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Updated: Jun 10, 2025
Synthesis of Near-Infrared Emitting Gold Nanoclusters for Biological Applications
Published on: March 22, 2020
Disturbing microtubule-endoplasmic reticulum dynamics by gold nanoclusters for improved triple-negative breast cancer
Kai Cao1, Kaidi Luo1, Yichen Zheng1
1Department of Chemistry, College of Chemistry and Life Science, Center of Excellence for Environmental Safety and Biological Effects, Beijing University of Technology, Beijing 100124, China. kcao@bjut.edu.cn.
Abstract:
Microtubules are highly dynamic structures, and their dynamic instability is indispensable for not only cell growth and movement, but also stress responses, such as endoplasmic reticulum (ER) stress. Docetaxel, a microtubule targeting agent (MTA), is the first-line drug for cancer treatment by simultaneously promoting microtubule dysregulation- and ER stress-induced cell death. However, it also causes adverse effects and drug resistance, especially in triple-negative breast cancer (TNBC) with a poor prognosis and high mortality rate. In this study, we developed a peptide-templated gold nanocluster, namely GA. GA significantly sensitizes TNBC cells to docetaxel, causing severe cell death. This effect is further validated by a 3D tumor spheroid model. Mechanistically, GA disrupted microtubule dynamic instability, meanwhile promoting PERK-mediated ER stress. Interestingly, ER stress inhibitors profoundly suppressed microtubule dysregulation, suggesting a retrograde regulation of ER stress on microtubules. In vivo, the combined administration of docetaxel and GA significantly suppresses tumor growth while docetaxel alone cannot. GA similarly elevated the level of caspases and PERK within tumors as in vitro. Importantly, GA treatment also profoundly promoted the production of anti-tumor inflammatory cytokines. Collectively, we developed an ER-microtubule regulatory nanomaterial that enhanced the therapeutic effect of docetaxel by elevating tumor cell death and anti-tumor cytokine production, providing a potential supplemental strategy for TNBC treatment.
Insights
This study introduces GA, a novel nanomaterial that enhances docetaxel cancer therapy by disrupting microtubules and inducing endoplasmic reticulum (ER) stress. GA shows promise in treating triple-negative breast cancer (TNBC) by boosting cell death and anti-tumor immunity.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Microtubules are crucial for cell functions, and their instability is linked to cancer.
- Docetaxel, a microtubule-targeting agent, treats cancer but faces challenges like drug resistance and side effects, particularly in triple-negative breast cancer (TNBC).
- Endoplasmic reticulum (ER) stress is another pathway implicated in cancer cell death.
Purpose of the Study:
- To develop a novel nanomaterial, GA, to enhance docetaxel's efficacy against TNBC.
- To investigate the combined effects of GA and docetaxel on microtubule dynamics and ER stress in TNBC.
- To evaluate the therapeutic potential of GA in combination with docetaxel for TNBC treatment.
Main Methods:
- Development of a peptide-templated gold nanocluster (GA).
- Assessment of GA's effect on TNBC cell lines and 3D tumor spheroid models.
- Analysis of microtubule dynamic instability and ER stress pathways (PERK-mediated).
- In vivo studies in tumor-bearing mice to evaluate tumor growth suppression and cytokine production.
Main Results:
- GA significantly sensitized TNBC cells to docetaxel, leading to severe cell death.
- GA disrupted microtubule dynamic instability and promoted PERK-mediated ER stress, with evidence of ER stress influencing microtubule dynamics.
- Combined docetaxel and GA administration suppressed tumor growth in vivo more effectively than docetaxel alone.
- GA treatment increased caspase and PERK levels in tumors and promoted anti-tumor inflammatory cytokine production.
Conclusions:
- GA acts as an ER-microtubule regulatory nanomaterial, enhancing docetaxel's therapeutic effect.
- The combination therapy increases tumor cell death and augments anti-tumor immune responses.
- GA represents a potential supplemental strategy for improving TNBC treatment outcomes.
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