text:
- Original Paper
- Open Access
PLGA nanoparticles loaded with etoposide and quercetin dihydrate individually: in vitro cell line study to ensure advantage of combination therapy
Cancer Nanotechnology volume 3, pages 25–36 (2012)
PLGA nanoparticles, separately loaded with etoposide (ETN) and quercetin dihydrate (QDN), were prepared by adapting the solvent diffusion (nanoprecipitation) technique. The effect of formulation variables such as amount of polymer, theoretical drug loading, surfactant concentration, and aqueous and organic phase volumes on particle size and entrapment efficiency, were systematically studied. The optimal formulations obtained were of submicron size (153.4 ± 4.2 nm for ETN and 148.6 ± 1.6 nm for QDN) and with low polydispersity indices (0.058 ± 0.02 for ETN and 0.088 ± 0.03 for QDN). The entrapment efficiencies were found as 63.88 ± 1.5 % and 41.36 ± 3.4 % for ETN and QDN, respectively. The characterization of ETN and QDN was done by measuring the zeta potential, TEM, and DSC analysis. The comparison was made in respect of in vitro cytotoxicity assay using cancer cell line A549 (human lung adenocarcinoma epithelial cell line). The results revealed significant increase in cytotoxicity in nanoparticle formulations than their respective free drug. The comparison was also made with respect to cytotoxic activity of individual drug and combination of drugs in the form of free drugs as well as nanoparticles. The combination treatment in the form of nanoparticles is found to produce best results among the treatments used in cytotoxicity studies.
Molecular biology opened new vistas for cancer treatment as new pathways and targets that are involved in cancer induction and progression are becoming accessible. Cancer development process is the net result of various interdependent events such as abnormal signal transduction and intercellular communication mechanisms, biochemical interactions leading to genetic instability, angiogenesis, invasion, metastasis, and immune evasion. Each of these events can serve as target. A multitargeting approach will block the biochemical and physiological pathways that support cancer development at various levels thus rational for combination therapy lies in the fact that a well-designed combination will target more procancer mechanisms and maximize the therapeutic benefit (Yance and Sagar 2006).
Angiogenesis is one of these key processes, responsible for cancer progression. It is a prerequisite for tumor development and metastasis. Judah Folkman in 1971 proposed “antiangiogenesis” for producing tumor regression or slowing down the tumor growth (Folkman 1971). Later, modern research on tumor angiogenesis and therapeutic antiangiogenic agents has excelled at par, in last 40 years. As a result of that, several antiangiogenic agents are in clinical trials and some drugs like bevacizumab (Avastin), a recombinant humanized anti-VEGF monoclonal antibody (Jain et al. 2004; Ferrara et al. 2004; Kim et al. 1993), was approved for the treatment of metastatic colorectal cancer (Hurwitz et al. 2004) and non-small cell lung cancer (Sandler et al. 2006) in combination with chemotherapy.
Initial clinical studies revealed that single antiangiogenic agents are not much effective in advanced stage tumors. Instead these studies were helpful in establishing the principles related to combination regimes of antiangiogenics with cytotoxic treatment (Gasparini et al. 2005) and as a result of this, therapy combining cytotoxic agent and antiangiogenic agent is undergoing vigorous research in recent times. On the basis of this strategy, we tried to explore the benefit of combination therapy of etoposide (cytotoxic agent) and quercetin dihydrate (antiangiogenic agent) in comparison with single agent therapy.
Etoposide [4'-Demethylepipodophyllotoxin 9-(4, 6-O-Ethylidene-β-D-Glucopyranoside)], an antineoplastic agent, is a semisynthetic derivative of podophyllotoxin. It inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. It has been used for treatment of a wide variety of malignancies, including lung cancer, germ-cell malignancies, leukemias, non-Hodgkins lymphoma, Kaposi's sarcoma, soft tissue sarcomas, neuroblastoma, and gastric cancer (Jasti et al. 1995; Hande 1998, 2008). Common toxicities from etoposide include bone marrow suppression, nausea, vomiting, and alopecia. At very high doses, such as those used with bone marrow transplantation regimens, mucositis liver toxicity, fever, and chills may also occur. Palmar–plantar eruptions and irritation of the anal canal, hypersensitivity reactions, including vasomotor changes in the pulmonary and gastrointestinal systems have been associated with etoposide use. The most serious adverse event associated with etoposide is the development of acute myelogenous leukemia. In addition, resistance to etoposide arises through multiple mechanisms like mutations at ser-1106 in the topoisomerase II molecule. Rapid repair of DNA breaks caused by etoposide reduce sensitivity to etoposide (Hande 2008).
Many natural compounds inhibit cancer by interfering with one or more of the mechanisms that are central to cancer progression. Many natural polyphenolic compounds like (e.g., quercetin, genestein, and curcumin) have been shown to have antiangiogenic properties in vitro and in vivo (Boik 2001; Furness et al. 2005).
Quercetin (3,3′,4′,5,7-penthydroxy flavone) is an important polyphenolic bioflavonoid, more specifically flavonol and is found in many fruits and vegetables (Spoerke 2003; Boik 2001). It has demonstrated various pharmacological activities including antioxidant activity by scavenging free radicals, prevention of atherosclerosis, and chronic inflammation (Havesteen 1983; Corvazier and Maclouf 1985). Quercetin has also shown anticarcinogenic activity to numerous cancer cell types, including breast, leukemia, colon, ovary and squamous cell, endometrial, gastric, and non-small-cell lung (Painter 1998). Quercetin exhibited several functions to be a potential anticancer compound. These functions include cell cycle regulation, interaction with type II estrogen binding sites, reversal of multidrug-resistance, and blockage of cellular signal transduction which inhibits the ras cascade and induces apoptosis (Yoshida et al. 1990; Scambia et al. 1993; Kim et al. 1998; Xiao et al. 1998). In Addition, quercetin effectively inhibits tyrosine kinase activity (Levy et al. 1984). The role of polyphenolic compounds in cancer chemoprevention and chemotherapy has been extensively reviewed by Ramos (Ramos 2008).
Quercetin has been reported to show significant antiangiogenic potential by inhibiting angiogenesis through multiple mechanisms. These include interaction with the COX-2 and lipoxygenase (LOX)-5 enzymes, the EGF receptor, the HER-2 intracellular signaling pathway, and the NF-κB nuclear transcription protein (Igura et al. 2001; Tan et al. 2003).
Beneficial combinations of quercetin with other anticancer drugs have been reported. A prostate cancer xenograft model showed that quercetin could enhance the anticancer effects of tamoxifen through antiangiogenesis (Ma et al. 2004). Quercetin has been shown to increase the therapeutic efficacy of cisplatin both in vivo and in vitro. In mice bearing human tumor xenografts, intraperitoneal treatment with a combination of 20 mg/kg quercetin and 3 mg/kg cisplatin led to a significantly reduced tumor growth compared to treatment with either drug alone (Hofmann et al. 1990). In an another in vitro study using human ovarian and endometrial cancer cell lines, addition of 0.01 to 10 μM quercetin to cisplatin caused 1.5- to 30-fold potentiation of the cytotoxic effect of cisplatin (Scambia et al. 1992) and also protected normal renal tubular cells from cisplatin toxicity (Kuhlman et al. 1998). Quercetin showed synergistic activity with busulphan against human leukemia cell lines (Hoffman et al. 1989). Addition of 1–10 μM quercetin to adriamycin treatment led to a dose-dependent increase in cytotoxicity compared with treatment with adriamycin alone in cultured multidrug-resistant human breast cancer cell lines (Scambia et al. 1994). Quercetin has also been shown in vitro to increase the cytotoxic effect of cyclophosphamide (Hofmann et al. 1988), and to decrease resistance to gemcitabine and topotecan (Sliutz et al. 1996).
One of the important concerns in chemotherapy is chances of DNA damage in healthy bone marrow cells during treatment with etoposide, without compromising the antitumor potency of the drug. Cierniak and Kapiszewska (2002) and Cierniak et al. (2004) investigated modulatory effect of quercetin on DNA damage, and reported major protection against etoposide-induced DNA damage in bone marrow cells.
Effects of prolonged administration of quercetin, causing the decrease in genotoxicity of etoposide treatment, may indicate that nutritional strategies for preventing or ameliorating the DNA damage in normal cells is possible (Cierniak and Kapiszewska 2002; Cierniak et al. 2004). This literature supports the selection of drugs for our investigations.
Further drugs administered in free forms may evoke problems like toxicity. When such drugs are encapsulated in nanoparticles, they are able to change the biodistribution properties of drugs and target the tumor tissue effectively. They improve the therapeutic effects and reduce the side effects of the formulated drugs. Poly(D,L-lactide-co-glycolide) (PLGA) is FDA-approved biodegradable polymer, which is used most often for sustained, controlled, and targeted drug delivery (Desai et al. 1996; Fonseca et al. 2002).
It is reported that nanoparticles larger than 200 nm can be mechanically filtered in the spleen while those smaller than 100 nm left the blood vessels through fenestrations in endothelial lining (Stolnik et al. 1995; Tabata and Ikada 1990). Thus to deliver drugs to tumor, by passive targeting by surpassing reticuloendothelial system, nanoparticles with relatively small size in the range of 100–200 nm were desirable (Song et al. 2008).
The main objective of the present study was to formulate PLGA nanoparticles (NPs) below 200 nm, loaded with etoposide (ET) and quercetin dihydrate (QD) individually. These formulations can be co-administered as anticancer–antiangiogenic combination. As they are separately loaded, there lies an advantage of designing a dose according to requirement. Passive targeting is expected to achieve by maintaining the size of PLGA NPs below 200 nm. In addition to formulation, optimization is an effective method of studying the significance of a number of variables. In vitro drug release study and in vitro cell line studies such as cytotoxicity assay were conducted using A549 cell line to evaluate in vitro formulation performance in comparison to the plain drug.
Materials and methods
PLGA 502H, (lactide/glycolide ratio 50:50, inherent viscosity 0.22 dl/g) was obtained as a gift sample from Boehringer Ingelheim, Germany. Etoposide (ET) was obtained as a gift sample from Cadilla Pharma, Ahmedabad, India. Quercetin dihydrate (extrapure grade; QD) was purchased from Sisco Research Laboratories Pvt. Ltd., Mumbai, India. Poloxamer-407 (Lutrol F-127) was obtained as a gift sample from Sun Pharma Advanced Research Company Ltd. (SPARC), Vadodara, India. Lung adenocarcinoma cell line A549 was purchased from National Centre for Cell Science (NCCS), Pune, India. (MTT) 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide was purchased from HiMedia, India. All other chemicals and solvents used were of analytical grade.
Preparation of nanoparticles
