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Polysialic Acid Self-assembled Nanocomplexes for Neutrophil-Based Immunotherapy to Suppress Lung Metastasis of Breast Cancer

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Abstract

The role of neutrophils in tumor metastasis has recently attracted widespread interest. Neutrophils are the most abundant immune cells in human peripheral blood, and large numbers can spontaneously migrate to metastatic sites, where they form an immunosuppressive microenvironment. Polysialic acid (PSA) can target peripheral blood neutrophils (PBNs) mediated by l-selectin, and abemaciclib (ABE) and mitoxantrone (MIT) can treat immunosuppressive microenvironments. Here, we aimed to inhibit lung metastasis of breast cancer and improve chemoimmunotherapy by designing a PSA-modified ABE and MIT co-delivery system (AM-polyion complex (PIC)) to target PBNs in mice with metastatic tumors. We found that through electrostatic interactions between the strong negative charge of PSA and the positive charge of the drug can form stable nanocomplexes and that spontaneous migration of neutrophils can mediate the aggregation of these complexes in the lungs, induce antimetastatic immune responses, enhance the effectiveness of cytotoxic T lymphocytes (CTLs), and inhibit regulatory T cell (Treg) proliferation in vivo and in vitro. Pharmacodynamic results suggested that neutrophil-mediated AM-PIC chemoimmunotherapy inhibited tumor metastasis in mice with lung metastasis of 4T1 breast cancer. Overall, PSA-modified nanocomplexes offer promising neutrophil-mediated, targeted drug delivery systems to treat lung metastasis of breast cancer.

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Funding

This research was supported by the National Natural Science Foundation of China (Grant Number 81973271).

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Authors and Affiliations

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

    Chuizhong Fan, Cong Li, Shuang Lu, Xiaoxue Lai, Shuo Wang, Xinrong Liu, Yanzhi Song & Yihui Deng

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  1. Chuizhong Fan
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  2. Cong Li
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  3. Shuang Lu
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  4. Xiaoxue Lai
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  5. Shuo Wang
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  6. Xinrong Liu
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  7. Yanzhi Song
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  8. Yihui Deng
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Contributions

Chuizhong Fan: conceptualization, analysis, investigation, methodology, validation, and writing

Cong Li: conceptualization, analysis, and investigation

Shuang Lu: data curation, analysis, methodology, and validation

Xiaoxue Lai: analysis and methodology

Shuo Wang: analysis and methodology

Xinrong Liu: supervision

Yanzhi Song: supervision

Yihui Deng: supervision, resources, and review

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Correspondence to Yihui Deng.

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Fan, C., Li, C., Lu, S. et al. Polysialic Acid Self-assembled Nanocomplexes for Neutrophil-Based Immunotherapy to Suppress Lung Metastasis of Breast Cancer. AAPS PharmSciTech 23, 109 (2022). https://doi.org/10.1208/s12249-022-02243-7

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