The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D, cyclin E, VEGFR-1, MMP-2, and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

Colorectal cancer cell-derived extracellular vesicles transfer miR-221-3p to promote endothelial cell angiogenesis via targeting suppressor of cytokine signaling 3.

BACKGROUND: Secreted microRNAs (miRNAs) can serve as promising diagnostic markers for colorectal cancer (CRC). Herein, we evaluated the potential clinical significance of a signature of four circulating serum-derived miRNAs in CRC. We also demonstrated that extracellular vesicles (EVs) containing miR-221-3p could facilitate endothelial cell angiogenesis. METHODS: The expressions of four circulating serum-derived miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) were measured by real-time quantitative PCR, and their associations with lymph node metastasis were determined in CRC patients. Receiver operating characteristic curve analysis was used to determine their diagnostic accuracy. EVs were isolated and characterized from the conditioned media of human CRC cells (HCT116 and Caco2). Cell proliferation, transwell migration, and tube formation assays were performed to investigate the pro-angiogenic effect of miR-221-3p transferred by CRC-EVs into the endothelial cells. In silico analysis was used to show the regulatory functions of miR-221-3p on SOCS3, validated by luciferase and Western blotting assays. RESULTS: The expression levels of serum-derived miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p were significantly higher in CRC than in healthy individuals. The expression of miR-19a-3p, miR-203-3p, and miR-221-3p were positively correlated with the lymph node metastasis status. Moreover, SOCS3 was identified as a direct target of miR-221-3p and the secreted miR-221-3p shuttled by CRC-EVs regulated STAT3/VEGFR-2 signaling axis by targeting SOCS3 in endothelial cells. CRC-EVs promoted endothelial cell proliferation, migration, and the formation of vessel-like structures. The proangiogenic effect of CRC-EVs on the cells was recapitulated by miR-221-3p overexpression, showing the importance of EVs-derived miR-221-3p in promoting endothelial cell angiogenesis. CONCLUSION: We introduced a signature of four-circulating miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) as a novel diagnostic biomarker for CRC. Besides, we revealed that miR-221-3p induces endothelial cell angiogenesis in vitro by targeting SOCS3.