The Impact of Improving Dermal Permeation on the Efficacy and Targeting of Liposome Nanoparticles as a Potential Treatment for Breast Cancer

Breast cancer is the most frequent malignancy in women. This work focuses on developing deformable liposomes as a potential carrier for breast cancer treatment and studying the impact of improving dermal permeation on the efficacy and targeting of liposomes. Raloxifene (RXF), an oestrogen antagonist, was used as a model drug. Using Box–Behnken design, different formulations of RXF-loaded deformable liposome (RLDL) were prepared using different propylene glycol, phospholipid and cholesterol concentrations. The percentage of entrapment efficiency (Y1), particle size (Y2), zeta potential (Y3) and steady-state flux (Y4) of the prepared formulations were all evaluated. Y1 and Y4 were significantly increased and Y2 and Y3 were significantly decreased when the propylene glycol concentration was increased. The optimization was obtained and the optimum formulation was that including phospholipid (1.40% w/w), cholesterol (0.15% w/w) and propylene glycol (10% v/v). The selected optimum formulation displayed a % EE of 78.34 ± 1.04% with a steady-state flux of 4.21 ± 0.02 µg/cm2/h. In order to investigate bioavailability, antitumor effectiveness and permeation, the optimum formulation was selected and included in a carbopol gel. The optimum gel formulation had 2.77 times higher bioavailability and, as a result, considerable antitumor action as compared to oral RXF. In conclusion, optimum RLDL gel may be an effective breast cancer treatment.

Improving the Antitumor Activity and Bioavailability of Sonidegib for the Treatment of Skin Cancer

Throughout the United States and the world, skin cancer is the most frequent form of cancer. Sonidegib (SNG) is a hedgehog inhibitor that has been used for skin cancer treatment. However, SNG has low bioavailability and is associated with resistance. The focus of this work is to enhance bioavailability, anti-tumor efficacy and targeting of SNG via developing ethosome gel as a potential treatment for skin cancer. SNG-loaded ethosomes formulation was prepared and characterized in vitro by %entrapment efficiency (%EE), vesicle size, morphology, %release and steady-state flux. The results showed that the prepared formulation was spherical nanovesicles with a %EE of 85.4 ± 0.57%, a particle size of 199.53 ± 4.51 nm and a steady-state flux of 5.58 ± 0.08 µg/cm2/h. In addition, SNG-loaded ethosomes formulation was incorporated into carbopol gel to study the anti-tumor efficacy, localization and bioavailability in vivo. Compared with oral SNG, the formulation showed 3.18 times higher relative bioavailability and consequently significant anti-tumor activity. In addition, this formulation showed a higher rate of SNG penetration in the skin’s deep layers and passive targeting in tumor cells. Briefly, SNG-loaded ethosome gel can produce desirable therapeutic benefits for treatment of skin cancer.

Sequential Injection Analysis for Automation and Evaluation of Drug Liberation Profiles: Clotrimazole Liberation Monitoring

A fully automated sequential injection system was tested in terms of its application in liberation testing, and capabilities and limitations were discussed for clotrimazole liberation from three semisolid formulations. An evaluation based on kinetic profiles obtained in short and longer sampling intervals and steady-state flux values were applied as traditional methods. The obtained clotrimazole liberation profile was faster in the case of Delcore and slower for Clotrimazol AL and Canesten cream commercial formulations. The steady-state flux values for the tested formulations were 52 µg cm−2 h−1 for Canesten, 35 µg cm−2 h−1 for Clotrimazol AL, and 7.2 µg cm−2 h−1 for Delcore measured in 4 min sampling intervals. A simplified approach for the evaluation of the initial rate based on the gradient between the second and third sampling points was used for the first time and was found to correspond well with the results of the conventional methods. A comparison based on the ratio of the steady-state flux and the initial rate values for Canesten and Clotrimazol AL proved the similarity of the obtained results. The proposed alternative was successfully implemented for the comparison of short-term kinetic profiles. Consequently, a faster and simpler approach for dissolution/liberation testing can be used.

Probabilistic Thermodynamic Analysis of Metabolic Networks

Motivation Random sampling of metabolic fluxes can provide a comprehensive description of the capabilities of a metabolic network. However, current sampling approaches do not model thermodynamics explicitly, leading to inaccurate predictions of an organism’s potential or actual metabolic operations. Results We present a probabilistic framework combining thermodynamic quantities with steady-state flux constraints to analyze the properties of a metabolic network. It includes methods for probabilistic metabolic optimization and for joint sampling of thermodynamic and flux spaces. Applied to a model of E. coli, we use the methods to reveal known and novel mechanisms of substrate channeling, and to accurately predict reaction directions and metabolite concentrations. Interestingly, predicted flux distributions are multimodal, leading to discrete hypotheses on E. coli’s metabolic capabilities. Availability Python and MATLAB packages available at https://gitlab.com/csb.ethz/pta. Supplementary information Supplementary data are available at Bioinformatics online.

