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

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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., Fichtner, I., 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
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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