Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers.

Abstract

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2μM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo.

• Authors: Arong Gaowa, Tomohisa Horibe, Masayuki Kohno, Yasuhiko Tabata, Hiroshi Harada, Masahiro Hiraoka, Koji Kawakami
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 92 Pg. 228-36 (May 2015) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 25801495 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• Dextrans
• Disulfides
• Drug Carriers
• Peptides
• carboxymethyl dextran
• ErbB Receptors
• Glutathione
• Cysteine

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cysteine (chemistry)
• Delayed-Action Preparations
• Dextrans (chemistry)
• Disulfides (chemistry)
• Drug Carriers (chemistry)
• Drug Delivery Systems
• ErbB Receptors (genetics)
• Female
• Glutathione (metabolism)
• Half-Life
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, pathology)
• Peptides (administration & dosage, chemistry, pharmacology)
• Xenograft Model Antitumor Assays