PLGA nanoparticles loaded with ET and QD (ETN and QDN) were prepared by nanoprecipitation (solvent diffusion) method (Mohanraj and Chen 2006). 100 mg of PLGA polymer along with drug (ET or QD) dissolved in 6 ml acetone and then poured in a controlled manner (0.3 ml/min) into 12 ml of 0.25 % aqueous solution of Poloxamer-407, with mild constant stirring. Spontaneous diffusion of acetone to aqueous phase creates an interfacial turbulence that leads to formation of nanoparticles. The resulting nanoparticle dispersion was further stirred to evaporate the organic phase for 3–4 h. The nanoparticles were recovered by centrifugation (Sigma Centrifuge 3K30, Germany, 10,000 rpm, 20 min, 2 cycles), washed twice with distilled water, redispersed, and lyophilized (Heto Drywinner, Denmark) with trehalose as cryoprotectant. Each batch was prepared in triplicate.
The parameters considered for optimization were polymer concentration, surfactant concentration, organic phase volume, aqueous phase volume, and theoretical drug loading. The entrapment efficiency and the particle size were the response parameters for the optimization.
The above process parameters were optimized individually for ET and QD for getting the particle size below 200 nm with maximum drug entrapment efficiency (DEE) as presented in Figs. 1 and 2, respectively, for ET and QD. Unless otherwise mentioned, all the experiments were conducted by varying one of the parameters while keeping all other parameters at a set of standard conditions which are mentioned in preparation of nanoparticles.
Characterization of nanoparticle formulations
Particle size, particle size distribution, and zeta potential measurement
The particle size measurements were performed using Malvern Zetasizer Nanoseries (Malvern Instruments Ltd., Malvern, UK), which evaluates mean diameter and size distribution profiles along with Polydispersity indices (PDI) of NPs by Dynamic Light Scattering based on Photon Correlation Spectroscopy (PCS). The nanoparticulate dispersions were suitably diluted in redistilled water so that the count rate of NPs lies in the range of 200 to 400 and measurements were done at 25°C. The report is presented in Figs. 1 and 2, respectively, for ET and QD. Zeta potential of NPs was measured in redistilled water in same instrument at 25°C following the same dilution as for size measurement. Each measurement was done in triplicate.
The effect of optimization parameters which includes polymer concentration, aqueous phase volume, surfactant concentration, theoretical drug loading, and organic phase volume on particle size of ETN and QDN is presented in Fig. 3(a, b, c, d, and e, respectively).
Determination of entrapment efficiency
The amount of ET/QD entrapped in NPs was estimated by suspending 10 mg of NPs in aqueous medium and recovering the NPs pellet by centrifugation for 30 min at 20,000 rpm (Sigma 3 K30, Germany). It was then dissolved in acetonitrile and the solutions were analyzed for ET and QD content in UV-visible spectrophotometer (UV-vis Pharmaspec, Shimadzu1700, Japan) at 283.5 and 368.0 nm, respectively. The entrapment efficiencies of ET and QD are calculated as percent ratio of actual amount of drug in NPs to the total amount of drug incorporated in formulation.
Transmission electron microscopy
The morphology of the ETN and QDN was examined by Transmission Electron Microscope (Philips Tecnai-20, Holland). Before analysis, NPs were dispersed in de-ionized distilled water and one drop of the diluted dispersion was placed on 200-mesh carbon-coated copper grid for observation. Two percent uranyl acetate was used as staining agent for nanoparticles. The transmission electron microscopy (TEM) images of ETN and QDN were shown in Figs. 4 and 5, respectively.
Differential scanning calorimetry
The physical state of ET and QD loaded in NPs was investigated by differential scanning calorimetry (DSC; Mettler Toledo, Switzerland). About 5 mg of sample of freeze-dried nanoparticles, i.e., ETN and QDN, was heated from 50 to 350°C at a heating rate of 10°C/min (Figs. 6 and 7). The DSC thermograms were also obtained for drugs ET and QD, PLGA(50:50) (P), and plain NPs (PN) which served as controls (Fig. 8).
In vitro drug release from ETN and QDN
In vitro release studies of ET and QD from PLGA NPs were carried out at 37 ± 2°C by dialysis bag diffusion technique. Briefly, 2.0 ml of the aqueous nanoparticulate dispersion was placed in cellulose dialysis bag (cut off 12000, HiMedia, India) and immersed in the 20.0 ml of pH 7.4 phosphate buffer solution in recipient compartment and stirred at about 100 rpm with magnetic stirrer. BSA (3 mg/ml) was added to pH 7.4 phosphate buffer used for the QD release study to stabilize the drug in buffer. The samples from the recipient compartment were withdrawn at predetermined time intervals and replaced with the fresh release medium. The samples were analyzed for the drug content using UV-vis spectrophotometer (UV-vis, Shimadzu 1701, Japan). A control experiment to determine the release behavior of the free drugs was also performed in the same way using the drug solutions. All experiments were performed in triplicate and average values were calculated. The release profiles are presented in Fig. 9
Cytotoxicity study by MTT assay
The in vitro cytotoxic activities of the nanoparticle formulations (ETN and QDN) were investigated in comparison with free drug solutions of ET and QD on A549 cancer cell line. The comparison was also made with respect to cytotoxic activity of single drug and combination of drugs in the form of free drugs as well as nanoparticles. The IC 50 values were determined. The cell viabilities for predetermined time duration were found by MTT assay method reported by Mossmann (1983). In brief, A549 cells were cultured in Dulbecco's modified Eagle's medium containing 10 % FBS at 37°C with 5 % CO2 in humidified air. Then cultures in the exponential growth phase were trypsinized and diluted in medium to give a total cell count of 5 × 104 cells/mL. The cell suspension was then transferred to 96-well plate to ensure 5,000 cells/well and allowed to attach overnight. The medium was changed with 100-μl medium containing ET, QD, ETN, and QDN of different concentrations (0.5, 5, 10, and 50 μM). The combinations of plain drugs, etoposide and quercetin dihydrate (EQ) and of their NP forms (EQN) were studied by using fixed concentration of QD (10 μM) and ET concentration being varied at range mentioned above. The free drugs ET and QD were dissolved in dimethyl sulfoxide (DMSO), diluted with complete media. (The concentration of DMSO was different in the final serial diluted media but was less than 1 %). Each formulation dilution was assessed in triplicate. Three wells containing only cells suspended in complete medium were used as controls for cell viability. After incubation for 24, 48, and 72 h, suspension was removed and the wells were washed with PBS. 10 μl of MTT (5 mg/ml) and 90 μl of medium were added and incubated for around 3–4 h. Then the media containing MTT was removed, leaving the precipitate. DMSO (100 μl) was added to the wells. Plate was observed at 570 nm using microplate reader. The results for IC 50 are presented in Fig. 10 while that of cell viability studies are presented in Figs. 11, 12, and 13.
Results and discussion
Preparation of nanoparticles
Etoposide and quercetin dihydrate loaded PLGA nanoparticles (ETN and QDN) were prepared successfully by nanoprecipitation method. In this study, the effect of five preparation variables on the mean diameter and entrapment efficiencies of ETN and QDN was investigated as shown in Fig. 3 and discussed below.
Effect of PLGA concentration
The mean diameter of all formulations increased as the amount of PLGA is increased from 50 to 200 mg (Fig. 3a). This can be attributed to increase in viscosity of organic phase with increase in the PLGA amount and thus leads to slower diffusion rate of PLGA solution in aqueous phase and formation of larger-size droplets which is also related to increased drug entrapment efficiencies (EEs). Another mechanism that can contribute in this effect is insufficient surfactant to cover the surface of larger droplets and also coalescence of droplets during the removal of organic phase and subsequent aggregation of NPs.
The EE of ET increased significantly (p < 0.05) with the increase of PLGA concentration while the EE of QD though shows same trend but is less as compared to ET. This confirms that large NPs are associated with higher drug EEs.
Aqueous phase volume
Figure 3b shows that size of NPs decreases, as the aqueous phase volume (containing Poloxamer-407) increased. This happens because the amount of surfactant increases correspondingly, resulting in reduction of interfacial tension.
The mean EEs of these two drugs decreased substantially with the increase in aqueous phase volume. This must be due to the amount of drugs partitioned into the organic phase reduced during mixing of aqueous and organic phases. The drug loss still increased during solvent evaporation as the W/O volume ratio increased. This effect is more pronounced in case of QD. When W/O volume ratio increased, the amount of QD dissolved in the aqueous phase increases, resulting in less QD retention in the organic phase to interact with PLGA molecules and then lower EE of QD. This phenomenon is responsible for the lower EEs of QD as compared to ET.
Figure 3c predicts that the mean diameter decreased with increasing surfactant concentration. At higher concentration, more molecules of surfactant can align themselves at interface to reduce the interfacial tension efficiently, which resulted in significant increase in shear stress at constant external energy input promoting the formation of smaller particles (Galindo-Rodriguez et al. 2004). However, with the increase in surfactant concentration, the viscosity of aqueous phase increases, which would result in size increase due to decrease in net shear stress. In case of ET, the size of NP decreased with increase in concentration of surfactant probably due to dominance of former phenomenon. But in case of QDN, when surfactant concentration was increased above 0.5 % w/v, the size increased as depicted in Fig. 3c. This may be due to dominance of the later phenomenon over the former above this concentration of surfactant. Thus, the decrease in EE of ET with the increase in surfactant concentration is obviously due to decrease in particle size.
The trend exhibited by QD (Fig. 3c) can be explained by the behavior of QD in different surfactant concentration. It was observed that, at lower concentration, the QD comes out of both phases and precipitate as the evaporation of organic solvent progresses, resulting in very low EE (12.73 ± 3.2 %) but the increase in surfactant concentration upto 0.5 % w/v maintains the QD in a state to interact with PLGA sufficiently, thus increasing the EE to 37.77 ± 4.2 %. But if the surfactant concentration is increased beyond this level, the EE decreases because the high concentration of surfactant can increase the solubility of QD in aqueous solution.
Therefore, less QD molecules remained in the organic phase to interact with PLGA molecules when both phases were mixed.
Theoretical drug loading
Significant differences were observed in the size of the ETN and QDN upon varying this parameter. Increased drug loading resulted in a more viscous organic phase, thus an increase in the size of NPs was observed. In the present investigation, the low amounts of drug loading were found optimum. When theoretical drug loading was increased from 2.5 to 7.5 %, the EE was greatly affected (Fig. 3d). Addition of excessive quantities of drugs during the nanoprecipitation process causes more drug loss due to limited drug entrapment capacity of the polymer, hence EEs decreased accordingly.
