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Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B

Item Type:Article
Title:Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B
Creators Name:Warnecke, A. and Fichtner, I. and Sass, G. and Kratz, F.
Abstract:Cathepsin B and plasmin are intra- or extracellular proteases that are overexpressed by several solid tumors. In order to exploit both proteases as molecular targets for tumor-specific cleavage of prodrugs, an albumin-binding formulation of methotrexate was developed that incorporated the peptide sequence D-Ala-Phe-Lys as the protease substrate. Albumin is a suitable carrier for cytostatic agents due to passive accumulation in solid tumors. Synthesis was performed by coupling the peptide linker EMC-D-Ala-Phe-Lys(Boc)-Lys-OH (EMC = epsilon-maleimidocaproic acid) to the gamma-COOH group of alpha-tert-butyl protected methotrexate. After cleavage of the protective groups and purification on reverse phase HPLC, a highly water-soluble methotrexate-peptide derivative was obtained that binds rapidly and selectively to human serum albumin. The albumin-bound form of the prodrug was shown to be efficiently cleaved by cathepsin B and plasmin as well as in an ovarian carcinoma homogenate (OVCAR-3) liberating a methotrexate-lysine derivative. In an OVCAR-3 xenograft model, the prodrug at a dose of 4x15 mg/kg methotrexate equivalents demonstrated distinctly superior antitumor efficacy compared to free methotrexate at a dose of 4x100 mg/kg [T/C(%) for MTX = 69; T/C(%) for MTX prodrug = 29]. The data provide a further proof of concept for the development of albumin-binding, enzymatically cleavable prodrugs of anticancer drugs.
Keywords:Cathepsin B, Human Serum Albumin, Macromolecular Prodrug, Methotrexate, Plasmin, Animals, Mice
Source:Archiv der Pharmazie
ISSN:0365-6233
Publisher:Verlag Chemie (Germany)
Volume:340
Number:8
Page Range:389-395
Date:August 2007
Official Publication:https://doi.org/10.1002/ardp.200700025
PubMed:View item in PubMed

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