Co-delivery of mitochondrial targeted lonidamine and PIN1 inhibitor ATRA by nanoparticulate systems for synergistic metastasis suppression

Mitochondria are highly involved in the metastasis of cancer cells. However, tumor cells impede the efficiency of mitochondrial targeted drugs by protecting mitochondria through an intrinsic and adaptive antioxidant mechanism. We aim to disturb the redox homeostasis by prolyl-isomerase PIN1 inhibitor all-trans retinoic acid (ATRA) to improve the therapeutic efficacy of mitochondrial targeted lonidamine (TL). The combination of ATRA and TL with a ratio of 2:1 was found to have the best synergistic effect in inhibiting the proliferation and metastasis of metastatic 4T1 breast cancer cells. Dual-drug loaded nanoparticles (TL-ATRA NPs) were further developed by self-assembly and were observed to disturb the redox homeostasis drastically and triggered a robust mitochondrial disruption on metastatic 4T1 breast cancer cells. The molecular mechanism was related to the downregulation of nuclear factor E2-related factor 2 (NRF2), a critical transcription factor that regulated antioxidant responses, and its downstream molecules. As a result, TL-ATRA NPs significantly suppressed the growth of primary tumors and the formation of lung metastasis nodes. Collectively, our findings showed that sensitizing mitochondria to anti-cancer drugs by disturbing redox homeostasis achieved a satisfactory therapeutic effect to inhibit tumor growth and metastasis.