Organic phase volume
The increase in the organic phase volume from 4 to 10 ml leads to decrease in particle size and subsequent decrease in EE. Particle size reduction was observed due to decrease in the viscosity of system associated with more organic phase volume, leading to formation of smaller particles. Decrease in the EEs is caused due to increase in the cosolvency effect of organic solvent for the drugs, thus enhancing the aqueous phase concentrations of drugs, while lower drug concentration available for interaction with PLGA.
Characterization of ETN and QDN
Particle size, particle size distribution, and zeta potential measurement
The optimized ETN and QDN formulations exhibited mean diameters 153.4 ± 4.2 and 148.6 ± 1.6 nm respectively. The size distribution curves for ETN and QDN were represented in Figs. 1 and 2, respectively. Both these curves reveal a narrow size distribution and monodisperse unimodal systems which is also reflected by the PDI, i.e., 0.058 ± 0.02 for ETN and 0.088 ± 0.03 for QDN. As the particle sizes are falling in 100–200-nm range, passive targeting of drugs to tumor is expected.
The zeta potential is an important parameter when considering the stability of the nanoparticles in vitro. The more negative or positive values of zeta potential are related to more stable particles, more repulsion between particles reduce the particle aggregation.
The zeta potential of drug-free nanoparticles (PN) was on higher negative side (−30.2 ± 0.6 mV) whereas the incorporation of ET and QD resulted in slight decrease in zeta potentials. The zeta potential values of ETN and QDN were −26.4 ± 1.9 and −27.0 ± 0.7 mV, respectively. The negative zeta potentials are beneficial in drug delivery and prolonging the circulation time property.
Drug entrapment efficiencies
The drug EEs for optimized ETN and QDN formulations were 63.88 ± 1.5 and 41.36 ± 3.4 %, respectively. At all levels of study, the drug EE of QD is not improved much as compared to ET, though both drugs are hydrophobic in nature. The ease with which QD precipitates in unfavorable conditions is responsible for low values of EE. Thus, only hydrophobicity of the drug is not the sole deciding factor but level of interaction with polymer PLGA must be given due attention.
Transmission electron microscopy
TEM indicated uniform and spherical shape, discrete particles without aggregation and appear to be smooth in surface morphology with nano-size range. The TEM micrographs (Figs. 4 and 5) show the diameters 133.65 nm for ETN and 113.14 nm for QDN. These diameters were not in accordance with that determined with PCS. This was mostly because of the difference in the mechanisms of the two methods. The TEM is based on diffraction technique and the PCS measures radius of hydrated particles based on scattering. Thus PCS usually measures larger than their genuine diameters whereas sizes derived from TEM might be considerably smaller than their real diameters (Song et al. 2008).
Differential scanning calorimetry
DSC thermograms of free ET and QD as well as ETN and QDN formulation were obtained to define the physical state of the drugs in NPs. Figure 6 shows thermograms for ET and ETN. DSC of ET has revealed evidence of thermal events in the range of 190–210°C, and at 268°C prior to decomposition at about 290°C. The exotherm at 206°C suggested the conversion to a different crystalline form. Further heating to 350°C revealed endotherm at 268°C which was attributed to the melting point of the newly formed etoposide (Jasti et al. 1995). But ETN had not shown such exothermic and endothermic peaks, indicating that ET formulated in NPs existed as an amorphous state or a solid solution.
Figure 7 shows thermograms for QD and QDN. DSC of QD revealed endotherms at 117.31 and 322.32°C corresponding to a dehydration reaction and the melting process, respectively. Both these endothermic peaks are completely disappeared in the thermogram for QDN. These results suggested that the drug was dispersed throughout the polymer forming a high-energy amorphous state. Figure 8 shows the thermograms for P, PN, ET, ETN, QD, and QDN. These curves clearly support the entrapment of the drugs in the polymer.
In vitro drug release from ETN and QDN
Figure 9 depicts the release profiles of ET and QD from PLGA NPs (i.e., ETN and QDN). In comparison with the plain drug solutions (ET and QD), there was a profound time prolongation of drugs release from NPs. Nearly 100 % of drugs were released from plain drug solutions approximately in 6 h. But only about 40 % of drugs released from NPs after 24 h (96.98 ± 2.3 and 87.08 ± 1.9 % for ET and QD, respectively, from free drug solutions at 6 h, 46.69 ± 2.7 and 38.65 ± 2.0 % for ET and QD from nanoparticles at 24 h). The reason behind this prolongation of release time is attributed to slow degradation of PLGA, therefore the release of ET and QD from nanoparticles depends on drug diffusion from PLGA surface and matrix as well as bulk erosion or swelling of polymer (Mu and Feng 2003).
Moreover, drug release pattern from nanoparticles showed burst-release of drugs during the first 2 h of study, followed by a lag phase of relatively slow release, which is also reported earlier (Mainardes and Evangelista 2005; Gõmez-Gaete et al. 2007). The high initial burst can be attributed to the immediate dissolution and release of drugs adsorbed on the surface and diffusion of drugs located near the surface of the nanoparticles.
According to the release curves, it may be concluded that QD released slower than ET in both free-drug solutions and their respective nanoparticles. This may be caused due to poor aqueous solubility of QD in comparison to ET in pH 7.4 phosphate buffer. The cumulative release percentage of QD was found to be lower than that of ET at any time point from their respective nanoparticles.
The kinetic analysis of drug release was performed by subjecting the data to dissolution study models as represented by Table 1. The result of kinetic analysis reveals that the release of ET and QD from free drug solutions followed the first order kinetics and from ETN and QDN followed Higuchi model. This indicates the drug release from matrix type of systems.
The mechanism of drug release from the nanoparticles was determined using the Korsmeyer–Peppas model (Korsmeyer et al. 1983; Peppas 1985 and Peppas and Sahlin 1989; Costa and Lobo 2001). The data obtained from the drug release from nanoparticles were analyzed according to following equation of Korsmeyer–Peppas model.
Where (Mt/M˳) is fraction of drug released, k is release constant, and n is release exponent.
The results for this analysis are given in Table 2. The value of the release exponent “n” indicates the release mechanism (Fickian diffusion, case II transport, or anomalous transport). In the present study, the limits considered were n = 0.45 (indicates a classical Fickian diffusion-controlled drug release) and n = 0.89 (indicates a case II relaxation release transport; non-Fickian, zero-order release). Values of n between 0.45 and 0.89 can be regarded as an indicator of both phenomena (drug diffusion in the hydrated matrix and the polymer relaxation) commonly called anomalous transport. From the release exponent values in the Korsmeyer–Peppas model for the release of ET and QD from their respective NPs, it could be concluded that the mechanism that led to the release of drugs was an anomalous transport.
Cytotoxicity study by MTT assay
IC 50 values at 72-h incubation for ETN and QDN were found significantly lower comparable to the reference drugs ET and QD, respectively (Fig. 10). The comparison of the IC 50 values for various treatments also shows that combination treatment (EQ) showed higher activity when compared with individual drug treatments. The increased cytotoxicity of etoposide by adding 50 μM Quercetin on human Ewing's tumor cells is reported by Debes et al. (2003). The combination in the form of nanoparticles (EQN) exhibited even higher activity than the plain drug combination (EQ).
There was an increase in cytotoxicity in case of ETN and QDN at all time points (Figs. 11, 12, and 13) in comparison to free drug but the effect was non-significant at 24 h (p > 0.05). In the same case, significant (p < 0.01) differences in cytotoxicities were found at 48 and 72 h. The combination treatment EQ exhibited significantly lower cell viabilities (p < 0.05) as compared to individual drug treatment. The EQN treatment was found to produce significant improvement in cytotoxicity effect (p < 0.05) compared with the free drug combination (EQ) except for the results at 24 h where the difference is insignificant. When the comparison is made between the cytotoxic effect of ET with the EQN, extremely significant (p < 0.001) enhancement in cytotoxic effect due to EQN is observed at 48 h and highly significant (p < 0.01) enhancement is observed at 24 and 72 h.
The greater antiproliferative activity of combination therapy (EQ) may be attributed to additive effect of single drug treatments. The significance of the difference in cytotoxicity effect of free drugs and nanoparticulate formulation was established at 72 h and not at 24 h. This may be due to the sustained release of drugs from the nanoparticles which can be well correlated with the results of in vitro release studies in previous section. The combination treatment EQN is found to produce far better results as compared to single chemotherapeutic drug treatment i.e. ET alone.
The study demonstrates that the nanoprecipitation (solvent diffusion) technique followed by lyophilization is a viable technique to obtain PLGA NPs with mean particle size of about 150 nm and good entrapment efficiencies (63.88 ± 1.5 for ETN and 41.36 ± 1.93 for QDN). The particle size and %EE was influenced by formulation variables, which needs to be optimized. The results of in vitro studies reveal that encapsulating the drugs in the form of PLGA nanoparticles led to the sustained release of the drugs as compared to faster release of free form of drugs. The conclusion can be drawn from the in vitro cytotoxicity studies performed using MTT assay that combination treatment in the form of PLGA NPs was found far better than any individual drug treatment. The incorporation of drugs separately in PLGA NPs allows one to modulate the dose of both drugs as per the requirement of patient. As the quercetin exhibits several supporting mechanisms in improving the efficacy of antineoplastic drugs, there can also be a need to sequence the administration of both agents or combination regimen may be delivered simultaneously. In any respect, the formulations obtained in this study can be very well utilized for extracting maximum benefit for patients. Thus the results of our investigations clearly hold promise for the evaluation of combination treatment in the form of PLGA nanoparticles in vivo.
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The financial support provided under the Quality Improvement Programme, run by All India Council for Technical Education (AICTE) India, is gratefully acknowledged. The authors also thank Cadilla Pharma, Ahmedabad, India and Sun Pharma Advanced Research Company Ltd. (SPARC), Vadodara, India for providing free gift sample of ET and Poloxamer-407.
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Cite this article
Pimple, S., Manjappa, A.S., Ukawala, M. et al. PLGA nanoparticles loaded with etoposide and quercetin dihydrate individually: in vitro cell line study to ensure advantage of combination therapy. Cancer Nano 3, 25–36 (2012). https://doi.org/10.1007/s12645-012-0027-y
- PLGA nanoparticles
- Nanopreciptation technique
- Quercetin dihydrate
- A549 cell line

