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Title (Primary) A cleavable cytolysin–neuropeptide Y bioconjugate enables specific drug delivery and demonstrates intracellular mode of action
Author Ahrens, V.M.; Kostelnik, K.B.; Rennert, R.; Böhme, D.; Kalkhof, S.; Kosel, D.; Weber, L.; von Bergen, M.; Beck-Sickinger, A.G.;
Journal Journal of Controlled Release
Year 2015
Department PROTEOM;
Volume 209
Language englisch;
POF III (all) F11;
Keywords Peptide–drug conjugate; Neuropeptide Y; Cytolysin; Breast cancer; SILAC; Quantitative proteomics
UFZ wide themes RU3;
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 [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.
ID 16149
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=16149
Ahrens, V.M., Kostelnik, K.B., Rennert, R., Böhme, D., Kalkhof, S., Kosel, D., Weber, L., von Bergen, M., Beck-Sickinger, A.G. (2015):
A cleavable cytolysin–neuropeptide Y bioconjugate enables specific drug delivery and demonstrates intracellular mode of action
J. Control. Release 209 , 170 - 178