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

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation for Distinguished Young Scholars (No. 81625023).

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Authors and Affiliations

  1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Cheng Chen, Qiuyi Li, Liyun Xing, Minglu Zhou, Chaohui Luo, Shujie Li, Lian Li & Yuan Huang

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  1. Cheng Chen
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Correspondence to Yuan Huang.

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12274_2021_3923_MOESM1_ESM.pdf

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

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Chen, C., Li, Q., Xing, L. et al. Co-delivery of mitochondrial targeted lonidamine and PIN1 inhibitor ATRA by nanoparticulate systems for synergistic metastasis suppression. Nano Res. 15, 3376–3386 (2022). https://doi.org/10.1007/s12274-021-3923-9

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