Toxicological study and efficacy of blank and paclitaxel-loaded lipid nanocapsules after i.v. administration in mice

PURPOSE: Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50 percent lethal dose (LD50) were studied.METHODS: Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg/kg per day for 5 consecutive days in comparison with blank LNCs and saline. Histological examination, complete blood counts and biochemical quantification were performed after a recovery of 7 days. Growth of NCI-H460 subcutaneous xenografts in nude mice receiving one of the aforementioned schedules was assessed. MTD and LD50 were determined by Irwin test. RESULTS: No mortality was observed in repeated injections studies. Histological studies revealed no lesions and no accumulation of lipids. Blood studies were normal. The tumoural growth was significantly reduced in the group treated by paclitaxel-loaded LNCs. The MTDs/LD50s of Taxol, paclitaxel-loaded LNCs and blank LNCs were 12/19.5, 96/216 and above 288/288 mg/kg, respectively. CONCLUSIONS: This study demonstrates that a five-day i.v. injection schedule of paclitaxel-loaded LNC dispersions induces no histological or biochemical abnormalities in mice and improves paclitaxel efficacy and therapeutic index in comparison with Taxol

Development and in vitro evaluation of a novel lipid nanocapsule formulation of etoposide.

Small cell lung cancer (SCLC) is the most aggressive carcinoma in thoracic oncology, unfortunately, despite chemotherapy, relapse is constant. The effect of etoposide, a major drug used against SCLC, can potentially be enhanced after its encapsulation in nanocarriers. The aim of this study was to use the technology of lipid nanocapsules (LNCs) to obtain nanocarriers with drug loadings compatible with clinical use and with an industrial process. Solubility studies with different co-solvent were first performed, then several process were developed to obtain LNCs. LNCs were then characterized (size, zeta potential, and drug loading). The best formulation called Ω-LNCs had a size of 54.1±2.0 nm and a zeta potential of -5.8±3.5 mV and a etoposide drug loading of 5.7±0.3mg/g. The characteristics of this formulation were maintained after freeze drying and after a 15× scale-up. Release studies in a media mimicking plasma composition showed that 40% of the drug was released from the LNCs after 48 h. Moreover the activity of etoposide after encapsulation was enhanced on H209 cells, IC50 was 100 μM and 2.5 μM for etoposide and etoposide LNCs respectively. Unfortunately the formulation failed to be more cytotoxic than etoposide alone on H69AR cells that are resistant to etoposide. This study showed that is was possible to obtain a new etoposide nanocarrier without the use of organic solvent, that the process is suitable for scale-up and freeze drying and finally that etoposide activity is maintained which is very promising for future treatment of SCLC

Complexity Bounds for Ordinal-Based Termination

`What more than its truth do we know if we have a proof of a theorem in a given formal system?' We examine Kreisel's question in the particular context of program termination proofs, with an eye to deriving complexity bounds on program running times. Our main tool for this are length function theorems, which provide complexity bounds on the use of well quasi orders. We illustrate how to prove such theorems in the simple yet until now untreated case of ordinals. We show how to apply this new theorem to derive complexity bounds on programs when they are proven to terminate thanks to a ranking function into some ordinal.Comment: Invited talk at the 8th International Workshop on Reachability Problems (RP 2014, 22-24 September 2014, Oxford

Interacting Ghost Dark Energy in Non-Flat Universe

A new dark energy model called "ghost dark energy" was recently suggested to explain the observed accelerating expansion of the universe. This model originates from the Veneziano ghost of QCD. The dark energy density is proportional to Hubble parameter, $\rho_D=\alpha H$, where $\alpha$ is a constant of order $\Lambda_{\rm QCD}^3$ and $\Lambda_{\rm QCD}\sim 100 MeV$ is QCD mass scale. In this paper, we extend the ghost dark energy model to the universe with spatial curvature in the presence of interaction between dark matter and dark energy. We study cosmological implications of this model in detail. In the absence of interaction the equation of state parameter of ghost dark energy is always $w_D > -1$ and mimics a cosmological constant in the late time, while it is possible to have $w_D < -1$ provided the interaction is taken into account. When $k = 0$, all previous results of ghost dark energy in flat universe are recovered. To check the observational consistency, we use Supernova type Ia (SNIa) Gold sample, shift parameter of Cosmic Microwave Background radiation (CMB) and the Baryonic Acoustic Oscillation peak from Sloan Digital Sky Survey (SDSS). The best fit values of free parameter at $1\sigma$ confidence interval are: $\Omega_m^0= 0.35^{+0.02}_{-0.03}$, $\Omega_D^0=0.75_{-0.04}^{+0.01}$ and $b^2=0.08^{+0.03}_{-0.03}$. Consequently the total energy density of universe at present time in this model at 68% level equates to $\Omega_{\rm tot}^0=1.10^{+0.02}_{-0.05}$.Comment: 19 pages, 9 figures. V2: Added comments, observational consequences, references, figures and major corrections. Accepted for publication in General Relativity and Gravitatio

