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An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid–Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis

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Abstract

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis.

Graphical abstract

Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.

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Abbreviations

TAMs:

Tumor-associated macrophages

CTCs:

Circulating tumor cells

EPI-S:

EPI solution

Glu:

Glucose

EPI-CL:

EPI-loaded conventional liposomes

EPI-PL:

EPI-loaded PEGylated liposomes

EPI-SL:

EPI-loaded SA-CH modified liposomes

DiR-CL:

DiR-loaded conventional liposomes

DiR-PL:

DiR-loaded PEGylated liposomes

DiR-SL:

DiR-loaded SA-CH modified liposomes

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Funding

This study was supported by the Career Development Support Plan for Young and Middle-aged Teachers at the Shenyang Pharmaceutical University (ZDN2021009).

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Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People’s Republic of China

    Xianmin Meng, Mingqi Wang, Kaituo Zhang, Dezhi Sui, Meng Chen, Zihan Xu, Tiantian Guo, Xinrong Liu, Yihui Deng & Yanzhi Song

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  1. Xianmin Meng
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  2. Mingqi Wang
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  3. Kaituo Zhang
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  4. Dezhi Sui
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  10. Yanzhi Song
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Contributions

Conceptualization: Xianmin Meng and Yanzhi Song; data curation: Xianmin Meng, Yihui Deng and Yanzhi Song; acquisition: Mingqi Wang, Kaituo Zhang, Zihan Xu and Tiantian Guo; writing: Xianmin Meng; analysis: Dezhi Sui and Meng Chen; supervision: Xinrong Liu. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yanzhi Song.

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Meng, X., Wang, M., Zhang, K. et al. An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid–Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis. AAPS PharmSciTech 23, 285 (2022). https://doi.org/10.1208/s12249-022-02432-4

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