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Published on: June 9, 2023
Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward
Zhengze Lu1, Yang Long1, Jiaxin Li1
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Abstract:
Inflammatory feed-forward loops including the steps of "inflammatory cell recruitment", "inflammatory signaling pathway activation" and "inflammatory factor production" are essential in the development of breast cancer and its metastasis. Herein, a doxorubicin-loaded micellar low-molecular-weight-heparin-astaxanthin nanoparticle (LMWH-AST/DOX, LA/DOX NP) was developed. The hydrophilic LMWH could decrease the recruitment of neutrophils in liver and myeloid-derived suppressor cells (MDSCs) in lung and tumor through P-selectin blockage. The hydrophobic AST could inhibit nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Therefore, LA/DOX NPs could block these loops and suppress the liver metastasis by inhibiting the formation of neutrophil extracellular traps (NETs), inhibit the lung metastasis and alleviate the inflammatory and immunosuppressive microenvironment in tumor. This is the first functional nanoparticle reported to shut down inflammatory feed-forward loops and the formation of NETs, which provides a promising therapeutic strategy for breast cancer and its liver and lung metastasis.
Insights
This study introduces a novel nanoparticle that blocks inflammatory pathways and neutrophil extracellular trap formation, offering a new therapeutic strategy for breast cancer metastasis to the liver and lungs.
Area of Science:
- Oncology
- Nanomedicine
- Immunology
Background:
- Inflammatory feed-forward loops are critical in breast cancer development and metastasis.
- These loops involve inflammatory cell recruitment, signaling pathway activation, and factor production.
Purpose of the Study:
- To develop a functional nanoparticle capable of disrupting inflammatory feed-forward loops.
- To investigate the nanoparticle's efficacy in suppressing breast cancer metastasis.
Main Methods:
- A doxorubicin-loaded nanoparticle (LMWH-AST/DOX) was engineered using low-molecular-weight-heparin and astaxanthin.
- The nanoparticle's ability to inhibit neutrophil recruitment, key signaling pathways (NF-κB, STAT3), and neutrophil extracellular trap (NET) formation was assessed.
Main Results:
- The LMWH component reduced neutrophil and myeloid-derived suppressor cell recruitment.
- The AST component inhibited NF-κB and STAT3 signaling pathways.
- The nanoparticle effectively suppressed liver and lung metastasis and modulated the tumor microenvironment.
Conclusions:
- This novel nanoparticle successfully blocks inflammatory feed-forward loops and NET formation.
- It presents a promising therapeutic strategy for managing breast cancer and its associated metastasis.
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