A new delivery system for auristatin in STxB-drug conjugate therapy

Eur J Med Chem. 2015 May 5:95:483-91. doi: 10.1016/j.ejmech.2015.03.047. Epub 2015 Mar 28.

Abstract

A key challenge in anticancer therapy is to gain control over the biodistribution of cytotoxic drugs. The most promising strategy consists in conjugating drugs to tumor-targeting carriers, thereby combining high cytotoxic activity and specific delivery. To target Gb3-positive cancer cells, we exploit the non-toxic B-subunit of Shiga toxin (STxB). Here, we have conjugated STxB to highly potent auristatin derivatives (MMA). A former linker was optimized to ensure proper drug-release upon reaching reducing environments in target cells, followed by a self-immolation step. Two conjugates were successfully obtained, and in vitro assays demonstrated the potential of this targeting system for the selective elimination of Gb3-positive tumors.

Keywords: Auristatin; Cancer; Carbamate; Conjugate; Disulfide; Shiga toxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobenzoates / chemistry*
  • Antineoplastic Agents / chemistry*
  • Drug Carriers / chemistry*
  • HT29 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Oligopeptides / chemistry*
  • Protein Conformation
  • Shiga Toxin / chemistry*

Substances

  • Aminobenzoates
  • Antineoplastic Agents
  • Drug Carriers
  • Oligopeptides
  • auristatin
  • Shiga Toxin