Theranostics 2019; 9(9):2618-2636. doi:10.7150/thno.32363

Research Paper

Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis

Xiaolan Qiu1*, Zhi Li1*, Xuedong Han1*, Linlin Zhen1, Chao Luo2, Minmin Liu1, Kun Yu3✉, Yi Ren1✉

1. Department of Breast and Thyroid Surgery, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, China
2. Department of Central Laboratory, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, China
3. Department of Cardiology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, China
* These authors contributed equally to this work.

Abstract

Tumor-derived nanovesicles have been widely used as a biomarker or therapeutic target in various tumor types. However, these nanovesicles have limited use in therapy due to the risk of advancing tumor development.

Methods: Exosome-like nanovesicles (ENVs) were developed from metastatic breast cancer 4T1 cells-derived exosomes. The distribution of ENVs and their impact on macrophage-mediated phagocytosis were evaluated. The effect of ENVs pretreatment on anti-lung metastasis therapeutic effects of chemotherapeutic drugs delivered by DOTAP/DOPE liposomes in breast cancer-bearing mice was also examined.

Results: We demonstrated that, following intravenous injection in mice, ENVs were preferentially uptaken by Kupffer cells and repressed phagocytosis. The decreased uptake appeared to be due to the translocation of membrane nucleolin from the inner face of the plasma membrane to the cell surface and intercellular Ca2+ fluxes, leading to altered expression of genes involved in phagocytosis by macrophages. Mice pretreated with 4T1-derived ENVs led to the decreased uptake of DOTAP: DOPE liposomes (DDL) in the liver. Consequently, doxorubicin-loaded DDL transported to the lungs instead of the liver, effectively inhibiting breast cancer lung metastasis. Importantly, 4T1 cells exosome-derived ENVs had no detectable toxicity in vivo and low-risk to promote tumor growth and metastasis compared to 4T1 cells exosomes.

Conclusion: Our results suggested that pretreatment with 4T1 ENVs represents a strategy to escape Kupffer cell-mediated phagocytosis effectively targeting drug delivery vehicles to tumor metastasis, reducing the IC50 of the chemotherapeutic drugs, and avoiding adverse side effects.

Keywords: Tumor-derived nanovesicles, Breast cancer, Lung metastasis, Kupffer cells, Phagocytosis, Nucleolin, Cell surface, Ca2+ flux, and DOTAP/DOPE liposome

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How to cite this article:
Qiu X, Li Z, Han X, Zhen L, Luo C, Liu M, Yu K, Ren Y. Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis. Theranostics 2019; 9(9):2618-2636. doi:10.7150/thno.32363. Available from http://www.thno.org/v09p2618.htm