Gold nanoparticles capped with benzalkonium chloride and poly (ethylene imine) for enhanced loading and skin permeability of 5-fluorouracil

Objective: To enhance 5-fluorouracil (5-FU) permeability through the skin by loading onto gold nanoparticles (GNPs) capped with two cationic ligands, benzalkonium chloride (BC) or poly (ethylene imine) (PEI). Whereas 5-FU has excellent efficacy against many cancers, its poor permeability through biological membranes and several adverse effects limit its clinical benefits. BC and PEI were selected to stabilize GNPs and to load 5-FU through ionic interactions.

Methods: 5-FU/BC-GNPs and 5-FU/PEI-GNPs were prepared at different 5-FU/ligand molar ratios and different pH values and were evaluated using different techniques. GNPs stability was tested as a function of salt concentration and storage time. 5-FU release from BC- and PEI-GNPs was evaluated as a function of solution pH. Ex vivo permeability studies of different 5-FU preparations were carried out using mice skin.

Results: 5-FU-loaded GNPs size and surface charge were dependent on the 5-FU/ligand molar ratios. 5-FU entrapment efficiency and loading capacity were dependent on the used ligand, 5-FU/ligand molar ratio and solution pH. Maximum drug entrapment efficiency of 59.0?±?1.7% and 46.0?±?1.1% were obtained for 5-FU/BC-GNPs and 5-FU/PEI-GNPs, respectively. 5-FU-loaded GNPs had good stability against salinity and after storage for 4?months at room temperature and at 4?°C. In vitro 5-FU release was pH- and ligand-dependent where slower release was observed at higher pH and for 5-FU/BC-GNPs. 5-FU permeability through mice skin was significantly higher for drug-loaded GNPs compared with drug-ligand complex or drug aqueous solution.

Conclusion: Based on these results, BC- and PEI-GNPs might find applications as effective topical delivery systems of 5-FU.     

Preparation and characterization of 5-fluorouracil pH-sensitive niosome and its tumor-targeted evaluation: in vitro and in vivo

The purpose of this study was to investigate preparation, characterization and tumor-targeted effect of pH-sensitive niosomes, composed of a nonionic surfactant mixed with cholesteryl hemisuccinate (CHEMS), a derivative of cholesterol (CHOL), as a pH-sensitive molecule.

CHEMS was synthesized with CHOL and succinic acid, the structure of which was analyzed by Mass spectrometry (MS) and ¹H Nuclear magnetic resonance (¹H NMR) spectrum. Niosomes were prepared via film hydration-probe ultrasound method. Both normal niosomes and pH-sensitive niosomes showed spherical morphology under transmission electron microscope (TEM) with a average particle sizes of 172?±?6.2?nm and 153?±?4.7?nm, respectively. The thermotropic behavior, structure changes and interaction of 5-fluorouracil (5-Fu) with other materials were characterized by differential scanning calorimetry (DSC), and the disappearance of the melting peak of drug revealed the fact that drug was encapsulated in niosomes. Bulk-equilibrium reverse-dialysis method was chosen to investigate the behavior of drug release from normal niosomes and pH-sensitive niosomes in different pH medium, and the results showed that the noisome containing CHEMS had a pH-sensitive property. Tumor-targeted effect was proved by the fact that pH-sensitive niosomes showed a remarkable high concentration in tumor site of the mice transplanted with tumor cell.     

Development and evaluation of novel microemulsion based oral formulations of 5-fluorouracil using non-everted rat intestine sac model

Oral formulations of 5-fluorouracil (5-FU) with enhanced bioavailability were developed using microemulsion as a drug carrier system. The formulations were evaluated for drug content, physicochemical characteristics such as globule size, zeta potential, viscosity, stability and permeation characteristics. Ex vivo permeation studies were performed using non-everted rat intestinal sac technique. Results of the ex vivo permeation studies revealed that from aqueous solution only 25.08% drug was permeated, whereas, the optimized microemulsion formulation showed 97.5% drug permeation in 8?h, suggesting, approximately, four times enhancement in the drug permeability. Also a 7-fold increase in the flux of drug was observed from microemulsion formulation when compared with the aqueous solution. Further, in vivo pharmacodynamic studies were carried to check the therapeutic efficacy against benzo(a)pyrene [B(a)P]-induced stomach tumors in albino mice (Balb/C strain). The treatment of mice with 5-FU and microemulsion (5-FU II), after the last dose of B(a)P i.e. during the initiation period, resulted in 25% and 67% reduction in tumor incidence, respectively suggesting significant enhancement in the bioavailability and therapeutic efficacy of 5-FU when it was formulated as a microemulsion. These promising results suggest that microemulsion formulation of 5-FU may be used for the treatment of human cancers after pharmacokinetic and clinical evaluation.     

