Synthesis and antitumor efficacy of a β-glucuronidase-responsive albumin-binding prodrug of doxorubicin

J Med Chem. 2012 May 10;55(9):4516-20. doi: 10.1021/jm300348r. Epub 2012 Apr 30.

Abstract

In this paper we describe the synthesis and biological evaluation of the first β-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology*
  • Glycosides / administration & dosage
  • Glycosides / chemical synthesis*
  • Glycosides / pharmacokinetics
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Magnetic Resonance Spectroscopy
  • Maleimides / administration & dosage
  • Maleimides / chemical synthesis*
  • Maleimides / pharmacokinetics
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemical synthesis*
  • Polyethylene Glycols / pharmacokinetics
  • Prodrugs / administration & dosage
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacokinetics
  • Spectrometry, Mass, Electrospray Ionization
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Glycosides
  • Maleimides
  • Prodrugs
  • Polyethylene Glycols
  • Doxorubicin