The organometallic ferrocene exhibits amplified anti-tumor activity by targeted delivery via highly selective ligands to αvβ3, αvβ6, or α5β1 integrins.

Autor: Ludwig BS; Department of Nuclear Medicine, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany., Tomassi S; Department of Pharmacy, University of Naples 'Federico II', Naples, Italy., Di Maro S; Università degli Studi della Campania 'Luigi Vanvitelli', Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Caserta, Italy., Di Leva FS; Department of Pharmacy, University of Naples 'Federico II', Naples, Italy., Benge A; Department of Obstetrics and Gynecology, Clinical Research Unit, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany., Reichart F; Institute for Advanced Study, Department of Chemistry, Technical University Munich, Garching, Germany., Nieberler M; Department of Oral and Maxillofacial Surgery, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany., Kühn FE; Molecular Catalysis, Catalysis Research Center, Technical University Munich, Munich, Germany; Department of Chemistry, Technical University Munich, Munich, Germany., Kessler H; Institute for Advanced Study, Department of Chemistry, Technical University Munich, Garching, Germany., Marinelli L; Department of Pharmacy, University of Naples 'Federico II', Naples, Italy., Reuning U; Department of Obstetrics and Gynecology, Clinical Research Unit, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany., Kossatz S; Department of Nuclear Medicine, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany; Department of Chemistry, Technical University Munich, Munich, Germany. Electronic address: s.kossatz@tum.de.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2021 Apr; Vol. 271, pp. 120754. Date of Electronic Publication: 2021 Mar 12.
DOI: 10.1016/j.biomaterials.2021.120754
Abstrakt: High levels of reactive oxygen species (ROS) in tumors have been shown to exert anti-tumor activity, leading to the concept of ROS induction as therapeutic strategy. The organometallic compound ferrocene (Fc) generates ROS through a reversible one-electron oxidation. Incorporation of Fc into a tumor-targeting, bioactive molecule can enhance its therapeutic activity and enable tumor specific delivery. Therefore, we conjugated Fc to five synthetic, Arg-Gly-Asp (RGD)-based integrin binding ligands to enable targeting of the cell adhesion and signaling receptor integrin subtypes αvβ3, α5β1, or αvβ6, which are overexpressed in various, distinct tumors. We designed and synthesized a library of integrin-ligand-ferrocene (ILF) derivatives and showed that ILF conjugates maintained the high integrin affinity and selectivity of their parent ligands. A thorough biological characterization allowed us to identify the two most promising ligands, an αvβ3 (L2b) and an αvβ6 (L3b) targeting ILF, which displayed selective integrin-dependent cell uptake and pronounced ferrocene-mediated anti-tumor effects in vitro, along with increased ROS production and DNA damage. Hence, ILFs are promising candidates for the selective, tumor-targeted delivery of ferrocene to maximize its anti-cancer efficacy and minimize systemic toxicity, thereby improving the therapeutic window of ferrocene compared to currently used non-selective anti-cancer drugs.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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