A cleavable cytolysin-neuropeptide Y bioconjugate enables specific drug delivery and demonstrates intracellular mode of action.

Abstract

Myxobacterial tubulysins are promising chemotherapeutics inhibiting microtubule polymerization, however, high unspecific toxicity so far prevents their application in therapy. For selective cancer cell targeting, here the coupling of a synthetic cytolysin to the hY1-receptor preferring peptide [F(7),P(34)]-neuropeptide Y (NPY) using a labile disulfide linker is described. Since hY1-receptors are overexpressed in breast tumors and internalize rapidly, this system has high potential as peptide-drug shuttle system. Molecular characterization of the cytolysin-[F(7),P(34)]-NPY bioconjugate revealed potent receptor activation and receptor-selective internalization, while viability studies verified toxicity. Triple SILAC studies comparing free cytolysin with the bioconjugate demonstrated an intracellular mechanism of action regardless of the delivery pathway. Treatments resulted in a regulation of proteins implemented in cell cycle arrest confirming the tubulysin-like effect of the cytolysin. Thus, the cytolysin-peptide bioconjugate fused by a cleavable linker enables a receptor-specific delivery as well as a potent intracellular drug-release with high cytotoxic activity.

• Authors: Verena M Ahrens, Katja B Kostelnik, Robert Rennert, David Böhme, Stefan Kalkhof, David Kosel, Lutz Weber, Martin von Bergen, Annette G Beck-Sickinger
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 209 Pg. 170-8 (Jul 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25935706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier B.V.

Chemical References

• Disulfides
• Neuropeptide Y
• Receptors, Neuropeptide Y
• Perforin

Topics

• Animals
• COS Cells
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chlorocebus aethiops
• Disulfides (chemistry)
• Drug Delivery Systems
• HEK293 Cells
• Humans
• Neuropeptide Y (administration & dosage, chemistry, pharmacology)
• Perforin (administration & dosage, chemistry, pharmacology)
• Receptors, Neuropeptide Y (genetics, metabolism)