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

Mol Pharm. 2021 Mar 1;18(3):822-835. doi: 10.1021/acs.molpharmaceut.0c00696. Epub 2021 Feb 15.

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.

Keywords: antimetastasis; diallyl trisulfide; inflammatory microenvironment; melanoma; microparticles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allyl Compounds / pharmacology*
  • Animals
  • Calgranulin A / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Extracellular Vesicles / metabolism*
  • Fibronectins / metabolism
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-6 / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Peroxidase / metabolism
  • Sulfides / pharmacology*
  • Toll-Like Receptor 4 / metabolism
  • Tumor Microenvironment / drug effects*

Substances

  • Allyl Compounds
  • Calgranulin A
  • Fibronectins
  • Interleukin-6
  • Sulfides
  • Toll-Like Receptor 4
  • diallyl trisulfide
  • Peroxidase