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

Yunfei Li; Dali Qian; Hsuan Pei Lin; Jie Xie; Ping Yang; Drew Maddy; Yajuan Xiao; Xuefei Huang; Zhishan Wang; Chengfeng Yang

doi:10.1016/j.jconrel.2020.10.015

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

Yunfei Li, Dali Qian, Hsuan Pei Lin, Jie Xie, Ping Yang, Drew Maddy, Yajuan Xiao, Xuefei Huang, Zhishan Wang, Chengfeng Yang

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 CHK_1/2-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.

Original language	English
Pages (from-to)	833-846
Number of pages	14
Journal	Journal of Controlled Release
Volume	329
DOIs	https://doi.org/10.1016/j.jconrel.2020.10.015
State	Published - Jan 10 2021

Bibliographical note

Publisher Copyright:
© 2020 Elsevier B.V.

Funding

This study was supported in part by a Research Scholar Grant (RGS-15-026-01-CSM) from the American Cancer Society; and by the Shared Animal Imaging and Histology Resources of UK Markey Cancer Center (P30CA177558).We thank Dr. Younsoo Bae at College of Pharmacy, University of Kentucky (UK) for providing us access to Malvern ZS-90 instrument for DLS measurements. This study was supported in part by a Research Scholar Grant ( RGS-15-026-01-CSM ) from the American Cancer Society . This research was also supported by the Shared Animal Imaging and Histology Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ).

Funders	Funder number
American Cancer Society-Michigan Cancer Research Fund
National Childhood Cancer Registry – National Cancer Institute	P30CA177558
National Childhood Cancer Registry – National Cancer Institute
University of Kentucky Markey Cancer Center

Keywords

Cancer stem cell (CSC)-like cells
Circulating tumor cells
DNA damage
Metastasis
Miriplatin ultrasmall dots
Triple negative breast cancer

ASJC Scopus subject areas

Pharmaceutical Science

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jconrel.2020.10.015

Cite this

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title = "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. 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.",

keywords = "Cancer stem cell (CSC)-like cells, Circulating tumor cells, DNA damage, Metastasis, Miriplatin ultrasmall dots, Triple negative breast cancer",

author = "Yunfei Li and Dali Qian and Lin, {Hsuan Pei} and Jie Xie and Ping Yang and Drew Maddy and Yajuan Xiao and Xuefei Huang and Zhishan Wang and Chengfeng Yang",

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doi = "10.1016/j.jconrel.2020.10.015",

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T1 - Nanoparticle-delivered miriplatin ultrasmall dots suppress triple negative breast cancer lung metastasis by targeting circulating tumor cells

AU - Li, Yunfei

AU - Qian, Dali

AU - Lin, Hsuan Pei

AU - Xie, Jie

AU - Yang, Ping

AU - Maddy, Drew

AU - Xiao, Yajuan

AU - Huang, Xuefei

AU - Wang, Zhishan

AU - Yang, Chengfeng

PY - 2021/1/10

Y1 - 2021/1/10

N2 - 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.

AB - 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.

KW - Cancer stem cell (CSC)-like cells

KW - Circulating tumor cells

KW - DNA damage

KW - Metastasis

KW - Miriplatin ultrasmall dots

KW - Triple negative breast cancer

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SN - 0168-3659

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JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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