Antibody-Based Imaging of Bioreductive Prodrug Release in Hypoxia.

Autor:	Tosun Ç; Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K., Wallabregue ALD; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K., Mallerman M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K., Phillips SE; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K., Edwards CM; Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7HE, U.K.; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, U.K., Conway SJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.; Department of Chemistry & Biochemistry, University of California, 607 Charles E. Young Drive East, Los Angeles, California CA90095, United States., Hammond EM; Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
Jazyk:	angličtina
Zdroj:	JACS Au [JACS Au] 2023 Nov 01; Vol. 3 (11), pp. 3237-3246. Date of Electronic Publication: 2023 Nov 01 (Print Publication: 2023).
DOI:	10.1021/jacsau.3c00562
Abstrakt:	Regions of hypoxia occur in most tumors and are a predictor of poor patient prognosis. Hypoxia-activated prodrugs (HAPs) provide an ideal strategy to target the aggressive, hypoxic, fraction of a tumor, while protecting the normal tissue from toxicity. A key challenge associated with the development of novel HAPs, however, is the ability to visualize the delivery of the prodrug to hypoxic regions and determine where it has been activated. Here, we report a modified version of the commonly used nitroimidazole bioreductive group that incorporates the fluoroethyl epitope of the antibody-based hypoxia imaging agent, EF5. Attachment of this group to the red fluorescent dye, dicyanomethylene (DCM), enabled us to correlate the release of the DCM dye with imaging of the reduced bioreductive group using the EF5 antibody. This study confirmed that the antibody was imaging reduction and fragmentation of the pro-fluorophore. We next employed the modified bioreductive group to synthesize a new prodrug of the KDAC inhibitor Panobinostat, EF5-Pano. Release of EF5-Pano in hypoxic multiple myeloma cells was imaged using the EF5 antibody, and the presence of an imaging signal correlated with apoptosis and a reduction in cell viability. Therefore, EF5-Pano is an imageable HAP with a proven cytotoxic effect in multiple myeloma, which could be utilized in future in vivo experiments. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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