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Anthocyanin Derived NIR Fluorogenic Probe for Direct Visualization and Monitoring of DNA G‑Quadruplex in Breast
Yuan Zhang1, Lingyun Zhao2, Yuxiang Zheng1
1College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, Hunan, P. R. China.
Abstract:
The dysregulation of the c-Myc gene has been embroiled in the pathogenesis of various human cancers, including breast cancer. It is notable that ∼90% of c-Myc expression is regulated by c-Myc DNA sequence that forms G4. Fluorescent probes for imaging c-Myc DNA G4 may provide valuable insights into the biological functions of the c-Myc DNA G4 oncogene and offer promising opportunities for TNBC treatment. However, the existing probes for c-Myc DNA G4s still exhibit low specificity and short absorption/emission wavelengths. Herein, a novel anthocyanin derivative with NIR absorption/emission was engineered for the priority response to c-Myc DNA G4. A series of ligands for preferentially responding to c-Myc DNA G4s were developed by conjugating N-Cy with varied electron-donating groups. It is shown that the ligand CYMT using methylbenzothiazole as the electron-donating group displayed NIR absorption/emission, good selectivity, high fluorescence activation ratio and priority for the detection of c-Myc DNA G4s. Molecular docking experiments indicate that CYMT interacts with c-Myc DNA G4 through hydrogen bond and multiple π-π stacking. It was shown that CYMT could recognize DNA G4s and priority response to c-Myc DNA G4 in breast cancer. We further utilized CYMT to image the dynamics of DNA G4s under oxidative stress in live MDA-MB-231 cells. The ability of CYMT to monitor DNA G4s in vivo was showcased by time dependent detecting of DNA G4 levels in MDA-MB-231-transplanted mice breast tumor models. It was further confirmed the detection ability of CYMT for endogenous DNA G4 in vivo by collecting periocular blood from healthy nude mice and xenograft MDA-MB-231 mouse models. This probe may regard as a meaningful implement for investigating the physiological and pathological roles of c-Myc DNA G4s.
Insights
A novel near-infrared fluorescent probe, CYMT, was developed to specifically detect c-Myc DNA G4s, crucial in breast cancer pathogenesis. This probe enables in vitro and in vivo imaging, offering new avenues for cancer research and treatment strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Dysregulation of the c-Myc gene is implicated in various human cancers, including breast cancer.
- Approximately 90% of c-Myc expression is regulated by G-quadruplex (G4) structures within its DNA sequence.
- Existing fluorescent probes for c-Myc DNA G4s suffer from low specificity and limited spectral properties.
Purpose of the Study:
- To engineer a novel fluorescent probe with near-infrared (NIR) absorption/emission for selective detection of c-Myc DNA G4.
- To evaluate the probe's efficacy in imaging c-Myc DNA G4 dynamics in vitro and in vivo.
- To explore the potential of the probe for investigating the roles of c-Myc DNA G4 in cancer biology.
Main Methods:
- Development of novel anthocyanin derivative-based ligands conjugated with electron-donating groups.
- Synthesis and characterization of the CYMT ligand, utilizing methylbenzothiazole.
- Molecular docking to elucidate binding interactions between CYMT and c-Myc DNA G4.
- In vitro fluorescence assays for selectivity and sensitivity.
- Live-cell imaging of DNA G4 dynamics under oxidative stress in MDA-MB-231 cells.
- In vivo imaging of DNA G4 levels in breast tumor models and detection in blood samples.
Main Results:
- The CYMT ligand exhibited selective NIR absorption/emission, high fluorescence activation, and preferential binding to c-Myc DNA G4.
- Molecular docking confirmed hydrogen bonding and π-π stacking interactions between CYMT and c-Myc DNA G4.
- CYMT successfully imaged DNA G4 dynamics in live MDA-MB-231 cells and monitored G4 levels in mouse breast tumor models.
- The probe demonstrated in vivo detection of endogenous DNA G4 in blood samples from healthy and tumor-bearing mice.
Conclusions:
- CYMT is a novel, selective NIR fluorescent probe for c-Myc DNA G4 detection.
- The probe facilitates in vitro and in vivo imaging of DNA G4 dynamics, crucial for understanding cancer progression.
- CYMT offers a promising tool for investigating the physiological and pathological roles of c-Myc DNA G4 in breast cancer and beyond.
