Bile salt-induced disintegration of egg phosphatidylcholine liposomes: a kinetic study based on turbidity changes

The disintegration kinetics of egg phosphatidylcholine small unilamellar liposomes in various bile salts (nine species) were investigated by monitoring turbidity changes with a stopped-flow apparatus. The pseudo-first-order rate constants obtained as a function of bile salt concentration (up to 25 mM) were analyzed based on a two-step model in which a penetration-saturation step of bile salt into the bilayer and a lamellar-micellar transition step were assumed for the disintegration mechanism of the bilayer. The order of the rate of the penetration-saturation step, which is assumed to be a measure of the disintegration ability, was as follows: SCDOC greater than SDOC greater than STCDOC greater than STDOC greater than STC greater than SC greater than SGCDOC greater than SGDOC greater than SGC. The results indicated that (1) the dihydroxy bile salts have a greater disintegration ability than the corresponding trihydroxy bile salts, (2) the chenodeoxy bile salts have a greater ability than the corresponding deoxy-bile salts regardless of non-conjugated or conjugated form, (3) the taurine conjugates always have a greater ability than the glycine conjugates. The penetration-saturation rate of the bile salts against the lipid bilayer depends considerably on the chemical nature of each bile salt, varying by a factor of about 10(5). In the conjugated bile salts alone, they were in a narrower range of a factor of 10(3). The physical integrity of liposomes can hardly be maintained in the bile salt-rich intestinal tract but the resulting mixed micelles may contribute substantially to solubilization and enhanced delivery of drugs.     

Effects of a bolaamphiphile on the structure of phosphatidylcholine liposomes

This paper describes the morphological characterization of aqueous dispersions of PC amphiphiles and bolaamphiphile AEC by microscopy, the liposomal membrane fluidity, and the zeta potential. Results indicate that the bolaamphiphile AEC can be included within conventional egg-PC liposome bilayers. This behavior could be due to their preference for the stretched conformation within the PC membranes.     

The hardness profile as a tool to detect spurious stationary points in the potential energy surface

In the present work, we have computed the energy and hardness profiles for a series of inter and intramolecular conformational changes at several levels of calculation. All processes studied have in common the fact that the choice of a weak methodology or a poor basis set results in the presence of spurious stationary points in the energy profile. At variance with the energy profiles, the hardness profiles calculated as the difference between the vertical ionization potential and electron affinity always show the correct number of stationary points independently of the basis set and methodology used. For this reason, we have concluded that hardness profiles can be used to check the reliability of the energy profiles for those chemical systems that, because of their size, cannot be treated with high level ab initio methods.     

Compensation effect as a tool in investigating surface reaction mechanisms

The apparent kinetic parameters for the dehydrohalogenation of 1-bromo-2-methylpropane to isopropylene on alumina modified with alkali halides have been calculated. Both true and apparent kinetic parameters give kinetic compensation effects, with different coherence of the Hv.s.S points. This leads to useful conclusions about the fitness of the two kinds of parameters for handling surface reaction mechanisms.

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Fast reversible isomerization of merocyanine as a tool to quantify stress history in elastomers

A mechanochemistry based approach is proposed to detect and map stress history during dynamic processes. Spiropyran (SP), a force sensitive molecular probe, was incorporated as a crosslinker into multiple network elastomers (MNE). When these mechanochromic MNEs are loaded, SP undergoes a well-known force-activated reaction to merocyanine (MC) changing its absorption in the visible range (visible blue color). This SP to MC transition is not reversible within the time frame of the experiment and the color change reports the concentration of activated molecules. During subsequent loading–unloading cycles the MC undergoes a fast and reversible isomerization resulting in a slight shift of absorption spectrum and results in a second color change (blue to purple color corresponding to the loading–unloading cycles). Quantification of the color changes by using chromaticity shows that the exact color observed upon unloading is characteristic not only of the current stress (reported by the shift in color due to MC isomerization), but of the maximum stress that the material has seen during the loading cycle (reported by the shift in color due to the change in MC concentration). We show that these two color changes can be separated unambiguously and we use them to map the stress history in the loading and unloading process occurring as a crack opens up and propagates, breaking the material. Color maps on fractured samples are compared with finite element simulations and the agreement is excellent.