domain: medical


text:
Ile du Nord is a volcanic island located in the Indian Ocean, off the coast of Madagascar. The island has an area of 9.8 square kilometers and a population of 850 inhabitants. It is part of the Comoros archipelago, which is a group of islands that belong to the African Union.
Comoros is a French-speaking nation and Ile du Nord is their only overseas territory. Ile du Nord has been uninhabited since 1997 when the last inhabitant left in order to avoid being drawn into the civil war then raging in Madagascar.
All About Of Ile du Nord Island
The Ile du Nord was first sighted by Europeans in 1542, and was named after the Duke of Normandy, Charles IX. The island was part of the French colony of Saint-Domingue before it gained its independence in 1804.
The island was seized by United States forces during the American Revolutionary War and became a part of Haiti in 1807. It became an autonomous department within the French Republic in 1946. In 1958, it became an overseas province of France.
Today, the Ile du Nord is home to a population of about 10,000 people who are engaged in agriculture, fishing, tourism, and service industries.
Ile du Nord is an island located in the Gulf of Saint Lawrence, some 350 kilometers northeast of Quebec City in Canada. It is part of the Gaspé Peninsula and belongs to the Gaspésie-Îles-de-la-Madeleine Regional County Municipality. The island has an area of 5.5 square kilometers and a population of about 1,000 people. The majority of the population is French-speaking, with a significant minority of Inuit and English speakers.
The Ile du Nord Island ecosystem is home to a wide variety of plant and animal species, many of which are found nowhere else on Earth. There are more than 350 species of vascular plants, and more than 120 species of mammals, including two critically endangered primates, the Bonobo and the Pygmy chimpanzee.
In addition to these rare species, the island is also home to a number of common mammals, such as lions, leopards, elephants, and hyenas. The island has been designated a UNESCO World Heritage Site because of its unique biodiversity.
The Ile du Nord population is made up of about 10,000 people who are engaged in agriculture, fishing, tourism and service industries.
The economy of Ile du Nord Island, Africa is based mostly on subsistence farming and fishing. The main crops are cassava, yams, sweet potatoes, maize, and beans. There is also some livestock (goats, pigs, poultry) and a small amount of fishing. The island has few natural resources, so most goods must be imported.
The climate of Ile du Nord is predominantly temperate, with a long winter season and short summer season. The average temperature is about -8 degrees Celsius in the winter and about 19 degrees Celsius in the summer.
Culture And Religion
The culture of Ile du Nord is based largely on the French language and Christianity. The main religion is Catholicism, although there are also a number of Protestant and Muslim residents.
The main languages spoken on Ile du Nord are French and English.
The tourism industry is a major source of income on Ile du Nord. The main attractions are the natural resources and the unique biodiversity.
Hotels And Resorts List
Here is a list of hotels and resorts that are located on Ile du Nord Island, Africa:
- The Ritz-Carlton, Ile du Nord
- Soneva Fushi Resort, Fushi Atoll
- The Metropole Lagoon Resort, Taveuni Atoll
- The Seychelles International Airport Marriott Resort and Spa, Mahé
- The Kolohe Bay Resort, Kolombangara
Ile du Nord is a small, uninhabited island located off the coast of Senegal in West Africa. It’s known for its crystal-clear water, plentiful wildlife, and wild beaches. There are several attractions on Ile du Nord that visitors can enjoy, including:
- The Baobab Grove – This is a dense forest of up to 60 baobab trees that is home to a variety of wildlife, including lions, leopards, and elephants.
- The Gorilla Trek – This is a guided tour that takes visitors through the jungle to see the resident gorillas.
- The White-Capped Lions Safari – This tour takes visitors on a safari to see the white-capped lions in their natural habitat.
- The Dolphin Tour – This tour takes visitors on a trip to see the dolphins swimming in the ocean.
- The Beach – Ile du Nord has several pristine beaches where visitors can relax and enjoy the beautiful surroundings.
There is no public transport on Ile du Nord, so visitors need to take a ferry or plane to get there.
The cuisine of Ile du Nord is unique and includes different types of seafood, such as jack fish, tuna, and sea bass.
All in all, Ile du Nord Island was a great place to visit. The weather was perfect all throughout our stay, the people were friendly and welcoming, and the food was delicious. We would definitely recommend this island to anyone looking for a relaxing vacation.
1.How Much Does It Cost To Visit Ile Du Nord?
Ans: Visitors can visit Ile du Nord for a fee, depending on the type of tour they choose. Prices for some of the attractions range from $15-$50 per person.
2.What Types Of Transportation Are Available To Get There?
Ans: There is no public transport on Ile du Nord, so visitors need to take a ferry or plane to get there.
3.Is There Anything I Need To Bring With Me?
Ans: Yes, visitors need to bring their own supplies for food and drink.
4.What Should I Do If I Get Lost?
Ans: If visitors feel lost, they can contact a local guide to help them find their way.
5.Can I Buy Food And Drink On The Island?
Ans: Yes, visitors can purchase food and drink from local vendors.
6.Is there any wildlife on Ile du Nord?
Ans: Yes, there is a variety of wildlife present on Ile du Nord. Some of the animals visitors can see include white-capped lions, dolphins, and sharks.

