To improve the pharmacological profile of tumor necrosis factor alpha(TNF-α),we have synthesized a new PEGylated prodrug,PEG-vcTNF-α,using a cathepsin B-sensitive dipeptide(valine-citrulline,vc) to link branched PEG and TNF-α.PEG-modified TNF-α without the dipeptide linker(PEG-TNF-α) and unconjugated TNF-α were also tested as controls.It was found for the first time that TNF-α released from PEG-vcTNF-α was specifically dependent on the presence of cathepsin B.PEG-vcTNF-α induced higher cytotoxicity and greater apoptosis against L929 murine fibrosarcoma cells than PEG-TNF-α.Reversal of these effects by a cathepsin-B inhibitor confirmed that these effects were mediated by cathepsin B-specific release of TNF-α.In vivo pharmacokinetics studies demonstrated that the plasma stability of PEG-vcTNF-α was significantly increased compared to TNF-α.Finally,the improved anticancer efficacy of PEG-vcTNF-α and the distinct activities among the three formulations confirmed the positive contribution of both PEGylation and the dipeptide linkage to the improved drug-like properties of PEG-vcTNF-α.The results here indicate that linking proteins and PEG via the cathepsin B-sensitive dipeptide may be a promising strategy for developing protein therapeutics.
DAI ChuanYunFU YaLI BiaoWANG YiGuangZHANG XuanWANG JianChengZHANG Qiang
Aminopeptidase N(APN)/CD13 is a transmembrane glycoprotein,which is overexpressed on tumor neovascular endothelial cells and most tumor cells,where it plays an important role in tumor angiogenesis.Peptides containing the Asn-Gly-Arg(NGR)motif can specifically recognize APN/CD13 allowing them to act as tumor-homing peptides for the targeted delivery of anti-tumor drugs to tumor neovascular endothelial cells and tumor cells.This article reviews the literature and recent developments related to APN/CD13,its role in tumor growth and some antitumor drug delivery systems containing NGR peptides designed to target APN/CD13.
