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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Novel Disulfiram-Loaded Metal-Organic Nanoparticles Inhibit Tumor Growth and Induce Immunogenic Cell Death of
Chung-Hui Huang1, Xuejia Kang2, Lang Zhou2
1Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Abstract:
Background/Objectives: Triple-negative breast cancer (TNBC) is among the most aggressive subtypes, lacking estrogen, progesterone, and HER2 receptors, which limits the efficacy of targeted therapies. Standard treatments often fail due to rapid drug resistance and poor long-term outcomes. Repurposing approved drugs with anticancer potential offers a promising alternative. Disulfiram (DSF), an FDA-approved alcohol-aversion drug, forms a copper complex [Cu(DDC)2] with potent anticancer activity, but its clinical translation is hindered by poor solubility, limited stability, and inefficient delivery. Methods: Here, we present an amphiphilic dendrimer-stabilized [Cu(DDC)2] nanoparticle (NP) platform synthesized via the stabilized metal ion ligand complex (SMILE) method. Results: The optimized nanocarrier achieved high encapsulation efficiency, enhanced serum stability, and potent cytotoxicity against TNBC cells. It induced immunogenic cell death (ICD) characterized by calreticulin exposure and ATP release, while modulating the tumor microenvironment by downregulating MMP-3, MMP-9, VEGF, and vimentin, and restoring epithelial markers. In a 4T1 TNBC mouse model, systemic [Cu(DDC)2] NP treatment significantly inhibited tumor growth without combinational chemo- or radiotherapy. Conclusions: This DSF-based metal-organic NP integrates drug repurposing, immune activation, and tumor microenvironment remodeling into a single platform, offering strong translational potential for treating aggressive breast cancers.
Insights
Repurposing the alcohol-aversion drug disulfiram into a copper complex nanoparticle effectively treats aggressive triple-negative breast cancer (TNBC) by activating the immune system and remodeling the tumor microenvironment.
Area of Science:
- Nanotechnology
- Drug Repurposing
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapy options.
- Standard treatments for TNBC often result in drug resistance and poor patient outcomes.
- Disulfiram (DSF), an FDA-approved drug, shows anticancer potential when complexed with copper ([Cu(DDC)2]), but faces delivery challenges.
Purpose of the Study:
- To develop a novel nanoparticle platform for enhanced delivery of the disulfiram-copper complex ([Cu(DDC)2]) for TNBC treatment.
- To evaluate the efficacy of this nanocarrier in preclinical TNBC models.
- To investigate the mechanisms of action, including immune activation and tumor microenvironment modulation.
Main Methods:
- Synthesis of an amphiphilic dendrimer-stabilized [Cu(DDC)2] nanoparticle using the stabilized metal ion ligand complex (SMILE) method.
- In vitro assessment of cytotoxicity, immunogenic cell death (ICD) markers (calreticulin exposure, ATP release), and tumor microenvironment factors (MMP-3, MMP-9, VEGF, vimentin, epithelial markers).
- In vivo evaluation of tumor growth inhibition in a 4T1 TNBC mouse model following systemic nanoparticle administration.
Main Results:
- The optimized nanoparticle exhibited high encapsulation efficiency, improved serum stability, and potent cytotoxicity against TNBC cells.
- Treatment induced ICD and modulated the tumor microenvironment by downregulating pro-tumorigenic factors and restoring epithelial markers.
- Systemic administration of the [Cu(DDC)2] nanoparticle significantly inhibited tumor growth in a TNBC mouse model without combination therapy.
Conclusions:
- The developed disulfiram-based metal-organic nanoparticle offers a promising platform for drug repurposing in aggressive breast cancers.
- This integrated approach combines drug delivery, immune activation, and tumor microenvironment modulation.
- The nanocarrier demonstrates significant translational potential for treating challenging TNBC cases.