A mechanochemistry based approach is proposed to detect and map stress history during dynamic processes.     

Microcalorimetric and zeta potential study on binding of drugs on liposomes

In this work, isothermal titration calorimetry (ITC) combined with zeta potential measurements was used to study the binding and partitioning of three β-blockers, alprenolol, labetalol and propranolol, and the local anaesthetic tetracaine into liposomes. The thermodynamic parameters of enthalpy, entropy, the Gibbs energy and the binding constant were determined using the one site model. Furthermore, the binding constants corrected for the electrostatic contribution were used to assess the partition coefficients for the drugs. Also, the effect of the concentration, ionic strength, temperature and membrane curvature on the interaction was included in the evaluation.     

Scanning white-light interferometry as a novel technique to quantify the surface roughness of micron-sized particles for inhalation

A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50x objective lens with 2.0x and 0.5x fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness ( Rrms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 +/- 3.80 nm to 110.90 +/- 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 +/- 15.90 nm to 229.20 +/- 68.20 nm for decanted and normal lactose, respectively. The Rrms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.     

Reaction path as a gradient line on the potential surface

It is shown that, in the infinitesimal motion approximation, the reaction path on the potential surface of a molecule may be only a gradient line between any two critical points. Correct rules are derived for point group conservation of the transition state vector along the whole gradient line on PES.Scientific-Research Institute of Physical and Organic Chemistry, Rostov State University. Translated fromZhurnal Strukturnoi Khimii, Vol. 34, No. 6, pp. 3–19, November–December, 1993.Translated by L. Smolina     

Ligand fishing as a tool to screen natural products with anticancer potential

Cancer is the second leading cause of death in the world and its incidence is expected to increase with the aging of the world's population and globalization of risk factors. Natural products and their derivatives have provided a significant number of approved anticancer drugs and the development of robust and selective screening assays for the identification of lead anticancer natural products are essential in the challenge of developing personalized targeted therapies tailored to the genetic and molecular characteristics of tumors. To this end, a ligand fishing assay is a remarkable tool to rapidly and rigorously screen complex matrices, such as plant extracts, for the isolation and identification of specific ligands that bind to relevant pharmacological targets. In this paper, we review the application of ligand fishing with cancer-related targets to screen natural product extracts for the isolation and identification of selective ligands. We provide critical analysis of the system configurations, targets, and key phytochemical classes related to the field of anticancer research. Based on the data collected, ligand fishing emerges as a robust and powerful screening system for the rapid discovery of new anticancer drugs from natural resources. It is currently an underexplored strategy according to its considerable potential.     

Adsorption of neutral polymers on negatively charged liposomes. A novel quantitative method to measure the rate of polymer adsorption on the liposomal surface

We studied the adsorption of two neutral polymers [poly(vinyl pyrrolidone) and poly(vinyl alcohol) (PVA)] on negatively charged liposomes composed of 25:2:3 (molar ratio) soy lecithin/dicetyl phosphate/cholesterol.The liposomes were prepared in buffered solution at pH 7.4 and were mixed with the solution of the polymers in the desired polymer/lipid ratios. Adsorption was measured by determination of the equilibrium bulk concentration of the polymer. Protamine hydrochloride was used to aggregate the liposomes with polymers adsorbed on their surface and to facilitate their separation from the equilibrium bulk solution. In the case of PVA, quantitative adsorption measurements with a specific reagent were possible. Adsorption isotherms were recorded at 25 ± 0.2 °C. It was concluded that adsorbed and nonadsorbed PVA molecules are in equilibrium even at low polymer/lipide ratios. The results were confirmed by dynamic laser light scattering, X-ray diffraction and thermal activity monitoring experiments. Received: 13 October 2000 Accepted: 8 March 2001     