The adaptation of lipid nanocapsule formulations for blood administration in animals

In many cell-culture and animal models, the therapeutic effects of the entrapped drugs in lipid nanocapsules (LNCs) were preserved with low toxicity. These results allow foreseeing further preclinical efficiency and toxicity studies in animals. In this article, preliminary studies were performed to check the genetically modified organism (GMO) status of the LNCs components and to determine the effects of the acidity of the LNCs dispersions in acid–base balance in rats. Then, several freezing protocols to store paclitaxel-loaded LNCs dispersions for a 6-month period were compared. Results indicate that the Lipoïd® S75-3 could not be certified GMO-free. The same soya bean lecithin certified to be GMO-free permitted to produce LNCs with expected characteristics. The blood administration of blank LNCs dispersions in rats induced no modifications of blood acidity, but a significant decrease of the base excess was observed. Injections of LNCs dispersions in animals might induce iatrogenic acidosis. We finally demonstrated that the best protocol to store LNCs dispersion for a 6-month period is by freezing in liquid nitrogen. This protocol minimized the characteristics modifications and interrupted the drug-release phenomenon. These original data are expected to prepare of LNCs dispersions well adapted for i.v. administration in animals

Nonlinear electrodynamics and CMB polarization

Recently WMAP and BOOMERanG experiments have set stringent constraints on the polarization angle of photons propagating in an expanding universe: $\Delta \alpha = (-2.4 \pm 1.9)^\circ$. The polarization of the Cosmic Microwave Background radiation (CMB) is reviewed in the context of nonlinear electrodynamics (NLED). We compute the polarization angle of photons propagating in a cosmological background with planar symmetry. For this purpose, we use the Pagels-Tomboulis (PT) Lagrangian density describing NLED, which has the form $L\sim (X/\Lambda^4)^{\delta - 1}\; X$, where $X=1/4 F_{\alpha\beta} F^{\alpha \beta}$, and $\delta$ the parameter featuring the non-Maxwellian character of the PT nonlinear description of the electromagnetic interaction. After looking at the polarization components in the plane orthogonal to the ($x$)-direction of propagation of the CMB photons, the polarization angle is defined in terms of the eccentricity of the universe, a geometrical property whose evolution on cosmic time (from the last scattering surface to the present) is constrained by the strength of magnetic fields over extragalactic distances.Comment: 17 pages, 2 figures, minor changes, references adde

Relative drifts and biases between six ozone limb satellite measurements from the last decade

As part of European Space Agency’s (ESA) climate change initiative, high vertical resolution ozone profiles from three instruments all aboard ESA’s Envisat (GOMOS, MIPAS, SCIAMACHY) and ESA’s third party missions (OSIRIS, SMR, ACE-FTS) are to be combined in order to create an essential climate variable data record for the last decade. A prerequisite before combining data is the examination of differences and drifts between the data sets. In this paper, we present a detailed analysis of ozone profile differences based on pairwise collocated measurements, including the evolution of the differences with time. Such a diagnosis is helpful to identify strengths and weaknesses of each data set that may vary in time and introduce uncertainties in long-term trend estimates. The analysis reveals that the relative drift between the sensors is not statistically significant for most pairs of instruments. The relative drift values can be used to estimate the added uncertainty in physical trends. The added drift uncertainty is estimated at about 3% decade$^{-1}$ (1σ). Larger differences and variability in the differences are found in the lowermost stratosphere (below 20 km) and in the mesosphere

Comprehensive Antigen Screening Identifies Moraxella catarrhalis Proteins That Induce Protection in a Mouse Pulmonary Clearance Model

Moraxella catarrhalis is one of the three most common causative bacterial pathogens of otitis media, however no effective vaccine against M. catarrhalis has been developed so far. To identify M. catarrhalis vaccine candidate antigens, we used carefully selected sera from children with otitis media and healthy individuals to screen small-fragment genomic libraries that are expressed to display frame-selected peptides on a bacterial cell surface. This ANTIGENome technology led to the identification of 214 antigens, 23 of which were selected by in vitro or in vivo studies for additional characterization. Eight of the 23 candidates were tested in a Moraxella mouse pulmonary clearance model, and 3 of these antigens induced significantly faster bacterial clearance compared to adjuvant or to the previously characterized antigen OmpCD. The most significant protection data were obtained with the antigen MCR_1416 (Msp22), which was further investigated for its biological function by in vitro studies suggesting that Msp22 is a heme binding protein. This study comprises one of the most exhaustive studies to identify potential vaccine candidate antigens against the bacterial pathogen M. catarrhalis