Co-delivery of shikonin and JQ1 inhibits triple-negative breast tumor progression and lung metastasis through inhibition of epithelial-mesenchymal transition and vasculogenic mimicry

Abstract

Triple-negative breast cancer (TNBC) is highly prone to lung metastasis, primarily driven by epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM). Therefore, inhibiting EMT and VM represents a promising therapeutic strategy for TNBC. The immunosuppressive tumor microenvironment contributes substantially to poor treatment outcomes, with M2-type macrophages secreting excessive levels of TGF-β that promote both EMT and VM. In this study, we proposed a combination therapy strategy involving shikonin (SHK) and JQ1 delivered via a mesoporous polydopamine-based Pickering emulsion (termed MPDA@PE). This formulation significantly suppressed tumor growth and lung metastasis by inducing apoptosis in TNBC and inhibiting TGF-β-induced EMT and VM. Furthermore, MPDA@PE can be incorporated into a thermosensitive hydrogel for application in the prevention of TNBC recurrence and lung metastasis following surgical resection. These findings highlight a potential therapeutic approach for effective TNBC treatment. The combined administration of SHK and JQ1 inhibits both EMT and VM. This approach disrupts the nutrient supply in tumor tissues by blocking VM and suppresses tumor metastasis through EMT inhibition. Consequently, it demonstrates therapeutic efficacy against TNBC recurrence post-surgery and effectively limits lung metastasis.

Keywords: JQ1; epithelial-mesenchymal transition; mesoporous polydopamine nanoparticle; pickering emulsion; shikonin; vasculogenic mimicry.