Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward loops.

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.