The effect on gas solubilities of adding partially fluorinated alkyl side chains either on imidazolium-based cations or on bis(perfluoroalkylsulfonyl)amide anions was studied. The aim was to gain ...knowledge of the mechanisms of dissolution of gases in fluorinated ionic liquids and, if possible, to improve physical absorption of carbon dioxide in ionic liquids. We have determined experimentally, in the temperature range of 298–343 K and at pressures close to atmospheric pressure, the solubility and thermodynamics of solvation of carbon dioxide, ethane, and nitrogen in the ionic liquids 1-octyl-3-methylimidazolium bistrifluoromethylsulfonylamide (C8mimNTf2), 1-octyl-3-methylimidazolium bispentafluoroethylsulfonylamide (C8mimBETI), 1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-3-methylimidazolium bistrifluoromethylsulfonylamide (C8H4F13mimNTf2), and 1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-3-methylimidazolium bispentafluoroethylsulfonylamide (C8H4F13mimBETI). Ionic liquids with partial fluorination on the cation were found to exhibit higher carbon dioxide and nitrogen mole fraction solubilities but lower ethane solubilities, compared to those of their hydrogenated counterparts. Molecular simulation provided insights about the mechanisms of solvation of the different gases in the ionic liquids.
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Glycosaminoglycans (GAGs) are natural polymers that are broadly used in gene delivery systems to increase stability as well as decrease toxicity and nonspecific interactions, thereby ...increasing transfection efficiency. In this work, we propose sorbitan ester-based lipid nanoparticles (SENS) functionalised with the GAGs chondroitin sulfate (CS) and hyaluronic acid (HA) as gene delivery systems. For this purpose, we describe the design and evaluation of these nanosystems loaded with plasmid DNA, including an evaluation of their physicochemical characteristics, stability properties, ability to protect and efficiently transfect cells with Enhanced Green Fluorescent Protein plasmid (pEGFP) in vitro, and biocompatibility both in vitro and in vivo. We confirm that molecules with high biological value and targeting potential, such as HA and CS, can be successfully incorporated into our recently developed sorbitan ester-based nanoparticles (SENS) and that this incorporation leads to effective stabilisation of both nanosystems as well as protects plasmid DNA. We demonstrated that the aforementioned incorporation of HA and CS enables long-term stability of the nanosystems in both liquid and lyophilised states, which is a remarkable property that can aid in their transfer to industry. The ability of these functionalised nanosystems to transfect the A549 cell line without compromising cell viability was also shown, as well as their innocuous safety profile in vivo. Thus, we provide valuable evidence of the suitable properties and potential of these hybrid nanoparticles as gene delivery systems.
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Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially ...complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo − in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.
Purpose
To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of ...alternative metrics of local skin bioavailability calculable from SC sampling experiments.
Methods
Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers.
Results
SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated.
Conclusions
Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.
We measured the densities of 1-alkyl-3-methylimidazolium (C n mim, n = 2,4,6) tris(pentafluoroethyl)trifluorophosphate ionic liquids (eFAP) as a function of temperature and pressure and their ...viscosities as a function of temperature. These ionic liquids are less viscous than those based in the same cations but with other anions such as bis(trifluoromethylsulfonyl)imide. The ionic liquids studied are only partially miscible with water, their solubility increasing with the size of the alkyl side-chain of the cation and with temperature (from x H2O = 0.20 ± 0.03 for C4mimeFAP at 303.10 K to x H2O = 0.49 ± 0.07 for C6mimeFAP at 315.10 K). The solubility of carbon dioxide, nitrous oxide, ethane, and nitrogen in the three ionic liquids was measured as a function of temperature and at pressures close to atmospheric. Carbon dioxide and nitrous oxide are the more soluble gases with mole fraction solubilities of the order of 3 × 10–2 at 303 K. The solubility of these gases does not increase linearly with the size of the alkyl-side chain of the cation. The solubilities of ethane and nitrogen are much lower than those of carbon dioxide and nitrous oxide (mole fractions 60% and 90% lower, respectively). The higher solubility of CO2 and N2O can be explained by more favorable interactions between the solutes and the polar region of the ionic liquids as shown by the enthalpies of solvation determined experimentally and by the calculation of the site–site solute–solvent radial distribution functions using molecular simulation.
We measured the densities of 1-alkyl-3-methylimidazolium (C(n)mim, n = 2,4,6) tris(pentafluoroethyl)trifluorophosphate ionic liquids (eFAP) as a function of temperature and pressure and their ...viscosities as a function of temperature. These ionic liquids are less viscous than those based in the same cations but with other anions such as bis(trifluoromethylsulfonyl)imide. The ionic liquids studied are only partially miscible with water, their solubility increasing with the size of the alkyl side-chain of the cation and with temperature (from x(H(2)O) = 0.20 ± 0.03 for C(4)mimeFAP at 303.10 K to x(H(2)O) = 0.49 ± 0.07 for C(6)mimeFAP at 315.10 K). The solubility of carbon dioxide, nitrous oxide, ethane, and nitrogen in the three ionic liquids was measured as a function of temperature and at pressures close to atmospheric. Carbon dioxide and nitrous oxide are the more soluble gases with mole fraction solubilities of the order of 3 × 10(-2) at 303 K. The solubility of these gases does not increase linearly with the size of the alkyl-side chain of the cation. The solubilities of ethane and nitrogen are much lower than those of carbon dioxide and nitrous oxide (mole fractions 60% and 90% lower, respectively). The higher solubility of CO(2) and N(2)O can be explained by more favorable interactions between the solutes and the polar region of the ionic liquids as shown by the enthalpies of solvation determined experimentally and by the calculation of the site-site solute-solvent radial distribution functions using molecular simulation.