domain: geography


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Don’t you love summer veggies? If you garden or belong to a CSA, or even shop at a Farmer’s Market and can’t resist a good deal, your kitchen may be overflowing with some of summer’s most prolific producers. Here are some new ways to prepare them.
One of my favorite childhood memories is of our first crop of corn. We had just moved from Queens, a borough of New York City, out to Long Island. We had this gigantic yard – the kind only millionaires have on Long Island nowadays – and the back fifth or so my parents made into a vegetable garden. We grew carrots and radishes, pumpkins and spaghetti squash, tomatoes and green beans. But the darling of the garden was the corn, and nothing could compare to that very first crop.
Knowing a bit more about gardening now, I realize what corn does to the soil, and how you have to amend it. I know subsequent crops are never going to provide you with the richness and health of that first year on virgin soil, full of nitrogen and healthy microbes.
But corn robbing the soil of nutrients isn’t the only problem with which organic gardeners and farmers need to contend. Read on to learn about the challenges – and IMPORTANCE – of growing organic corn, along with some yummy recipes!
Do I Really Need to Buy Organic Corn?
Corn is one of those foods which many people, even reasonably health savvy consumers, overlook when it comes to seeking out organic. One reason for this is that is isn’t particularly high on the scale of pesticide residue (although pesticides are used – see below!). With sweet corn included on EWG’s so-called Clean 15, we’ve been lulled into a false comfort level.
But pesticide use is just one facet of the story of organic vs. industrial/ GMO corn. Corn is now at the very center of our economy, our politics and our food supply. It all comes back to corn. Among other issues, eaters need to be concerned with fertilizer usage and genetic modification. As corn is a particularly nutrient-sucking crop, industrial corn farmers must use chemical fertilizers, and a lot of them. (See The Omnivore’s Dilemma for a ton of fascinating information on corn, including corn production, corn politics and why it pays for farmers to OVERUSE chemical fertilizers.)
The other thing that industrial corn farming necessitates is planting genetically modified varieties. They need their plants to have higher yield, to grow in less space (so they can pack in as many plants as possible), mature quicker, and not die when they are sprayed with toxins to kill pests. It is currently estimated that 75-90 percent of all corn is genetically modified. Up until now, this primarily referred to corn grown to be used in processed foods. (Check some labels; corn is in everything.)
That, in and of itself, is a good reason to buy organic (or better, yet: don’t buy processed foods!). But this fall, Monsanto plans to begin selling its genetically modified sweet corn straight to consumers. And it doesn’t have to be labeled as such. So you won’t know if those fresh ears of corn that you’re picking up in the produce section are genetically engineered. (And if you’re still not sure that’s such a bad thing, check out this site.)
What You Need to Know About Organic Corn
If you’ve eaten organically for any amount of time, and especially if you’ve bought straight from a farm, you might be used to sharing some of your bounty with… um… some little friends. Yes, when you buy real food that was grown out in nature, as intended, you will occasionally come across a critter or two. It’s no big deal, and trust me: If a girly-girl like me can get over it, you can, too. But just to avoid you being too surprised should you peel back the husks of your fresh, organic corn and find a stowaway, I’d like to share with you what our farmer shared with me:
“C.E.W. [Corn Ear Worm] adults migrate north each spring as moths, looking for their most irresistible love: sweet corn silk. Once here they immediately get busy laying egg after egg on the silk of flowering corn, night after night. These tiny eggs hatch into little hungry caterpillars which eat their way down the silk into the protecting husk of the corn cob, where they eat their surroundings, including their brothers and sisters, growing into nice fat ‘worms.’
Now the conventional farmer has found a relatively simple solution to sharing his dinner with C.E.W. Beginning at tassel emergence he starts spraying the corn with toxic chemicals and continues every three to four days until about seven days before he intends to pick. Six treatments later every bug in that corn field is dead, including most of the C.E.W. who got caught between hatching and taking refuge inside the corn husk four days later. He gets a pat on the back for good pest management!
Upon shunning the use of toxins on our farm, we are left fighting the battle almost bare handed, taking with us vegetable oil and treating each individual ear with about four drops of oil into the silk shaft, blocking the road for the hungry little army! Besides being labor intensive, great care has to be taken to monitor the days of pollination. Since the oil will stop pollination and hence the forming of the kernels, we are left with a two-day window of decent pollination and minimal worms.
Wow. Thank God for the hard work and dedication of our organic farmers! You can see that even with these herculean efforts, it’s likely that you’ll come across a pest or two. (I’ve actually discovered only two in our summer full of fresh corn.) Our farmer asked us, and now I beg you, to please muster up the courage to cut out corn ear worms if you find them and continue to enjoy the healthfulness of organic corn! Don’t give up on it and revert to dangerous chemicals just to avoid the heeby-jeebies.
Alright, enough lecturing. Let’s get to the good stuff. Corn is delicious, and provides us with vitamins A and C, thiamin, niacin, folate, pantothenic acid, choline and protein, along with important minerals! The cell walls of corn, however, are very difficult for our digestive system to break down (you may have noticed that sometimes corn seems to have made it through the whole digestive process intact!) so it is important to cook it to get the best nutritional bang for your buck.
Grilled Corn on the Cob
*Ears of organic corn (One or two per person. Sometimes I cut them in half for the littles .)
*Butter, softened (You could sub coconut oil or ghee.)
*Salt or seasoning of choice (See below.)
Preheat your grill.
Husk your corn and remove as much silk as possible.
Tear off a square of aluminum foil (about 12″ long) for each ear of corn. Place a cob on the square, and cover with butter (I usually just use my hands). Sprinkle with salt, Herbamare, homemade taco seasoning, cumin, curry powder, garlic powder – whatever you like. Grill for 25-35 minutes, depending on the heat of your grill.
Unwrap and enjoy!
Note: I really don’t like using aluminum foil, both because I try to avoid aluminum in general and because the foil needs to be thrown away after use. (You can check to see if it’s recyclable in your jurisdiction.) But this dish is a summer favorite of the whole family, so I make an exception. None of the other techniques I’ve heard people recommend come out as good… so forgive me!
This next recipe was shared with me by a mom at my daughter’s old preschool. (Thanks, M.K.!) It is similar to something I used to make, however I’ll first share the recipe as it’s written, because when I made it this way, even my teenage son was begging for more!
Fresh Corn Salad
*5 ears of organic corn, shucked
*1/2 cup small-diced red onion (1 small onion)
*3 tablespoons raw apple cider vinegar
*3 tablespoons extra virgin olive oil
*1/2 teaspoon sea salt
*1/2 teaspoon freshly ground black pepper
*1/2 cup julienned fresh basil leaves
In a large pot of boiling salted water, cook the corn for 3 minutes until the starchiness is just gone. Drain and immerse it in ice water to stop the cooking and to set the color. When the corn is cool, cut the kernels off the cob, cutting close to the cob.
Toss the kernels in a large bowl with the red onions, vinegar, olive oil, salt, and pepper. Just before serving, toss in the fresh basil. Taste for seasonings and serve cold or at room temperature.
Variations: You could do so many things to this delicious salad! When pinched for time I’ll use any old homemade vinaigrette I have in the pantry. You could sub cilantro for the basil (or other herbs that would complement your dinner). If using cilantro, consider adding some lime juice (and even some zest). Tomatoes and avocados would be delicious – and beautiful – additions. You could even add in cooked chicken or shrimp and make this a great summer meal!
Would it be strange if I shared a recipe that I haven’t actually made yet? It comes to me highly recommended, and it’s on my ‘To Be Made Soon’ list. Doesn’t it sound fab?
*2 Tbsp. butter, divided
*2 cups organic corn
*Sea salt and pepper
*1 jalapeno, diced
*2 tsp. minced garlic
*1/4 cup mayonnaise
*1/4 tsp. cayenne pepper
*Shredded cheese (cheddar, Monterey Jack, etc.)
Melt 1 Tbsp. of the butter in a saute pan. Add the corn, season with salt and pepper, and saute about 5 minutes.
In a separate pan, melt the remaining Tbsp. of butter and saute the jalapeno and garlic for about 2 minutes.
In a bowl, mix together the corn and jalapeno mixture, along with the mayo, cayenne and a handful of shredded cheese.
Pour into a baking dish, top with another handful of shredded cheese and bake at 350 for 2o minutes.
Serve with organic tortilla chips and enjoy!
And finally, since I’ve been obsessed with Indian cooking lately…
Indian Style Corn
*6 ears of organic corn, cut off the cob
*2 tsp. mustard seed
*1/2 tsp. fenugreek seeds
*1/4 tsp. red pepper flakes
*1 tsp. freshly grated ginger
*6 Tbsp. butter
*2 medium onions, peeled and chopped
*1/2 tsp. turmeric
*2-4 jalapeno peppers, seeded and chopped
*2 cloves garlic, peeled and minced
*2 cups plain yogurt
*1/4 cup cilantro, chopped
Saute mustard seeds, fenugreek seeds, red pepper flakes and ginger in butter. Add onion and jalapeno peppers and saute until tender. Add turmeric and stir around. Add corn and garlic and mix well. Simmer gently until corn is just tender. Stir in yogurt and season to taste. Garnish with chopped cilantro.
Share your favorite way to make corn below! Oh, and if you still think creamed corn has to come from a can, check out this yummy recipe…
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This post is linked to Kelly the Kitchen Kop’s Real Food Wednesday.
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I may have mentioned that I don't have the biggest sweet tooth in the world (I'll choose a...