Buccal Bioadhesive Delivery System of 5-Fluorouracil: Optimization and Characterization

The objective of this work was to apply the response surface approach in the development of buccal bioadhesive tablets of 5-fluorouracil (5-FU). Experiments were performed according to a 3² factorial design to evaluate the effects of two polymers, Gantrez MS-955 (X₁) and hydroxypropylmethyl cellulose (HPMC) K15M (X₂) on the bioadhesive force, percentage drug release in 8 h (Rel_{8 h}), time taken for 50% drug release (t_50%), and diffusion coefficient (n). The effect of the two independent variables on the response variables was studied by response surface plots and contour plots generated by the Design Expert® software. The compatibility between 5-FU and the tablet excipients was confirmed by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) studies. Both the polymers were found to have synergistic effect on bioadhesion but the effect of Gantrez was more pronounced. A nonlinear twisted relationship was obtained for Rel_{8 h} at the intermediate and high levels of the polymers, which indicated an interaction between them at the corresponding factor levels. Kinetic treatment to the dissolution profiles revealed that the drug release ranged from Fickian to anomalous transport, which was mainly dependent on both the independent variables. The desirability function was used to optimize the response variables, and the observed responses were in agreement with the experimental values.     

Preparation and characterization of titanium-containing MFI from highly siliceous ZSM-5: effect of precursors synthesized with different templates

Titanium-containing MFI zeolites (Ti-ZSM-5) have been prepared by gas–solid reaction between highly siliceous ZSM-5 precursors synthesized with different organic molecules, and TiCl₄ vapor at elevated temperature. XRD, FT-IR, UV-Vis, ²⁹Si and ²⁷Al solid NMR techniques are used to characterize precursors and Ti-ZSM-5 zeolites. Highly siliceous ZSM-5 synthesized with different templates possesses different amount of internal silanol groups clustered as silanol nests in framework. When the precursor is contacted with TiCl₄ vapor at elevated temperature, titanium atoms are incorporated into the tetrahedral sites by the reaction between TiCl₄ and silanol nests, not by the isomorphous substitution of titanium for framework aluminium or/and silicon. Highly siliceous ZSM-5 precursor synthesized with NBA, TEABr or HDA template possesses relatively large amount of internal silanol groups, and then obtains high concentrations of framework titanium after contacted with TiCl₄ vapor, compared to those synthesized with TPAOH or TPABr template. In addition, Ti-ZSM-5 with precursors obtained by using NBA, TEABr or HDA template can occupy higher catalytic activity in the epoxidation of propylene with diluted hydrogen peroxide.     

Sunflower seed shells: a novel and effective low-cost adsorbent for the removal of the diazo dye Reactive Black 5 from aqueous solutions

In this paper, the potential of two low-cost adsorbents such as sunflower seed shells (SS) and mandarin peelings (MP) in the removal of the synthetic anionic dye Reactive Black 5 (RB5) from aqueous solutions was investigated. SS led to a percentage of dye removal higher than MP (85% and 71% after 210min, respectively, for an initial RB5 concentration of 50mgL(-1) and an initial pH of 2.0). The rate of adsorption followed a pseudo-second-order kinetic model and the intra-particle diffusion was found to be the rate-controlling stage. In addition, the equilibrium data fitted well both the Freundlich and multilayer adsorption isotherm equations indicating the heterogeneity of the adsorbent surface. This was also corroborated by the SEM photographs. On the whole, the results in this study indicated that SS were very attractive materials for removing anionic dyes from dyed effluents.