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. SIGNIFICANCE: The
miriplatin ultrasmall dots developed from clinically-prescribed
miriplatin may serve as a potent systemically-administered agent to target CTCs and reduce
cancer metastasis.