamyl Aminopeptidase / Q000378:metabolism; D008297:Male; D051379:Mice; D008823:Micelles; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D008823:Micelles; C526428:NGR peptide; D009842:Oligopeptides; D010714:Phosphatidylethanolamines; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D043384:Glutamyl Aminopeptidase; D017239:Paclitaxel