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

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.

SUBMITTER: Qiu X

PROVIDER: S-EPMC6525995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tumor-specific delivery of therapeutics is challenging. One of the major hurdles for successfully delivering targeted agents by nanovectors is the filtering role of the liver in rapidly sequestering nanovectors from the circulation. Exosomes, a type of endogenous nanoparticle, circulate continuously in the peripheral blood and play a role in intercellular communication. The aim of this study was to determine whether the level of endogenous exosomes has an effect on nanovector delivery efficiency of targeted agents. Methods: Exosomes were isolated from peripheral blood and intravenously (I.V.) injected into tumor-bearing mice. Subsequently, 1,1-dioctadecyl-3,3,3'3'-tetramethylindotricarbocyanine-iodide (DiR) fluorescent dye-labeled nanoparticles, including grapefruit nanovectors (GNV) and standard liposomes, were I.V. injected in the mice. The efficiency of redirecting GNVs from liver to other organs of injected mice was further analyzed with in vivo imaging. The concentration of chemo drugs delivered by GNV was measured by HPLC and the anti-lung metastasis therapeutic effects of chemo drugs delivered by GNVs in mouse breast cancer and melanoma cancer models were evaluated. Results: We show that tail vein-injected exosomes isolated from mouse peripheral blood were predominately taken up by liver Kupffer cells. Injection of peripheral blood-derived exosomes before I.V. injection of grapefruit-derived nanovector (GNV) decreased the deposition of GNV in the liver and redirected the GNV to the lung and to the tumor in breast and melanoma tumor-bearing mouse models. Enhanced therapeutic efficiency of doxorubicin (Dox) or paclitaxel (PTX) carried by GNVs for lung metastases was demonstrated when there was an I.V. injection of exosomes before therapeutic treatment. Furthermore, we found that CD36 and IGFR1 receptor-mediated pathways played a critical role in the exosome-mediated inhibitory effect of GNV entry into liver macrophages. Conclusions: Collectively, our findings provide a foundation for using autologous exosomes to enhance therapeutic vector targeted delivery to the lung.

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

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