Tissue distribution and safety evaluation of a claudin-targeting molecule, the C-terminal fragment of Clostridium perfringens enterotoxin.

Abstract

We previously found that claudin (CL) is a potent target for cancer therapy using a CL-3 and -4-targeting molecule, namely the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE). Although CL-3 and -4 are expressed in various normal tissues, the safety of this CL-targeting strategy has never been investigated. Here, we evaluated the tissue distribution of C-CPE in mice. Ten minutes after intravenous injection into mice, C-CPE was distributed to the liver and kidney (24.0% and 9.5% of the injected dose, respectively). The hepatic level gradually fell to 3.2% of the injected dose by 3 h post-injection, whereas the renal C-CPE level gradually rose to 46.5% of the injected dose by 6 h post-injection and then decreased. A C-CPE mutant protein lacking the ability to bind CL accumulated in the liver to a much lesser extent (2.0% of the dose at 10 min post-injection) than did C-CPE, but its renal profile was similar to that of C-CPE. To investigate the acute toxicity of CL-targeted toxin, we intravenously administered C-CPE-fused protein synthesis inhibitory factor to mice. The CL-targeted toxin dose-dependently increased the levels of serum biomarkers of liver injury, but not of kidney injury. Histological examination confirmed that injection of CL-targeted toxin injured the liver but not the kidney. These results indicate that potential adverse hepatic effects should be considered in C-CPE-based cancer therapy.

• Authors: Xiangru Li, Rie Saeki, Akihiro Watari, Kiyohito Yagi, Masuo Kondoh
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 52 Pg. 132-7 (Feb 14 2014) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 24231339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Claudin-3
• Claudin-4
• Enterotoxins
• Peptide Fragments
• Protein Synthesis Inhibitors
• Recombinant Proteins
• enterotoxin, Clostridium

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cells, Cultured
• Claudin-3 (metabolism)
• Claudin-4 (metabolism)
• Clostridium perfringens
• Enterotoxins (chemistry, genetics, pharmacology)
• Female
• Fibroblasts
• Intestinal Mucosa (metabolism)
• Kidney (drug effects, metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mutation
• Peptide Fragments (chemistry, pharmacology)
• Protein Synthesis Inhibitors (chemistry, pharmacology)
• Recombinant Proteins (chemistry, pharmacology)
• Thyroid Gland (metabolism)
• Tissue Distribution