Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Researchers from CEBAS-CSIC and IMDEA set out to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.

Effect of cellular uptake inhibitors on the antiproliferative activity of EXO-CUR in MCF-7 cells

Inhibitors and EXO-CUR were incubated for 4 h. Then, the cell medium was replaced by another one without inhibitors or EXO-CUR and kept for 48 h. EXO-CT: non-loaded EXOs. Phe: phenylarsine; Cyt: Cytochalasin D; Mon: monensin; Chlor: chlorpromazine. ** p < 0.01; *** p < 0.001. NS: not significantly different. Experiments were carried out three times for each treatment (n = 3 plates per experiment).

González-Sarrías A, Iglesias-Aguirre CE, Cortés-Martín A, Vallejo F, Cattivelli A, Del Pozo-Acebo L, Del Saz A, López de Las Hazas MC, Dávalos A, Espín JC. (2022) Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity. Int J Mol Sci 23(5):2860. [article]

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