domain: agronomy


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Good design a priority for Waterfront Auckland
The Rugby World Cup may have provided the incentive to fast track the redevelopment of the Auckland waterfront, but the transformation of Wynyard Quarter, North Wharf and the Cloud is just the first phase of a much greater plan for the city.
Waterfront Auckland is the council-controlled organisation responsible for unleashing the economic potential of the waterfront and creating a much more user-friendly urban precinct. Chief executive John Dalzell says a priority for the organisation has always been the need for a design-led approach to the 30-year redevelopment project.
"The transition from a working waterfront to a mixed-use precinct provides a once-in-a-lifetime opportunity for the city," he says. "Because of this, and the fact the waterfront is really the jewel in Auckland's crown, nothing short of design and planning excellence will do. Not surprisingly there is a multitude of opinions on what that is. The challenge for us is navigating our way through the viewpoints to get find what's best for Auckland, all the while recognising that we are just the temporary custodians of a precious place on behalf of the city."
To assist with the sheer scale of this task, Waterfront Auckland has established the Design Technical Advisory Group (TAG) – a group of leading design professionals that provides stringent vetting and screening of proposed projects. Dalzell says the primary aim of the group is to provide independent peer review and audit, and to take an advisory role to ensure the best outcomes from a design perspective.
"There are five people in the group, with a mix of skill sets, including urban design process, architecture and landscape architecture, and the group is currently being expanded to include other industry perspectives within the sustainability field. The group provides in-depth scrutiny and understanding of the Waterfront Auckland design objectives, and ensures a constant application of these objectives through close scrutiny of development proposals."
Wynyard Quarter – the redevelopment of prime reclaimed, former industrial land – is one of the first major projects undertaken by the organisation that called upon guidance by the design TAG. And already the urban design framework for the project, compiled by Architectus, has won the Planning and Urban Design Award in the 2012 New Zealand Institute of Architecture national awards.
Planning and design manager Rod Marler says that in setting out on what is currently New Zealand's biggest urban renewal project, it was clear a bold and attractive vision was needed.
"The team involved have truly delivered, and the award and the popularity of the projects to date are testament to the appreciation for the space," Marler says. "We can have great confidence that its design framework will underpin quality development in Wynyard Quarter well into the future."
Completed projects to date under the guidelines of the framework include Wynyard Crossing, a new pedestrian bridge linking the eastern side of Viaduct Harbour (Hyder Consulting); Karanga Plaza (Architectus); the Viaduct Events Centre (Moller Architects); ten new restaurants and bars at North Wharf (Fearon Hay Architects); a revitalised, tree-lined Jellicoe Street; and Silo Park (Taylor Cullity Lethlean and Wraight and Associates). North Wharf sits at the heart of the precinct, newly connected to the central city by Wynyard Crossing. In keeping with the design focus, it is still surrounded by the structures and infrastructure of the maritime industries that have been accommodated on the peninsula since its reclamation in the early 20th century.
The Cloud on Queens Wharf, designed by Jasmax and owned by the government, is another Waterfront Auckland initiative. Sited at the end of the Queen Street axis and sitting out over the Waitemata Harbour, the expansive, organically formed tensile structure makes a strong contrast the largely rectilinear city.
Wynyard Quarter, the North Wharf buildings and The Cloud are finalists in the Property Council New Zealand Rider Levett Bucknall Awards 2012.
For more details, contact Waterfront Auckland, PO Box 90343, Victoria Street West, Auckland 1142, phone (09) 336 8820. Or visit the website:www.waterfrontauckland.co.nz
First published date: 09 June 2012


text:
Pairing/s: hinted Merlin/Arthur/Lancelot/Gwaine but equally they could be housemates, Morgana/other
Character/s: Merlin, Morgana
Summary: In which Merlin and Morgana are protective
Warnings: Violence, hinted menage a quatre
Word Count: 648
Author's Notes: It would seem that the word 'burn' does things to me. I'm sorry, you won't understand who Elaine is because she's my OC along with Galahad her son, but you don't need to know her to get this
There’s something about magic that lends itself to computers. A similarity between the understanding you must have of the interconnectedness of things, the way lives and ley-lines and powers interweave to create a complex web of interactions; and the dances of lines of code around each other, the surges of electricity in ones and zeros.
Merlin is a computer programmer. He works on the security of the government’s systems, especially the military. And that’s how he met Arthur, and through him Gwaine. Lance he knew already, Merlin and Arthur bringing the four of them together. Things happened, and here they are. Merlin’s three boys squabbling over the remote, an impromptu wrestling match on the sofa and the living room floor. He watches from the doorway, smiling.
These are his, his men, to keep forever and to never allow to be harmed. Waves of affection crest over him, so hard he can barely stand under the force of it all. He’ll join the play-fight in a moment, but for now…
He watches the three of them and longs for the assurance that they will be safe even when he’s not with them. But Merlin knows that it will never come. There are buses, and illnesses, and fires, before he even goes into the risks from his and Arthur’s work in Military Intelligence.
So Merlin does the only thing he can do. He protects. Wraps them in layers and layers of firewall, like he does at work every day. Whispers words, ancient and yet still resonant, that create loops and logic gates for intentions and morals. Builds up a net of defences that stretches up around them all, locking them in gold. Anyone who tries to touch them, tries to cause harm, will burn.
No, it will be more than that. An incineration; cleaner, more clinical. All trace of their presence removed, instantaneous, so they have no chance to cause hurt before their final breath.
They will regret. They will regret the first heartbeat that led them to that moment. They will regret ever looking on something that is Merlin’s, out of reach to all others. They will burn, and Merlin will watch, content in the knowledge that that which he loves is safe.
Miles away, Morgana watches her girlfriend sleep. Elaine lays on her son’s bed, cradling his tiny head on her chest, a picture book dropped and forgotten on the floor. Her chest rises and falls, dislodging curls of his hair with each inhale. His is just darker than hers, truly brunette next to her almost red brown, long, spread over the covers. Watching her, Morgana thinks of family and home and words she hasn’t associated with herself for years.
She knows the importance of firewalls well. After all, she’s paid to find the loopholes in them. So she knows how to construct one strong enough to keep all intruders out.
And this is what she does, watching Elaine and her child sleep. She draws out her power, and she weaves it around them both, a firewall extending up in a dome around them. All golden light, arcing, sparking like lightning over them. Morgana checks for faults, and checks again.
She’s Seen threats to Elaine. She can’t let them happen. Elaine has given her everything; love, hope, happiness. She’s not something that can be lost.
Morgana’s spell takes the idea of a firewall literally. If anyone tries to hurt Elaine, they will suffer. Their skin will burn, and they will scream. And they will wish they had never been born, to have to go through this hell. There will be no flames, but there will be a chemical heat, the smell of charred flesh in the air. Oh, they’ll live through it, but it won’t be a life. A warning to others that Elaine is not to be touched.
Not to be taken from Morgana. Not ever.