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The existing strategies in the design of non-viral vectors for gene therapy are primarily conceived for cationic systems. However, the safety concerns associated with the use of ...positively charged systems for nucleic acid delivery and several reports regarding the efficacy of negatively charged systems highlights the need for improved gene-delivery vectors. With these premises in mind, we investigated the development of new negatively charged nanoparticles based on Sorbitan esters (Span®) – extremely cheap excipients broadly used in the pharmaceutical industry – on the basis of a simple, one-step and easily scalable procedure. For their specific use in gene therapy, we have incorporated oleylamine (OA) or poly-l-arginine (PA) into these nanosystems. Thus, we used Sorbitan monooleate (Span® 80) to design Span® 80-oleylamine and Span® 80-poly-l-arginine nanosystems (SP–OA and SP–PA, respectively). These systems can associate with the model plasmid pEGFP-C3 and show mean particle sizes of 304nm and 247nm and surface charges of −13mV and −17mV, respectively.
The nanoparticles developed were evaluated in terms of in vitro cell viability and transfection ability. Both systems exhibited an appropriate cell-toxicity profile and are able to transfect the plasmid effectively. Specifically, the nanosystems including OA among their components provided higher transfection levels than the SP–PA nanoparticles. In conclusion, anionic nanoparticles based on Span® 80 can be considered low-cost, simple and efficient non-viral anionic gene-transfection systems.
The choice of cation and anion in an ionic liquid (IL) as well as the design of ion side chains determine the fundamental properties of ILs, which permits creating tailor-made lubricants and ...lubricant additives. So, the study of the influence of molecular structure on thermophysical properties of ionic liquids is essential for their use in lubrication. Recent results from the literature, essentially based on ammonium, phosphonium, or imidazolium cations, are promising from the tribological point of view, but still new investigations should be performed, for example, in elastohydrodynamic lubrication (EHL), for which calculations of the universal pressure–viscosity coefficient,
α
film
, and central thickness are needed. In this work viscosity and density data from the literature on broad pressure and temperature ranges for the ILs C
4
C
1
imPF
6
, C
4
C
1
imTf
2
N, C
4
C
1
imBF
4
, C
8
C
1
imPF
6
, C
8
C
1
imBF
4
, C
6
C
1
imPF
6
, and C
6
C
1
imTf
2
N are used to determine their
α
film
values over a wide temperature range. The American Gear Manufacturers Association relation of the central thickness with the pressure viscosity coefficient is used to estimate the film-generating capability of these lubricants. Furthermore, an overview of the literature data on tribological and physical properties of the ionic liquids is presented.
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To direct stem cell fate, a delicate control of gene expression through small interference RNA (siRNA) is emerging as a new and safe promising strategy. In this way, the expression of ...proteins hindering neuronal commitment may be transiently inhibited thus driving differentiation. Mesenchymal stem cells (MSC), which secrete tissue repair factors, possess immunomodulatory properties and may differentiate towards the neuronal lineage, are a promising cell source for cell therapy studies in the central nervous system. To better drive their neuronal commitment the repressor Element-1 silencing transcription (REST) factor, may be inhibited by siRNA technology. The design of novel nanoparticles (NP) capable of safely delivering nucleic acids is crucial in order to successfully develop this strategy. In this study we developed and characterized two different siRNA NP. On one hand, sorbitan monooleate (Span®80) based NP incorporating the cationic components poly-l-arginine or cationized pullulan, thus allowing the association of siRNA were designed. These NP presented a small size (205nm) and a negative surface charge (−38mV). On the other hand, lipid nanocapsules (LNC) associating polymers with lipids and allowing encapsulation of siRNA complexed with lipoplexes were also developed. Their size was of 82nm with a positive surface charge of +7mV. Both NP could be frozen with appropriate cryoprotectors. Cytotoxicity and transfection efficiency at different siRNA doses were monitored by evaluating REST expression. An inhibition of around 60% of REST expression was observed with both NP when associating 250ng/mL of siRNA–REST, as recommended for commercial reagents. Span NP were less toxic for human MSCs than LNCs, but although both NP showed a similar inhibition of REST over time and the induction of neuronal commitment, LNC–siREST induced a higher expression of neuronal markers. Therefore, two different tailored siRNA NP offering great potential for human stem cell differentiation have been developed, encouraging the pursuit of further in vitro and in vivo in studies.
The experimental measurements of dynamic viscosity for squalane, pentaerythritol tetra-2-ethylhexanoate (PEB8), and pentaerythritol tetranonanoate (PEC9) have been performed using a Ruska ...rolling-ball viscometer over the temperature range of 303.15−353.15 K and a pressure range of 0.1−60 MPa. A total of 2016 experimental measurements of the rolling time have been obtained for the determination of 252 dynamic viscosity data. The available literature viscosity data for squalane at high pressures have been compared with the new measurements, and an average deviation of 1.5% has been obtained, which is within the experimental uncertainty (±3%). The higher viscosity values are reached for PEB8, followed by PEC9. For the pentaerythritol esters, it has been observed that the dynamic viscosity increases with the branching degree of the molecule. The relative change in viscosity with temperature is biggest for PEB8 and, consequently, the poorer viscosity index (VI) values and higher temperature coefficients have been obtained for this fluid. The lowest pressure−viscosity coefficient and the highest VI have been obtained for PEC9.
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