Effective suppression of triple negative breast cancer by paclitaxel nanoparticles conjugated with transmembrane TNF-α monoclonal antibody

Abstract

Transmembrane TNF-α (tmTNF), a transmembrane form of TNF-α, was reported overexpressed in approximately 84% of triple-negative breast cancer (TNBC) patients and has emerged as a valid candidate biomarker for targeting TNBC. Paclitaxel is a first-line chemotherapeutic agent for the treatment of triple-negative breast cancer, but suffers from low water solubility, resulting in its low bioavailability. To achieve site-specific delivery of the anticancer chemotherapeutic drug (paclitaxel) on TNBC, we developed tmTNF-α monoclonal antibody (mAb)-conjugated paclitaxel (PTX) nanoparticles (NPs) (tmTNF-α mAb-PTX NPs) as potential nanocarriers. This targeted delivery-therapy nanocarriers was conducted by using an emulsification-evaporation method. tmTNF-α mAb-PTX NPs displayed favorable physicochemical properties. Compared with the control groups, tumor growth in human MDA-MB-231 xenograft mice was suppressed significantly by tmTNF-α mAb-PTX NPs. TmTNF-α mAb-PTX NPs exerts anti-tumor effects via promoting apoptosis and regulating mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) cascade, as well as AMP-activated protein kinase (AMPK) and nuclear factor Kappa-B (NF-κB) pathways. Moreover, tmTNF-α mAb-PTX NPs can inhibit the process of epithelial-mesenchymal transition (EMT) in TNBC to suppress tumor progression and metastasis. Together, the novel tmTNF-α mAb-PTX NPs based targeted drug delivery system is a potentially highly effective approach for treating TNBC.

Keywords: EMT; PLGA nanoparticles; Paclitaxel; Signaling pathway; Triple negative breast cancer; tmTNF-α mAb.