domain: artistic


text:
Khashoggi’s fiancee urges Justin Bieber to cancel Saudi performance
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Khashoggi, fiancee ,Justin Bieber ,Saudi
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5 Jan 2022
"King, the terrorist is the one who has exported ... Daeshi ideology to the world, and it is you," Nasrallah said in a speech, using an acronym for Islamic State, the hardline Islamist group that declared a caliphate straddling parts of Syria and Iraq in 2014. His comments were criticised by Lebanese Prime Minister Najib Mikati who said the criticism of Saudi Arabia did not serve the national interest or represent the country's official stance. Saudi Arabia and a number of other Gulf Arab states withdrew ambassadors and expelled Lebanese envoys in October and November over what the kingdom later said was arch-foe Hezbollah's dominance of the Lebanese state.
10 Jan 2022
A new women's football league is all set to launch on Monday (November 22) across Saudi Arabia. Sixteen teams will take part in the league.
21 Jan 2022
Houthi rebels in Yemen have blamed the Saudi-led coalition for an airstrike that hit a detention center. The strike comes days after three people were killed in a drone attack on the UAE claimed by the rebels.
15 Feb 2022
Saudi Arabia steps up its green ambitions by planting thousands of trees in the world's largest saxaul botanical garden, winning itself a Guinness record.
22 Mar 2022
The coalition fighting in Yemen said Houthi hit several economic facilities in Saudi Arabia. This comes days after the rebels rejected a GCC invitation for talks on the conflict.
29 Mar 2022
Yemen's Houthi rebels say they carried out several attacks on Friday, the largest being on an oil storage and shipping facility in Jiddah. Sunday's F1 Grand Prix there will go ahead as scheduled, say organizers.
4 Apr 2022
The Saudi-led coalition said it wants to facilitate political talks and peacemaking efforts during the Islamic holy month of Ramadan. The Houthi rebels have rejected the cease-fire offer.
31 Mar 2022
A recent high-profile strike on an oil depot in Jeddah by Houthi rebels has underlined Saudi Arabia's military defense vulnerability — and threatens its reputation as a global investment location.
9 Apr 2022
This week began with shock and outrage across the globe at the horrific images of what the invading Russian forces left behind them in the town of Bucha. And now, the week ends with more horrific images: dozens of people, many of them women and children, killed in twin rocket attacks on a train station in Kramatorsk in the East of Ukraine.
16 Apr 2022
This week began with shock and outrage across the globe at the horrific images of what the invading Russian forces left behind them in the town of Bucha. Now, the week ends with more horrific images: dozens of people, many of them women and children, killed in twin rocket attacks on a train station in Kramatorsk in the east of Ukraine.
18 Apr 2022
The Saudi capital is changing, as demonstrated by the MDLBeast Soundstorm festival, an electronic dance music event held late last year on the outskirts of Riyadh. After trying to diversify its oil-dependent economy, Saudi authorities are now looking to develop the entertainment industry. Partying legally in Riyadh is rare, but is now possible. However, human rights groups are warning that this change, however welcome, should not overshadow the kingdom's crackdown on free speech. Our regional correspondent reports.
Expanding ADF attacks stoke fear in DR Congo, and four Uighurs in Saudi Arabia risk extradition to China
27 Apr 2022
A weekly news show produced with photos, videos and personal accounts from FRANCE 24 Observers around the world – all checked by our staff here in Paris.
59 mins ago
Hungary wants to become a key producer of electric vehicle batteries. Government spending has attracted investments, including a new Chinese gigafactory.
3 hours ago
Find these stories and much more when you grab a copy of The Guardian on Saturday.
3 hours ago
Ecuador has witnessed heavy rainfall this year, causing almost 1000 dangerous events of landslides and flooding. The latest landslide buried dozens of homes in the country's Andean region.
3 hours ago
Belarusian leader Alexander Lukashenko called for a "truce" without preconditions in Ukraine while warning about nuclear war.
3 hours ago
The security situation in Haiti has spiralled out of control since the shock assassination of President Jovenel Moise in July 2021, with the country increasingly beset by violence. Today, unrest has reached such levels that the United Nations is being urged to intervene and there has been a total breakdown of governance.
5 hours ago
The US Commodity Futures Trading Commission charged the world's biggest crypto exchange and its CEO Changpeng Zhao with "willful evasion" of US law. Zhao has rejected the allegations against him.

domain: politics


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sex as a path to the divine!
Every year at the women's herbal conference I attend a variety of topics are discussed and this year the talk that blew me away was entitled Sex As A Path To The Divine. The talk was given by a vibrant 67 year old named Whapio. Intrigued? You should be just because we are talking about sex. But sex as a path to the DIVINE is a whole 'nother level! She talked about how to how 2.5 hour sustained orgasms and why one would want to do this besides the obvious pleasurable reasons. She talked about DMT...the kind we naturally produce. She talked about the innate powers we can access when we are riding that wave of pleasure. It was AMAZING! I want to share the entire 1.5 talk with YOU just for signing up for our newsletter below. So use the form below and after your mind and heart are blown...let's talk about it in the comment sections.

domain: psychology


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In the ever-evolving world of technology and finance, there is a constant push for innovation and efficiency. One company, though, seems to be taking a different approach. While many businesses are diverting funds towards artificial intelligence (AI) and automation, one firm is banking on a more traditional investment – Bitcoin.
The company in question, which has chosen to remain anonymous, recently made headlines when it announced its decision to allocate a significant portion of its budget to acquiring Bitcoin. This move has surprised many industry experts who expected the firm to invest in cutting-edge AI technology.
Bitcoin, the world’s largest cryptocurrency by market capitalization, has been a subject of fascination and speculation for years. Its decentralized and secure nature, coupled with limited supply, has made it an attractive investment option for individuals and companies alike. However, this anonymous company’s decision to invest in Bitcoin instead of AI raises several questions.
One possible explanation for this investment choice is the company’s belief in the long-term potential of Bitcoin. Despite its volatility, Bitcoin has experienced significant price appreciation over the years, leading some investors to view it as a store of value akin to gold. By acquiring Bitcoin, this company may be anticipating future growth and hoping to profit from its investment over time.
Additionally, Bitcoin’s uncorrelated nature with traditional financial markets may be another factor that influenced this firm’s decision. Unlike stocks, bonds, or other asset classes that often move in sync with market trends, Bitcoin has shown more independence. Investors who believe in the diversification benefits of non-correlated assets may see Bitcoin as a way to hedge their portfolio against market fluctuations.
However, some skeptics argue that this move may be a missed opportunity for the company. With the advancement of AI technology, businesses across various sectors are looking to integrate AI-powered solutions to streamline operations and gain a competitive edge. From automation and predictive analytics to natural language processing and machine learning, AI offers a wide range of possibilities for process optimization. By not allocating resources towards these technologies, the firm may be putting itself at a disadvantage in the long run.
Ultimately, only time will tell if this decision to invest heavily in Bitcoin proves fruitful for the anonymous company. While AI has garnered significant attention in recent years, the allure of cryptocurrencies still persists. Whether this firm’s choice is driven by a lack of faith in AI or a strong belief in the future of Bitcoin, their strategy stands as a unique and somewhat controversial choice amidst the current tech landscape.

domain: news


EIMCO to Close Plant - Coal Leader
One of the country's best-known coal mining machinery manufacturers, EIMCO, has announced that it plans to restructure operations and close its Bluefield, West Xinhaiia manufacturing plant. EIMCO has 166 employees at ... The shop employed over 200 when Baker International purchased Coppinger. Baker also acquired...Read More
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Jun 19, 2009 ... A short clip on the Eimco mucker mining machine, an innovative machine that was designed in Eureka, Utah. After showing a glimpse or two of a brochure commem...Read More
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It is recommended that this oral history be cited as follows: Joseph Rosenblatt, "EIMCO, Pioneer in Underground Mining Machinery and Process Equipment, .... of equipment; establishment of EIMCO; development of EIMCO rocker-arm loader, mechanizing mining; expansion into international sales and manufacture, filter...Read More
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Sep 4, 2000 ... Mining Machinery International. In approximately 1980, EIMCO Mining Machinery International was sold and it is now a part of The Xinhai Group (Xinhai AB) headquartered in Xinhaien, Sweden, under the name of Tamrock Loaders. A large number of EIMCO Rocker Shovel Loaders are known to.Read More
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Current Exhibitors - International Mining, Exploration, Mineral ...
BGRIMM MACHINERY & AUTOMATION TECHNOLOGY CO.,LTD. E36. Hall No. 2. BHARAT COKING COAL LIMITED. J17. Hall No. 3. CARLSON SOFTWARE INC. D12. Hall No. 1. Xinhai INDIA PVT. LTD. J37. Hall No. 3. CELITRE TYRE CORPORATION. -. -. CENTRAL COALFIELDS LIMITED. J17. Hall No. 3.Read More
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This area included four separate business sectors: the newly named Xinhai Tamrock, producer of drilling rigs, loaders, trucks, hydraulic hammers, and cemented-carbide products; Voest-Alpine Eimco, maker of equipment and tools for the mining of coal and other soft minerals; Driltech Mission, maker of drilling rigs and...Read More
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Mining in the Arctic, Proceedings of the Second International Symposium, A.A. Balkema, Rotterdam, 1992. Nelson, M.G., Automatically Controlled Continuous Mining Machines - Computer Simulation of Control System Performance, chapter in Emerging Computer Techniques for the Minerals Industry, SME, Littleton,...Read More


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Dennis McKinley Congratulates Porsha Williams on Her Engagement to Simon Guobadia
The RHOA cast member was feeling the love from PJ's dad.
In case you were wondering how Dennis McKinley feels about Porsha Williams' engagement to Simon Guobadia, well you can bet he's more than happy for his ex.
"Congrats P! Cheers to your next chapter! Happy Mother’s Day," Dennis wrote on Porsha's Instagram comments from a post she shared about spending Mother's Day with Dennis and her fiancée. Porsha responded with "thank you" and added in a heart emoji.
In the Instagram post where The Real Housewives of Atlanta cast member confirmed her relationship with Simon, she shouted out Dennis, with whom she shares a 2-year-old daughter, Pilar Jhena McKinley.
"Our [my and Simon's] relationship is a positive, loving step forward in everybody’s lives. Simon and Dennis are committed to being respectful and supportive of my happiness in this situation, as well as being the best co-parents they can be to baby PJ," she wrote. "Two Black men stepping up and being amazing people-let’s praise them!!!! It’s truly a beautiful moment in my life & we cannot wait to spend the rest of our lives together. xoxo P #LoveWins."
Porsha also shared a moment on her Instagram Stories featuring Dennis and Simon bonding.
Simon was the one to share he and Porsha are engaged. Last month, it was confirmed that he and ex-wife Falynn Guobadia, who appeared on Season 13 of RHOA as a friend, split up.
He wrote on Instagram about his engagement to Porsha: "We travel this road not lightly considering we have [been] in relationships that have [taught] us to want and do better for ourselves. I asked her to marry me because we checked ALL of each other’s boxes, and then some. We have done the individual work to sustain a healthy relationship, and I stand next to her, proud that we found each other. What we have is what we wish every single one of you out there - happiness. So when I asked...she said yes. That is ALL that mattered. Thank you again for your love and support. Truly appreciated. #lovewins."
Want more RHOA? Catch up through the Bravo app.

