Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis
Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis
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DOI：
10.7150/thno.32363
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Ren, Yi
中科院分区：
文献类型：
--
作者：
Qiu, Xiaolan;Li, Zhi;Ren, Yi
肿瘤源性纳米囊泡作为生物标志物或治疗靶点广泛应用于各种肿瘤。然而，由于有促进肿瘤发展的风险，这些纳米囊泡在治疗中的应用有限。方法：从转移性乳腺癌4T1细胞来源的外泌体中培养外泌体样纳米囊泡（env）。评估env的分布及其对巨噬细胞介导的吞噬作用的影响。研究了ENVs预处理对DOTAP/DOPE脂质体给药乳腺癌小鼠抗肺转移治疗效果的影响。结果：我们证明，静脉注射小鼠后，env优先被Kupffer细胞吸收并抑制吞噬。摄取减少似乎是由于膜核蛋白从质膜内表面转移到细胞表面和细胞间Ca2+通量，导致巨噬细胞吞噬作用相关基因的表达改变。用4t1来源的env预处理小鼠，导致肝脏中DOTAP: DOPE脂质体（DDL）的摄取减少。因此，负载阿霉素的DDL转运到肺部而不是肝脏，有效地抑制了乳腺癌的肺转移。重要的是，与4T1细胞外泌体相比，4T1细胞外泌体衍生的env在体内没有可检测到的毒性，并且促进肿瘤生长和转移的风险较低。结论：我们的研究结果表明，4T1 env预处理是一种逃避Kupffer细胞介导的吞噬的策略，可以有效地将药物传递载体靶向肿瘤转移，降低化疗药物的IC50，并避免不良副作用。
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.