A cleavable cytolysin-neuropeptide Y bioconjugate enables specific drug delivery and demonstrates intracellular mode of action
| Autor: | Lutz Weber, Stefan Kalkhof, David Kosel, Katja B. Kostelnik, Annette G. Beck-Sickinger, David Böhme, Martin von Bergen, Robert C. Rennert, Verena M. Ahrens |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
media_common.quotation_subject Pharmaceutical Science Biology Peptide-drug conjugate SILAC Microtubule polymerization Drug Delivery Systems Breast cancer Cell Line Tumor Chlorocebus aethiops medicine Quantitative proteomics Animals Humans Neuropeptide Y Disulfides Mode of action Internalization media_common Cytolysin Perforin Receptors Neuropeptide Y Cell biology HEK293 Cells Biochemistry Mechanism of action COS Cells Drug delivery bacteria medicine.symptom Linker Intracellular |
| Zdroj: | 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 ', Journal of Controlled Release, vol. 209, 7658, pp. 170-178 . https://doi.org/10.1016/j.jconrel.2015.04.037 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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