PRONIOSOMAL GEL MEDIATED TRANSDERMAL DELIVERY OF GLIBENCLAMIDE AND ATENOLOL COMBINATION: EXVIVO AND PHARMACODYNAMIC STUDIES

Objective: The objective of the present work was to develop an optimized dosage form for treating comorbidity in combination and evaluate it for its pharmacodynamic performance in male Wistar albino rats. Methods: Transdermal proniosomal gel for Combination of Glibenclamide (GLB) and Atenolol (ATN) was developed and optimized by Box Behnken design. This optimized combinational proniosomal gel (OCPG), which was selected by a point prediction method, was evaluated for its ex vivo, skin irritation studies and pharmacodynamic activities of both drugs in rats in comparison with its oral therapy. Results: The ex-vivo permeation behavior through different skins was studied and the findings were also confirmed by the values of the steady-state flux (Jss). The OCPG observed an increase of more than twice in the cumulative amount of impregnated drugs compared to pure drug films. The study on skin irritation revealed the non-irritability of the developed OCPG applied. OCPG significantly showed sustained hypoglycemic activity in rats (p<0.001), when compared to orally treat animals up to 24 h. Systolic blood pressure (SBP) lowering effect of OCPG was found to be significant (p<0.02), when compared to orally treat rats up to 24 h. However, the reduction was slow and sustained in the case of OPCG where a significant response was observed in the performed studies. Conclusion: Overall, the results show that controlled release GLB and ATN proniosomes offer a useful and promising transdermal delivery system. Henceforth this may be an achievement in treating the diabetic hypertensive patient.

Probabilistic Thermodynamic Analysis of Metabolic Networks

Random sampling of metabolic fluxes can provide an unbiased description of the capabilities of a metabolic network. However, current sampling approaches do not model thermodynamics explicitly, leading to inaccurate predictions of an organism’s potential or actual metabolic operations. We present a probabilistic framework combining thermodynamic quantities with steady-state flux constraints to analyze the properties of a metabolic network. It includes methods for probabilistic metabolic optimization and for joint sampling of thermodynamic and flux spaces. Applied to a model of E. coli, we use the methods to reveal known and novel mechanisms of substrate channeling, and to accurately predict reaction directions and metabolite concentrations. Interestingly, predicted flux distributions are multimodal, leading to discrete hypotheses on E. coli ‘s metabolic capabilities. C++ source code with MATLAB interface available at https://gitlab.com/csb.ethz/pta.

DIFFUSION THROUGH SODIUM AND POLYMER ENHANCED BENTONITES EXPOSED TO DILUTE AND AGGRESSIVE SOLUTIONS

Chemical incompatibility between sodium bentonite (NaB) and aggressive waste solutions has led to the development of enhanced bentonites for geoenvironmental applications. Enhanced bentonites, such as bentonite-polyacrylic-acid composite (BPC), have been shown to maintain low enough values of hydraulic conductivity (e.g. < 10-10 m/s) for diffusion to be the dominant transport mechanism, even upon exposure to aggressive solutions. However, quantification of diffusion properties of enhanced bentonites has been limited. In this study, apparent diffusion coefficients (Da) for chloride were measured for NaB and polymer enhanced NaBs. Diffusion tests were performed using dilute (5 mM) to aggressive (100 mM) calcium chloride (CaCl2) solutions. In addition, scanning electron microscopy was performed to support interpretation of diffusion results. For CaCl2 solutions < 100 mM, Da values for BPC were lower (by approximately half an order of magnitude) than Da values for NaB. However, differences in Da due to polymer enhancement diminished as CaCl2 concentration increased. Predicted steady-state flux through a BPC geosynthetic clay liner (GCL) was dominated by diffusion and up to two orders of magnitude lower than flux through an NaB GCL. These results provide insight regarding diffusion in polymer enhanced bentonites and expected performance of containment barriers with enhanced-bentonite GCLs.

Miscible displacement of copper in soil columns using increasing doses of bentonite

The objective of this research was to evaluate the effect of applying increasing doses of bentonite to the soil on the miscible displacement of copper, quantifying copper retention in the soil and elimination by leachate, in order to prevent potential risks for environmental contamination. The experiment was conducted on a laboratory using leaching columns filled by a sandy texture soil contaminated with 250 mg kg-1 of copper each. The experimental design was a completely randomized with four doses of bentonite, 0; 30; 60 and 90 t ha-1, and three replications totalizing 12 experimental units. The leaching columns were made with PVC tubes constituted by three rings, overlaid and joined with silicone glue. Each column was filled with 4 kg of Cu contaminated soil, mixed with the doses of bentonite specified by the treatments (0; 45; 90 and 135 g). After the filling of the columns, each one received five pore volumes of distillated water, and left to percolation under a steady state flux. After percolation, the Cu concentrations in the soil and in the percolate, the breakthrough curves of the flux density and the percolation velocity were determined. The results were submitted to variance analyses using the F test and regressions. The increasing doses of bentonite until 90 t ha-1 increased the adsorption of copper by the soil, reducing the percolation of this element around 72%. Bentonite application to the soil decreased the flux density and flux velocity of the copper percolation, diminishing the potential risks for the environment contamination.

Tuning the Transdermal Delivery of Hydroquinone upon Formulation with Novel Permeation Enhancers

Hydroquinone (HQ) is an anti-hyperpigmentation agent with poor physicochemical stability. HQ formulations are currently elaborated by compounding in local pharmacies. Variability in the characteristics of HQ topical formulations can lead to remarkable differences in terms of their stability, efficacy, and toxicity. Four different semisolid O/W formulations with 5% HQ were prepared using: i) Beeler´s base plus antioxidants (F1), ii) Beeler´s base and dimethyl isosorbide (DMI) as solubiliser (F2), iii) olive oil and DMI (F3), and iv) Nourivan®, a skin-moisturising and antioxidant base, along with DMI (F4). Amongst the four formulations, F3 showed the greatest physicochemical stability with less tendency to coalescence but with marked chromatic aberrations. An inverse correlation was established by multivariate analysis between the mean droplet size in volume and the steady-state flux, which explains why F3, with the smallest droplet size and the most hydrophobic excipients, exhibited the highest permeation across both types of membranes with enhancement ratios of 2.26 and 5.67-fold across Strat-M® and mouse skin, respectively, compared to F1. It is crucial to understand how the HQ is formulated, bearing in mind that the use of different excipients can tune the transdermal delivery of HQ significantly.