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

作者：Ahrens Verena M; Kostelnik Katja B; Rennert Robert; Boehme David; Kalkhof Stefan; Kosel David; Weber Lutz; von Bergen Martin; Beck Sickinger Annette G^*

来源：Journal of Controlled Release, 2015, 209: 170-178.

DOI：10.1016/j.jconrel.2015.04.037

• Peptide-drug conjugate
• Neuropeptide Y
• Cytolysin
• Breast cancer
• SILAC
• Quantitative proteomics

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.

• 出版日期2015-7-10