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Gold nanorods demonstrate a recognized role in the treatment of breast cancer cell lines as an efficient nanocarrier for chemotherapeutic drug delivery.

Gold nanorods (GNRs) have gained pronounced recognition in the diagnosis and treatment of cancers driven by their distinctive properties. Herein, a gold-based nanosystem was prepared by utilizing a phospholipid moiety linked to thiolated polyethylene glycol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG-SH, as a surface decorating agent. The synthesized phospholipid-PEG-GNRs displayed good colloidal stability upon exposure to the tissue culture medium. Cytotoxicity of phospholipid-PEG-GNRs was investigated toward MCF-7 and T47D breast cancer cells using sulforhodamine B test. The results revealed that phospholipid-PEG-GNRs demonstrated high cytotoxicity to MCF-7 cells compared to T47D cells, and minimal cytotoxicity to human dermal fibroblasts. The cellular uptake studies performed by imaging and quantitative analysis demonstrated massive internalization of phospholipid-coated GNRs into MCF-7 cells in comparison to T47D cells. The cellular death modality of cancer cells after treatment with phospholipid-PEG-GNRs was evaluated using mitochondrial membrane potential assay (JC-1 dye), gene expression analysis, and flow cytometry study. The overall results suggest that phospholipid-modified GNRs enhanced mainly the cellular apoptotic events in MCF-7 cells in addition to necrosis, whereas cellular necrosis and suppression of cellular invasion contributed to the cellular death modality in the T47D cell line upon treatment with phospholipid-PEG-GNRs. The phospholipid-coated GNRs interact in a different manner with breast cancer cell lines and could be considered for breast cancer treatment.

Biodentine™ is a tricalcium silicate-based cement material that has a great impact on different biological processes of dental stem cells, compared to other biomaterials. Therefore, we aimed to investigate the optimum biocompatible concentration of Biodentine™ with stem cells derived from periodontal ligament (hPDLSCs) by determining cell proliferation, cytotoxicity, migration, adhesion and mineralization potential. hPDLSCs were treated with Biodentine™ extract at different concentrations; 20, 2, 0.2 and 0.02 mg/mL. Cells cultured without Biodentine™ were used as a blank control. The proliferation potential of hPDLSCs was evaluated by MTT viability analysis for 6 days. Cytotoxicity assay was performed after 3 days by using AnnexinV/7AAD. Migration potential was investigated by wound healing and transwell migration assays at both cellular and molecular levels. The expression levels of chemokines CXCR4, MCP-1 and adhesion molecules FGF-2, FN, VCAM and ICAM-1 were measured by qPCR. The communication potentials of these cells were determined by adhesion assay. In addition, mineralization potential was evaluated by measuring the expression levels of osteogenic markers; ALP, OCN, OPN and Collagen type1 by qPCR. Our results showed significant increase in the proliferation of hPDLSCs at low concentrations of Biodentine™ (2, 0.2 and 0.02 mg/mL) while higher concentration (20 mg/mL) exhibited cytotoxic effect on the cells. Moreover, 2 mg/mL Biodentine™ showed a significant increase in the migration, adhesion and mineralization potentials of the derived cells among all concentrations and when compared to the blank control. Our findings suggest that 2 mg/mL of Biodentine™ is the most biocompatible concentration with hPDLSCs, showing a high stimulatory effect on the biological processes.

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Combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors are emerging. Targeting multiple signaling pathways decreases the chances of cancer cells switching and adapting new signaling processes that may occur when using a single therapeutic modality. Aberrant functioning of Notch-1, Wnt/β-catenin, and STAT3 proteins and their crosstalk signaling pathways have been found to be involved in tumor survival, drug resistance, and relapse. In the current study, we describe a therapeutic potential of single and combinations of siRNA designed for silencing Notch-1, Wnt/β-catenin, and STAT3 in MCF7_DoxS (wild type) and MCF7_DoxR (doxorubicin resistant) breast cancer cells. The MCF7_DoxR cells were developed through treatment with a gradual increase in doxorubicin concentration, the expression of targeted genes was investigated, and the expression profiling of CD44/CD24 of the MCF7_DoxS and MCF7_DoxR cells were detected by flow cytometry. Both MCF7_DoxS and MCF7_DoxR breast cancer cells were treated with single and combinations of siRNA to investigate synergism and were analyzed for their effect on cell proliferation with and without doxorubicin treatment. The finding of this study showed the overexpression of targeted genes and the enrichment of the CD44−/CD24+ phenotype in MCF7_DoxR cells when compared to MCF7_DoxS cells. In both cell lines, the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/β-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA treatment. Our study shows the possibility of using single and combinations of siRNA to enhance the chemosensitivity of cancer cells to conventional antitumor chemotherapy.

BackgroundBreast cancer is the most common type of cancer among females. Hypoxia mediates cancer hallmarks and results from reduced oxygen level due to irregularities in tumor vascularization or when the tumor size prevents oxygen diffusion and triggers angiogenesis to compensate for low oxygen. Cancer stem cells (CSCs) are a rare subpopulation, able to self-renew and to give rise to tumor-initiating cells. It is proposed that CSCs’ secretions help to recruit endothelial cells via angiogenic factors to establish tumor vascularization. In the tumor microenvironment, the effect of hypoxia on CSCs and the impact of their secretions on triggering angiogenesis and tumor vascularization remain questionable. In this study, three-dimensional (3D) CSCs derived from MCF-7 were directly exposed to repetitive long-term cycles of hypoxia to assess its effect on CSCs and then to evaluate the role of the hypoxic CSCs’ (CSCsHYP) secretions in angiogenesis using (HUVECs) as a model for tumor neovascularization response.MethodsCSCs derived from MCF-7 cell-line were expanded under repetitive, strictly optimized, long-term/continuous and intermittent hypoxic shots for almost four months to assess hypoxic effect on CSCs, sorted based on CD44+/CD24− biomarkers. Hypoxic phenotype of CSCsHYP was evaluated by assessing the acquired chemoresistance using MTT assay and elevated stemness properties were assessed by flow cytometry. To evaluate the effect of the secretions from CSCsHYP on angiogenesis, HUVECs were exposed to CSCsHYP conditioned-medium (CdM)—in which CSCs had been previously grown—to mimic the tumor microenvironment and to assess the effect of the secretions from CSCsHYP on the HUVECs’ capability of tube formation, migration and wound healing. Additionally, co-culture of CSCsHYP with HUVECs was performed.ResultsCSCsHYP acquired higher chemoresistance, increased stemness properties and obtained greater propagation, migration, and wound healing capacities, when compared to CSCs in normoxic condition (CSCsNOR). HUVECs’ tube formation and migration abilities were mediated by hypoxic (CSCs) conditioned media (CdM).DiscussionThis study demonstrates that chemoresistant and migrational properties of CSCs are enhanced under hypoxia to a certain extent. The microenvironment of CSCsHYP contributes to tumor angiogenesis and migration. Hypoxia is a key player in tumor angiogenesis mediated by CSCs.

A new combination strategy of an active loading and active targeting approach was applied in this work.