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Hypoxia Engineered Bone Marrow Mesenchymal Stem Cells Targeting System with Tumor Microenvironment Regulation for Enhanced Chemotherapy of Breast Cancer.

ABSTRACT: Improving the tumor targeting of docetaxel (DTX) would not only be favored for the chemotherapeutic efficacy, but also reduce its side effects. However, the regulation of the tumor microenvironment could further inhibit the growth of tumors. In this study, we introduced a system consisting of hypoxia-engineered bone marrow mesenchymal stem cells (H-bMSCs) and DTX micelles (DTX-M) for breast cancer treatment. First, the stem cell chemotherapy complex system (DTX@H-bMSCs) with tumor-targeting ability was constructed according to the uptake of DTX-M by hypoxia-induced bMSCs (H-bMSCs). DTX micellization improved the uptake efficiency of DTX by H-bMSCs, which equipped DTX@H-bMSCs with satisfactory drug loading and stability. Furthermore, the migration of DTX@H-bMSCs revealed that it could effectively target the tumor site and facilitate the drug transport between cells. Moreover, in vitro and in vivo pharmacodynamics of DTX@H-bMSCs exhibited a superior antitumor effect, which could promote the apoptosis of 4T1 cells and upregulate the expression of inflammatory factors at the tumor site. In brief, DTX@H-bMSCs enhanced the chemotherapeutic effect in breast cancer treatment.

SUBMITTER: Zu J

PROVIDER: S-EPMC8160638 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The transcriptional profile induced by hypoxia plays important roles in the chondrogenic differentiation of marrow stromal/stem cells (MSC) and is mediated by the hypoxia inducible factor (HIF) complex. However, various compounds can also stabilize HIF's oxygen-responsive element, HIF-1α, at normoxia and mimic many hypoxia-induced cellular responses. Such compounds may prove efficacious in cartilage tissue engineering, where microenvironmental cues may mediate functional tissue formation. Here, we investigated three HIF-stabilizing compounds, which each have distinct mechanisms of action, to understand how they differentially influenced the chondrogenesis of human bone marrow-derived MSC (hBM-MSC) in vitro. hBM-MSCs were chondrogenically-induced in transforming growth factor-β3-containing media in the presence of HIF-stabilizing compounds. HIF-1α stabilization was assessed by HIF-1α immunofluorescence staining, expression of HIF target and articular chondrocyte specific genes by quantitative polymerase chain reaction, and cartilage-like extracellular matrix production by immunofluorescence and histochemical staining. We demonstrate that all three compounds induced similar levels of HIF-1α nuclear localization. However, while the 2-oxoglutarate analog dimethyloxalylglycine (DMOG) promoted upregulation of a selection of HIF target genes, desferrioxamine (DFX) and cobalt chloride (CoCl2 ), compounds that chelate or compete with divalent iron (Fe2+ ), respectively, did not. Moreover, DMOG induced a more chondrogenic transcriptional profile, which was abolished by Acriflavine, an inhibitor of HIF-1α-HIF-β binding, while the chondrogenic effects of DFX and CoCl2 were more limited. Together, these data suggest that HIF-1α function during hBM-MSC chondrogenesis may be regulated by mechanisms with a greater dependence on 2-oxoglutarate than Fe2+ availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. Stem Cells 2018;36:1380-1392.

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Hypoxia Engineered Bone Marrow Mesenchymal Stem Cells Targeting System with Tumor Microenvironment Regulation for Enhanced Chemotherapy of Breast Cancer.

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