Journal
JOURNAL OF CONTROLLED RELEASE
Volume 209, Issue -, Pages 170-178Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2015.04.037
Keywords
Peptide-drug conjugate; Neuropeptide Y; Cytolysin; Breast cancer; SILAC; Quantitative proteomics
Funding
- Federal Ministry of Education and Research (BMBF) [0315919A/031519B]
- State of Saxony
- European Union [ESF 22117016]
- graduate school Leipzig School of Natural Sciences - Building with Molecules and Nano-objects (BuildMoNa)
- graduate school Helmholtz Interdisciplinary GRADuate School for Environmental Research (HIGRADE)
- Helmholtz Centre for Environmental Research (UFZ)
- [SFB TR 67]
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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 [F7, P34]-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-[F7, P34]-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. (C) 2015 Elsevier B.V. All rights reserved.
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