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Polyanhydride Copolymer-Based Niclosamide Nanoparticles for Inhibiting Triple-Negative Breast Cancer: Metabolic
Susheel Kumar Nethi1,2, Siddhant Kothadiya1, Brianna M White1
1Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States.
Abstract:
The heterogeneity of tumors and the lack of effective therapies have resulted in triple-negative breast cancer (TNBC) exhibiting the least favorable outcomes among breast cancer subtypes. TNBC is characterized by its aggressive nature, often leading to high rates of relapse, metastasis, and mortality. Niclosamide (Nic), an Food and Drug Administration-approved anthelmintic drug, has been repurposed for cancer treatment; however, its application for TNBC is hindered by significant challenges, including strong hydrophobicity, poor aqueous solubility, and low bioavailability. This study aimed to develop Nic nanoparticles (Nic NPs) using biodegradable and biocompatible polyanhydride copolymers to enhance Nic's bioavailability and therapeutic efficacy. Nic NPs effectively inhibited migration, proliferation, and clonogenicity in both murine and human TNBC cells, inducing apoptosis and suppressing STAT3 signaling. For the first time, we utilized Raman spectroscopy and Seahorse extracellular flux assays to demonstrate the metabolic responses of TNBC cells to Nic NPs, revealing significant metabolic alterations, including the inhibition of mitochondrial respiration and glycolysis. Additionally, this study is the first to explore the combination therapy of repurposed Nic with the approved chemotherapeutic agent paclitaxel in the 4T1 TNBC immunocompetent mouse model. The combination of Nic NPs and paclitaxel significantly reduced tumor growth without adversely affecting the body weight of tumor-bearing mice. In summary, these findings suggest that Nic NPs could serve as a promising component in combination therapies for the effective treatment of TNBC.
Insights
Niclosamide nanoparticles effectively treat triple-negative breast cancer (TNBC) by inhibiting cell growth and altering metabolism. Combination therapy with paclitaxel shows significant tumor reduction in mice.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) presents poor prognosis due to tumor heterogeneity and limited therapeutic options.
- Existing treatments for TNBC face challenges, including drug resistance and poor bioavailability of repurposed agents like niclosamide.
- Niclosamide (Nic), an anthelmintic drug, shows potential but suffers from poor solubility and bioavailability, limiting its use in TNBC.
Purpose of the Study:
- To develop niclosamide nanoparticles (Nic NPs) using biodegradable polyanhydride copolymers to improve bioavailability and efficacy for TNBC treatment.
- To investigate the anti-cancer effects of Nic NPs on TNBC cell migration, proliferation, clonogenicity, and apoptosis.
- To elucidate the metabolic impact of Nic NPs on TNBC cells and evaluate combination therapy with paclitaxel in a preclinical model.
Main Methods:
- Formulation of biodegradable polyanhydride copolymer-based niclosamide nanoparticles (Nic NPs).
- In vitro assessment of TNBC cell behavior (migration, proliferation, clonogenicity, apoptosis) and STAT3 signaling.
- Raman spectroscopy and Seahorse extracellular flux assays to analyze metabolic changes in TNBC cells.
- In vivo evaluation of combination therapy (Nic NPs + paclitaxel) in a 4T1 TNBC immunocompetent mouse model.
Main Results:
- Nic NPs significantly inhibited migration, proliferation, and clonogenicity of murine and human TNBC cells, inducing apoptosis and suppressing STAT3 signaling.
- Raman spectroscopy and Seahorse assays revealed that Nic NPs induce significant metabolic alterations in TNBC cells, including inhibition of mitochondrial respiration and glycolysis.
- Combination therapy of Nic NPs with paclitaxel demonstrated significant tumor growth reduction in the 4T1 TNBC mouse model without causing adverse effects on body weight.
Conclusions:
- Niclosamide nanoparticles (Nic NPs) represent a promising strategy to overcome the bioavailability limitations of niclosamide for TNBC treatment.
- Nic NPs exhibit potent anti-cancer effects by targeting TNBC cell proliferation, migration, and key metabolic pathways.
- Combination therapy with paclitaxel enhances the therapeutic efficacy of Nic NPs, suggesting a potential new treatment approach for triple-negative breast cancer.
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