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Updated: Oct 4, 2025
Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts
Published on: April 26, 2018
Activatable fluorescence molecular imaging and anti-tumor effects investigation of GSH-sensitive BRD4 ligands
Hang Zhang1, Mingliang Zhang1, Yujie Zhang1
1Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
Abstract:
Overexpression of bromodomain 4 (BRD4) is closely correlated with a variety of human cancers by regulating the histone post-translational modifications, which renders BRD4 a promising target for pharmacological discoveries of novel therapeutic agents for cancer therapy. We herein present the design, chemical synthesis, cellular imaging and biological assessment of a novel tumor-sensitive BRD4 ligand (compound 4) by introducing anticancer BRD4 inhibitor into naphthalimide moiety (fluorescent reporter) via a sulfonamide unit as glutathione (GSH)-specific cleavable linker. Upon reaction with abundant intramolecular GSH in cancer cells or free GSH in aqueous solution (pH = 7.4), sulfonamide cleavage of 4 occurs, leading to the release of BRD4 inhibitor and concomitant fluorescence-on. This activatable fluorescence molecular imaging was demonstrated to preferentially occur in tumor cells. Moreover, towards cancer cell lines MGC-803 cells and THP-1, compound 4 was identified to show better antitumor efficacy than net BRD4 inhibitor. Collectively, this study presents a drug delivery strategy, wherein the drug release can be directly monitored in the cellular content by fluorescence imaging, and provides a valuable compound 4 as a potential antitumor agent. Compound 4 may represent a useful tool for explorative studies of BRD4 inhibition, such as an improved understanding of BRD4 inhibitor release-related information.
Insights
Researchers developed a novel tumor-sensitive bromodomain 4 (BRD4) ligand (compound 4) that releases an anticancer BRD4 inhibitor and activates fluorescence in cancer cells. This compound shows enhanced antitumor efficacy and allows for direct monitoring of drug release.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Bromodomain 4 (BRD4) overexpression is linked to human cancers, making it a key therapeutic target.
- BRD4 regulates histone modifications, highlighting its role in cancer progression.
Purpose of the Study:
- To design, synthesize, and evaluate a novel tumor-sensitive BRD4 ligand (compound 4) for cancer therapy.
- To develop a strategy for monitoring drug release and efficacy in situ using fluorescence imaging.
Main Methods:
- Chemical synthesis of compound 4, incorporating a BRD4 inhibitor, a naphthalimide fluorescent reporter, and a glutathione-cleavable sulfonamide linker.
- Cellular imaging to assess fluorescence activation and localization in tumor cells.
- Biological assessment of compound 4's antitumor efficacy in cancer cell lines (MGC-803 and THP-1).
Main Results:
- Compound 4 demonstrated selective cleavage and release of the BRD4 inhibitor in the presence of glutathione (GSH), leading to "fluorescence-on" in cancer cells.
- Activatable fluorescence imaging preferentially occurred in tumor cells, enabling visualization of drug release.
- Compound 4 exhibited superior antitumor efficacy compared to the free BRD4 inhibitor in MGC-803 and THP-1 cells.
Conclusions:
- Compound 4 represents a novel drug delivery strategy with direct fluorescence monitoring of drug release.
- This activatable prodrug shows potential as an effective antitumor agent and a valuable tool for studying BRD4 inhibition.
- The findings offer insights into understanding BRD4 inhibitor release mechanisms in cancer therapy.
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