This article describes the size control synthesis of silicon quantum dots with simple microemulsion techniques. The silicon nanocrystals are small enough to be in the strong confinement regime and photoluminesce in the blue region of the visible spectrum and the emission can be tuned by changing the nanocrystal size. The silicon quantum dots were capped with allylamine either a platinum catalyst or UV-radiation. An extensive purification protocol is reported and assessed using (1)H NMR to produce ultra pure silicon quantum dots suitable for biological studies. The highly pure quantum dots were used in cellular uptake experiments and monitored using confocal microscopy. The results showed that the amine terminated silicon nanocrystals accumulated in lysosome but not in nuclei and could be used as bio-markers to monitor cancer cells over long timescales.
Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS 2a (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC 50 (drug concentration for 50% reduction in colony formation) was 0.1 lM for MCF-7 and 1 lM for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC 50 concentration was 0.1 lM for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endolysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. ' 2006 Wiley-Liss, Inc.Key words: photodynamic therapy; photochemical internalization; doxorubicin resistant breast cancer cells Multiple drug resistance (MDR) is a major clinical problem that seriously reduces the efficacy of many chemotherapy agents. The establishment of a MDR phenotype by cancer cells is a result of complex molecular events. The most extensively studied mechanism is the over-expression of cell surface efflux pumps (the ABCtransporter family P-glycoprotein, MDR-associated protein, etc.) that can successfully purge a wide spectrum of chemotherapeutic agents from cells, 1 thereby decreasing their intracellular accumulation. 2 Other possible mechanisms are mutation of the DNA topoisomerase, or altered intracellular distribution of anticancer drugs. 2,3 Inhibition of ABC-transporters as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents (e.g. cyclosporin, verapamil) were limited by unacceptable toxicity, whereas secondgeneration agents (e.g. valspodar, biricodar) had better tolerability, but were confounded by unpredictable pharmacokinetic interactions and interactio...
RNA-binding proteins (RBPs), in addition to their functions in cellular homeostasis, play important roles in lineage specification and maintaining cellular identity. Despite their diverse and essential functions, which touch on nearly all aspects of RNA metabolism, the roles of RBPs in somatic cell reprogramming are poorly understood. Here we show that the DEAD-box RBP DDX5 inhibits reprogramming by repressing the expression and function of the non-canonical polycomb complex 1 (PRC1) subunit RYBP. Disrupting Ddx5 expression improves the efficiency of iPSC generation and impedes processing of miR-125b, leading to Rybp upregulation and suppression of lineage-specific genes via RYBP-dependent ubiquitination of H2AK119. Furthermore, RYBP is required for PRC1-independent recruitment of OCT4 to the promoter of Kdm2b, a histone demethylase gene that promotes reprogramming by reactivating endogenous pluripotency genes. Together, these results reveal important functions of DDX5 in regulating reprogramming and highlight the importance of a Ddx5-miR125b-Rybp axis in controlling cell fate.
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