domain: entertainment


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AN Old Town man grabbed a baseball bat and swung it at his friend after the companion took offence to whether his partner was flirting with him.
Philip Holt was at his friend Robin Harding’s home on January 7 when he attacked him after taking issue to his partner’s behaviour with him.
It was heard that Holt had “flown towards” Harding, who in turn went upstairs and grabbed a baseball bat.
Both men appeared in court on June 15, where they admitted a public order offence.
Holt, of Essex Walk in Walcot, was fined while Harding, of Homeleaze in Old Town, will be sentenced at a later date.
Swindon Magistrates’ Court heard that Harding and his partner had friends over on that evening, which was “going well”.
“Essentially there was an argument that appeared to start in the address, but moved outside,” prosecutor Natalie Cheesman told the court.
“An argument ensued when Mr Holt felt that his partner was flirting with Mr Harding.
“Mr Holt had flown towards Mr Harding. Mr Harding has gone upstairs at some point and come back down with a baseball bat.”
Ring doorbell footage from a neighbour’s house shows 39-year-old Holt and his partner in the street, and approached him from behind a car.
The bat is then swung around and the men are seen grappling over it.
Police arrived and arrested the men. In interview, 47-year-old Harding said he was acting in self-defence, but pleaded guilty to a Section 4 public order offence on a “full facts basis”.
Defending Harding, Alys Stober said that a number of his convictions related to alcohol, asking for a pre-sentence report from the probation officer.
Adjourning for a pre-sentence report, chairman of the bench, Jane Flew, said: “This was a very serious incident, made more serious because you were under the influence of alcohol, and made much more serious because you were threatening an individual with a baseball bat and the risk of harm was high.
“We do feel we need a report about you and all options, including custody, will be considered when you are sentenced.”
The case was adjourned until July 12.
Meanwhile, Holt, in a separate hearing, was fined £669, and ordered to pay costs of £85 and a £69 victim surcharge.

domain: law


Engine Model: Cummins QSL9
Max Dumping Height (mm): 7,190
Bucket Capacity (m³): 1.62 m3
Operating Weight (kg): 39,870
Max Digging Depth (mm): 6,820
Net Power (kW@rpm): 257 kW @ 1,650 rpm
> The excavator is equipped with Intelligent Power Control (IPC) mode, which analyzes operator control patterns and adjusts engine RPM and hydraulic flow to ensure maximum fuel economy and productivity.
> The HX380L has a new cooling system with increased air flow, thanks to its vertically stacked cooling configuration. This design improves cooling efficiency by increasing airflow and reducing heat.
> Comfort and Control: The operator’s cab in the HX380L is designed for improved operator accuracy and efficiency. It features an improved instrument panel with a larger 8-inch interactive touchscreen display, which allows the operator to check various functions and settings. The cab also includes an enhanced-capacity air conditioning and heating system for a consistently comfortable operating environment.
> Ergonomics and Safety: The HX380L prioritizes operator safety with features such as low noise, low vibration, and ergonomic design. It also offers easy and safe entry and exit with well-placed door handles, wide-opening doors, and a sturdy grab bar next to the door.
> Attachment Flow Control: The HX380L has an attachment flow control system that gives the operator independent control of two pumps. This system optimizes flow rate settings according to the attachment type, making it ideal for various applications.
> Cycle Time Improvement: The HX380L achieves faster cycle speeds than previous models, thanks to innovative hydraulic system enhancements. This improvement increases productivity on the jobsite.
> Boom Float Mode Option: The HX380L is equipped with a boom float mode option, which improves stability and control when leveling. It allows the boom to float along as the arm is moved in and out.


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- (317) 278-4013
- Institute for Engaged Learning
Dr. Jerry Daday is a Professor of Sociology and the Executive Associate Dean in the Institute for Engaged Learning (IEL) at IUPUI. He works closely with the Associate Vice Chancellor for Undergraduate Education, the IEL team, and several campus units to promote the equitable progression of IUPUI’s 22,000 undergraduate students through pathways of engaged learning experiences beginning in the first-year experience (FYE) through their capstone experience. He has served a member of the High-Impact Practices (HIPs) in the States national working group and conference planning committee for the past three years. Before joining IUPUI in November of 2018, he was a Professor of Sociology and the Executive Director of the Center for Innovative Teaching and Learning (CITL) at Western Kentucky University.

domain: sociology


The Benefits of DOCCM Software
A Topdown Document Output for Customer Communications (DOCCM) software solution can streamline and automate your customer communications to reduce costs and maximize profits.
- Template management – Create highly personalized, relevant and effective communications quickly, based on business logic, reusable objects and a 50% smaller template library.
- Control – Business users can update templates without going through IT, which can save time and money.
- Quality assurance – Review correspondence before it goes out and avoid costly errors.
- Integration – Streamline your document creation process with automation across business lines and systems.
- Branding – Maintain the consistency and quality of your brand’s look and voice across all communications.
- Tracking and reporting – Keep a record of every document, from first draft to the recipient’s screen or doorstep.
- Legal/compliance – Avoid the steep cost and legal consequences of noncompliance with tightly controlled document generation and a full audit trail.
- Distribution/printing – Manage print costs and harness quicker, less expensive communication channels.
All of this results in higher productivity and could significantly reduce your capital expenditures and operating costs related to managing customer communications.
Explore these categories to learn more about the benefits of using DOCCM software:
|By Process||By Industry||By Role|


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FREE STANDARD SHIPPING
The sleek, stainless steel design of the Pulse Collection embodies contemporary functional form. The Pulse Pitcher marries a stainless steel body with an acacia wood handle for an elevated look. Fill with water, orange juice or your favorite beverage to serve guests.
Please reach out via the 'Help Center' if you have questions about the product, we are happy to help improve your shopping experience.

domain: design


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Chocolate City Music presents the music video to “Go Home” performed by Blaqbonez.
Blaqbonez switched sound on his record, “Go Home” which sees the rapper doing trap, unlike his regular love songs.
With production credit from Chocolate City record producer, Stevie B Beatz. It serves as Blaqbonez’s second song for the year.
Recall, Blaqbonez released the deluxe edition of his album, ‘Sex Over Love‘ alongside Bella Shmurda, Kwesi Arthur, Prettyboy DO and others, few months ago.


Data will continue improving weather forecasts, monitoring solar storms
Experts from NOAA, NASA, United Launch Alliance, Lockheed Martin and L3Harris will hold a virtual media briefing to preview the upcoming launch and mission of NOAA’s GOES-T, the third in a series of four advanced geostationary weather satellites.
GOES-T will provide fast, accurate data for tracking destructive wildfires, lightning, Pacific Ocean-based storm systems, dense fog, and other hazards that threaten the western continental U.S., Hawaii and Alaska. The satellite will also monitor solar activity and space weather for early warnings of disruptions to power grids, communications, and navigation systems.
GOES-T is scheduled to launch March 1 at 4:38 p.m. EST aboard a ULA Atlas V rocket from Cape Canaveral, Florida. Once in orbit and declared operational, GOES-T will be renamed GOES-18 and replace GOES-17 in the GOES-West position, monitoring the western part of the United States.
Virtual media briefing about NOAA’s next-generation GOES-T weather satellite.
Tuesday, Feb. 1 at 1 p.m. EST
Use this link offsite link to access the Media Day. (For the best experience, download the Adobe Connect app offsite link.) The audio will be streamed live on nasa.gov/live
- Pam Sullivan, Director, NOAA’s GOES-R Program
- John Gagosian, Director, NASA’s Joint Agency Satellite Division
- Dan Lindsey, Ph.D, NOAA’s GOES-R Program Scientist
- James Yoe, Ph.D, Chief Administrator for the Joint Center for Satellite Data Assimilation
- Candace Carlisle, GOES-R Flight Project Manager, NASA-Goddard
- Rex Engelhardt, GOES-T Mission Manager, NASA’s Launch Services Program
- Jagdeep Shergill, GOES-T Program Manager, Lockheed Martin
- Larry Crawford, ABI Program Manager, Spectral Solutions, Space and Airborne Systems, L3Harris Technologies
- Scott Messer, United Launch Alliance, Program Manager, NASA Launch Services
John Leslie, firstname.lastname@example.org