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 Ca 2+ 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 IC 50 of the chemotherapeutic drugs, and avoiding adverse side effects.

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

“…It is suggested that tumor cell-derived EVs (TEVs), especially autologous TEVs, carry tumor antigen repertoires, costimulatory molecules, and DNA fragments similar to their parental cells (Qiu et al, 2019;Rahbarghazi et al, 2019). This nature could elicit a potent T cell-dependent anti-tumor immune response and achieve therapeutic effects in mouse models of melanoma (Mannavola et al, 2019), hepatocellular carcinoma (Moris et al, 2017), and colon carcinoma (Teng et al, 2017).…”

Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium

“…As naturally derived nanovesicles, exosomes efficiently deliver exogenous RNAs (siRNAs and miRNAs) to target tissues/cells in vivo 3. Despite multiple advantages over existing synthetic systems, such as less immunogenicity and higher affinity, exosomes suffer from the drawback of endocytosis by the mononuclear phagocyte system (MPS), such as in the liver and spleen, limiting their distribution in other tissues like heart 4. Due to the high prevalence of heart disease, there is a great demand for improving the cardiomyocyte-specific delivery of exosomes.…”

Targeted delivery of extracellular vesicles in heart injury

“…Even though EVs have various advantages compared to existing delivery systems, such as lower immunogenicity and higher affinity, their distribution to the heart is limited by rapid clearance from the blood by the MPS and subsequent accumulation in the liver and spleen 154 . The plasma half-life of EVs is only 70-80 min 155 , 156 .…”