Integrating Epigenetic Modulators in Nanofibers for Synergistic Gastric Cancer Therapy via Epigenetic Reprogramming
Lirui Wang1, Chunlei Zhang1, Yuping Hong1
1Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
Abstract:
Epigenetic dysregulations resulting from the defects of epigenetic regulators are often reversible in tumorigenesis, making them promising cancer therapeutic targets. However, the limited specificity of action, short-term stability, and low retention of the epigenetic drugs greatly impede their clinical efficacy against solid tumors. Herein a method of combinatorial delivery of epigenetic modulatory drugs via a molecular self-assembly strategy was developed using inhibitors of DNA methyltransferases and histone deacetylases. The drug-drug conjugates can self-assemble into nanofibers with enhanced chemical stability. The nanofibers synergistically regulate aberrant DNA methylation and histone deacetylation, subsequently reprogram the gene expression profiles, and finally inhibit gastric cancer cell proliferation and promote cell apoptosis. The superior in vivo therapeutic efficacy of the nanofibers could be ascribed to the prolonged retention and accumulation in tumors and the minimized off-target effects. Therefore, this design of epigenetic-drug-based nanofiber formulation may provide a valuable paradigm for cancer therapy through epigenetic reprogramming.
Insights
Novel nanofibers combine epigenetic drugs to effectively treat gastric cancer. This approach enhances drug stability and tumor retention, offering a promising new strategy for cancer therapy.
Area of Science:
- Oncology
- Nanotechnology
- Epigenetics
Background:
- Epigenetic dysregulation is a hallmark of cancer and a target for therapy.
- Current epigenetic drugs face challenges in specificity, stability, and tumor retention for solid tumors.
Purpose of the Study:
- To develop a combinatorial drug delivery system for epigenetic modulatory drugs.
- To enhance the stability and tumor targeting of epigenetic therapies for gastric cancer.
Main Methods:
- Utilized molecular self-assembly to create drug-drug conjugates of DNA methyltransferase and histone deacetylase inhibitors.
- Formulated conjugates into nanofibers with improved chemical stability.
- Investigated the synergistic effects of combined epigenetic drugs on cancer cells and in vivo models.
Main Results:
- The self-assembled nanofibers demonstrated enhanced chemical stability.
- Nanofibers synergistically regulated DNA methylation and histone deacetylation, reprogramming gene expression.
- Significant inhibition of gastric cancer cell proliferation and promotion of apoptosis were observed.
- Superior in vivo therapeutic efficacy was attributed to prolonged tumor retention and reduced off-target effects.
Conclusions:
- Epigenetic-drug-based nanofibers offer a promising strategy for cancer therapy.
- This approach provides a valuable paradigm for epigenetic reprogramming in cancer treatment.
- The developed formulation overcomes limitations of conventional epigenetic drugs in solid tumors.
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