Nanoparticle-delivered miriplatin ultrasmall dots suppress triple negative breast cancer lung metastasis by targeting circulating tumor cells

Abstract

No effective therapy is yet available to treat triple negative breast cancer (TNBC), which has poor prognosis due to frequent metastasis. Cancer stem cells (CSCs) or CSC-like cells play crucial roles in cancer metastasis and are exceptionally tolerant with genetic lesions. The extent of DNA damages has an important impact on the fate of CSCs. Despite the importance of platinum [Pt(II)] agents in cancer therapy, accumulating reports showed the treatment failure of conventional Pt(II) drugs, which is likely due to their inadequate DNA damage effects. Miriplatin is a clinically approved drug only being locally-used for treating liver cancer. In this study, we developed a novel ultrasmall Pt(II) dot (uPtD) from miriplatin and encapsulated it into our recently-reported integrin α5(ITGA5) active targeting nanoparticles (uPtDs NPs) and tested their therapeutic efficacy against TNBC metastasis. It was found that uPtDs NPs displayed a superior DNA damage capability via enhanced-interactions with DNA and a significantly stronger effect in reducing CSC-like property of TNBC cells, compared to conventional cisplatin and miriplatin. Mechanistically, the severe DNA damages induced by uPtDs NPs activated the CHK1/2-CDC25A-cyclin A/E pathway to induce cell cycle arrest. Moreover, uPtDs NPs could target the in vivo circulating tumor cells (CTCs) to suppress TNBC lung metastasis. Given the desired-safety profile of miriplatin, the uPtDs represent a promising therapeutic agent of the metal-based nanomedicines to reduce cancer metastasis. SignificanceThe miriplatin ultrasmall dots developed from clinically-prescribed miriplatin may serve as a potent systemically-administered agent to target CTCs and reduce cancer metastasis.