Photoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo

Photoactivatable molecules enable ablation of malignant cells under the control of light, yet current agents can be ineffective at early stages of disease when target cells are similar to healthy surrounding tissues. In this work, we describe a chemical platform based on amino-substituted benzoselen...

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Bibliographic Details
Published in:Nature communications 2021-04, Vol.12 (1), p.2369-12, Article 2369
Main Authors: Benson, Sam, de Moliner, Fabio, Fernandez, Antonio, Kuru, Erkin, Asiimwe, Nicholas L, Lee, Jun-Seok, Hamilton, Lloyd, Sieger, Dirk, Bravo, Isabel R, Elliot, Abigail M, Feng, Yi, Vendrell, Marc
Format: Article
Language:English
Subjects:
Ablation
Animals
Bacterial diseases
Bacterial Infections - drug therapy
Biocompatibility
Biological activity
Coculture Techniques
Fluorescent Dyes - administration & dosage
Fluorescent Dyes - adverse effects
Fluorescent Dyes - chemistry
Fluorescent Dyes - radiation effects
Glioblastoma - drug therapy
Glioblastoma - pathology
Humans
Intravital Microscopy
Light
Metabolism
Metabolites
Microbial Sensitivity Tests
Microscopy, Confocal
Microscopy, Fluorescence
Organoselenium Compounds - administration & dosage
Organoselenium Compounds - adverse effects
Organoselenium Compounds - chemistry
Organoselenium Compounds - radiation effects
Photochemotherapy - methods
Photodynamic therapy
Photosensitivity
Side effects
Spheroids, Cellular
Warheads
Xenograft Model Antitumor Assays
Zebrafish
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Description
Summary:Photoactivatable molecules enable ablation of malignant cells under the control of light, yet current agents can be ineffective at early stages of disease when target cells are similar to healthy surrounding tissues. In this work, we describe a chemical platform based on amino-substituted benzoselenadiazoles to build photoactivatable probes that mimic native metabolites as indicators of disease onset and progression. Through a series of synthetic derivatives, we have identified the key chemical groups in the benzoselenadiazole scaffold responsible for its photodynamic activity, and subsequently designed photosensitive metabolic warheads to target cells associated with various diseases, including bacterial infections and cancer. We demonstrate that versatile benzoselenadiazole metabolites can selectively kill pathogenic cells - but not healthy cells - with high precision after exposure to non-toxic visible light, reducing any potential side effects in vivo. This chemical platform provides powerful tools to exploit cellular metabolic signatures for safer therapeutic and surgical approaches.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-22578-2