Cationic liposomes have been successfully used as an alternative approach to viral systems to deliver nucleic acids. However, high toxicity and inconsistent transfection efficiency have been associated with the currently available liposomes. Therefore, a novel cationic liposome was developed based on a synthetic cationic cardiolipin analogue (CCLA) to test the DNA transfection efficiency. This CCLA-based liposome was also used to determine the therapeutic efficacy of c-raf small interfering RNA (siRNA) in mice. In this report, we showed that the CCLA-based liposome was less toxic and effectively transfected reporter genes in vitro and in vivo. The transfection efficiency in mice was seven-fold higher than the commercially available DOTAP-based liposome. In addition, craf siRNA in the presence of CCLA-based liposome induced up to 62% of growth inhibition in cancer cells. Treatment of c-raf siRNA/CCLA complex in SCID mice bearing human breast xenograft tumors resulted in 73% of tumor growth suppression as compared to free c-raf siRNA group. In conclusion, a novel CCLA-based liposome showed less toxicity and broad usage both in vitro and in vivo with DNA and siRNA.

Articles you may be interested inAlternative current conduction mechanisms of organic-inorganic compound [N(CH3)3H]2CuCl4

Endoxifen is the key active metabolite of tamoxifen, a widely used breast cancer drug. Orally administered tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize tamoxifen to varying degree and may not receive the optimal benefit from tamoxifen treatment. We show that oral administration of endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of endoxifen may avoid a potential serious drug interaction found between tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered endoxifen is rapidly absorbed and systemically available when tested in female rats. The endoxifen-treated rats showed 787% higher exposure (AUC(0-infinity)) and 1,500% higher concentration (C (max)) levels of endoxifen when compared with tamoxifen. Oral endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on endoxifen as a potentially new therapeutic agent for breast cancer.

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Humidity sensing characteristics of NiO∕Al2O3 nanocomposites, prepared by sol-gel method, are studied by impedance spectroscopy. Modeling of the obtained impedance spectra with an appropriate equivalent circuit enables us to separate the electrical responses of the tightly bound chemisorbed water molecules on the grain surfaces and the loosely associated physisorbed water layers. Dependence of the dielectric properties and ac conductivity of the nanocomposites on relative humidity (RH) were studied as a function of the frequency of the applied ac signal in the frequency range of 0.1–105Hz. The electrical relaxation behavior of the investigated materials is presented in the conductivity formalism, where the conductivity spectra at different RHs are analyzed by the Almond-West formalism [D. P. Almond et al., Solid State Ionics 8, 159 (1983)]. The dc conductivity and the hopping rate of charge carriers, determined from this analysis, show similar dependences on RH, indicating that the concentration of mobile ions is independent of RH and is primarily determined by the chemisorption process of water molecules. Finally, the results are discussed in view of a percolation-type conduction mechanism, where mobile ions are provided by the chemisorbed water molecules and the percolation network is formed by the physisorbed water layers.

Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 micromol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 micromol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.

In the present paper, the ion dynamics and relaxation of fluoride ions in Pb(1-x)Sn(x)F(2) (with x=0.2-0.6) solid solutions, prepared by mechanochemical milling, are studied in the conductivity formalism over wide ranges of frequencies and temperatures. The conductivity spectra of the investigated materials are analyzed by the Almond-West (AW) power-law model. The estimated values of the hopping rates and the dc conductivity of different compositions are thermally activated with almost the same activation energy. The calculated values of the concentration of mobile ions, n(c), are almost independent of temperature and composition for x=0.2-0.4. The maximum value of n(c) is obtained for the x=0.6 sample, although it does not show the maximum conductivity. Therefore, the composition dependence of the ionic conductivity of these solid solutions could be explained based on the extracted parameters. The results presented in the current work indicate that the AW model represents a reasonable approximation of the overall frequency-dependent conductivity behavior of the investigated materials. The conductivity spectra at different temperatures for each composition are successfully scaled to a single master curve, indicating a temperature-independent relaxation mechanism. For different compositions, however, the conductivity spectra cannot be scaled properly, indicating composition-dependent relaxation dynamics.

Superionic material PbSnF 4 prepared by precipitation from aqueous solution was characterized by x-ray diffraction, DTA and 19 F nuclear magnetic resonance (NMR) techniques. The temperature and frequency dependence of the conductivity, the modulus and the dielectric properties were investigated by means of impedance spectroscopy. The Arrhenius plot of the dc conductivity shows a gradual slope change around 355 K from a high-activation-energy (E σ = 30 kJ mol −1 ) region to a low-activation-energy region (E σ = 22 kJ mol −1 ). At lower temperatures the real part of the ac conductivity exhibited a power-law behaviour as found in most ionic conductors. At high temperatures, on the other hand, a low-frequency dispersion of the conductivity was observed due to the space charge polarization, which resulted from the high ionic conductivity. An extremely large dielectric constant was observed with decreasing frequency due to the space charge polarization. A dielectric anomaly was also observed around the phase transition temperature. The modulus formalism was used to estimate the conductivity relaxation times and was compared with those from the line width transition of the 19 F NMR.