Extracellular Microparticles Encapsulated with Diallyl Trisulfide Interfere with the Inflammatory Tumor Microenvironment and Lung Metastasis of Invasive Melanoma

Abstract

Lung metastasis is a fatal and late-stage event for many solid tumors. Multiple lines of evidence have demonstrated that diallyl trisulfide (DATS), an active ingredient of garlic, possesses striking antimetastatic effects. However, the lack of highly efficient organ-compatible carriers restricts its application. In the present study, we showed that extracellular microparticles encapsulated with DATS (DATS-MPs) were capable of interfering with the prometastatic inflammatory microenvironment in local tissues. DATS-MPs were successfully prepared and exhibited typical characteristics of B16BL6-derived extracellular vesicles. The DATS-MPs preferentially fused with cancer cells and endogenous cells (mouse lung epithelial MLE-12 cells) from the metastatic organs in vitro. More interestingly, the systemically administered MPs predominantly accumulated in the lung tissue that serves as their main metastatic organ. The drug-loaded MPs exerted higher antimetastatic effects than DATS alone in both the spontaneous and the experimental metastasis models in mice (*p < 0.05). Additionally, we found that DATS-MPs inhibited tumor cell migration and interfered with the prometastatic inflammatory microenvironment via decreasing the release of S100A8/A9, serum amyloid A (SAA), and interleukin-6 (IL-6) and inhibiting the expression of fibronectin, MRP8, myeloperoxidase (MPO), and the toll-like receptor 4 (TLR4)-Myd88 in the lung tissues. Collectively, DATS-MPs appeared to enhance the antimetastatic efficiency of DATS in animal models under study.

Icaritin ameliorates extracellular microparticles‐induced inflammatory pre‐metastatic niche via modulating the cGAS‐STING signaling

“…lial cells were able to uptake MPs, initiate an inflammatory response, and promote the formation of PMN(Liu et al, 2021). In the present study, we found that 10 μg/ml of MPs could induce both MLE-12 andMH-S cells to secret critical inflammatory factors including MCP-1.…”

“…It has been held that lung tissue is rich in alveoli, which are mainly composed of macrophages and epithelial cells (Altorki et al, 2019). Previous studies showed that both lung macrophages and lung epithelial cells were able to uptake MPs, initiate an inflammatory response, and promote the formation of PMN (Liu et al, 2021). In the present study, we found that 10 μg/ml of MPs could induce both MLE‐12 and MH‐S cells to secret critical inflammatory factors including MCP‐1.…”

“…B16BL6 melanoma cells were exposed to ultraviolet radiation (UVB; 300 J/m 2 ) for 1 hr, and after 16 hr, the supernatants were used for MP isolation (Liu et al, 2021). Briefly, the supernatants were firstly centrifuged at 300 g for 5 min to remove whole cells, followed by centrifugation at 1300 rpm for 10 min and 14,000 g for 2 min to remove the debris.…”

“…However, the role of tumor cellsderived MPs with 100-1,000 nm size cannot be ignored. Our previous study revealed that the existence of the relatively wide gaps (0.3-3 μm in size) in the pulmonary capillary allowed the MPs to enter into the lung parenchyma via the alveolar capillaries(Liu et al, 2021; F I G U R E 9 Schematic diagram of the underlying mechanisms of ICT inhibiting the formation of PMN and lung metastasisSirianni, Chu, & Walker, 2003). Our results verified that the MPs could be uptaken by the lung epithelial cells and macrophages, which was essential for the remodeling of the microenvironment.…”

A Meta-analysis on the Effectiveness of Extracellular Vesicles as Nanosystems for Targeted Delivery of Anticancer Drugs

“…The result showed that the heterogeneity was not driven by a single study. However, after the removal of Liu et al 76 (Figure 5) and Pan et al 85 (Figure 7b), the heterogeneity was reduced to 41% and 27% for cancer metastasis and targeting.…”