Effect of ionic size on the deposition of charge-regulated particles to a charged surface

The deposition of charge-regulated particles to a rigid, planar charged surface is modeled theoretically, taking the effects of the excluded area arising from deposited particles and finite ionic sizes into account. Here, a particle comprises a rigid core and an ion-penetrable charged membrane layer, which represents a general type of particle. If the membrane layer has a negligible thickness, the particle simulates a regular inorganic particle, and if the membrane layer has a finite thickness, it simulates biocolloids such as cells. The results of numerical simulation reveal that the rate of particle deposition is faster under the following conditions: (1) lower potential of the planar surface, (2) thicker membrane, (3) higher counterion valance, (4) lower fixed charge density, (5) smaller counterions, (6) larger co-ions, (7) larger functional group, and (8) lower pH. Neglecting the sizes of ionic species may lead to an appreciable deviation in both the electrical repulsive force between particle and surface and the rate of deposition. Typical deviation for the former is approximately 20%, and that for the latter is approximately -75%.     

Review of DBS methods as a quantitative tool for anticancer drugs

An overview of published dried blood spot (DBS) methods for the quantitation of various classes of anticancer drugs from clinical and preclinical studies is presented. The increased reporting of DBS methods in the literature for quantitation of various classes of drugs is a testimony to their utility in bioanalytical applications. While DBS offers several advantages as compared with conventional wet sampling techniques, there remain a number of nuances that may impede the assay adaptability of DBS method in routine quantitative bioanalysis. This review covers several case studies of DBS application in the quantitation of anticancer drugs. Some perspectives are provided on the optimization of the DBS method with respect to the selection of DBS card, spot volume, hematocrit effect and other regular validation parameters, which are essential in quantitative bioanalysis. Some thoughts are provided on the existing gaps in the DBS method and possible remedial measure(s) to address such gaps. Although DBS methods have great potential, there is the need for a global consensus including regulatory support on the type of validation experiments to be performed to support quantitative data.     

Steric blocking as a tool to control molecular film geometry at a metal surface

The application of steric blocking in surface science is exemplified by the control of surface patterns through the selective methylation of pentacenetetrone. Pentacenetetrones interact (with one another) on Cu(111) via intermolecular hydrogen bonding involving the carbonyl oxygen and the adjacent hydrogen atoms. Steric blocking of the intermolecular interaction by the successive insertion of inert methyl groups at terminal locations transforms a dense molecular pattern first into isolated double rows and eventually into single rows in a highly predictable fashion. Density functional theory modeling reveals the underlying energetics.     

Reaction path as a gradient line on a potential energy surface

The reaction path is shown to be always a gradient line on a potential energy surface (PES ) of a molecule. The properties of gradient lines on the PES are elucidated. Correct symmetry conservation rules along the gradient line are derived. The behavior of the gradient line on a PES with different topologies are considered. © 1994 John Wiley & Sons, Inc.     

Solid‐state NMR as a tool to describe and quantify the morphology of photoactive layers used in plastic solar cells

The optimization and control of the nanomorphology of thin films used as active layer in bulk heterojunction (BHJ) plastic solar cells is of key importance for a better understanding of the photovoltaic mechanisms and for increasing the device performances. Hereto, solid‐state NMR relaxation experiments have been evaluated to describe the film morphology of one of the “work‐horse” systems poly(2‐methoxy‐5‐(3′,7′‐dimethyloctyloxy)‐1,4‐phenylene‐vinylene)/[6, 6]‐phenyl‐C₆₁butyric acid methyl ester (MDMO‐PPV/PCBM) in a quantitative way. Attention is focused on the influence of the processing solvent (toluene vs. chlorobenzene), the blend composition, and the casting technique, that is, spin coating versus doctor blading. It is demonstrated that independently of the solvent and casting technique, part of the PCBM becomes phase separated from the mixed phase. Whereas casting from toluene results in the development of well‐defined PCBM crystallites, casting from chlorobenzene leads to the formation of PCBM‐rich domains that contain substructures of weakly organized PCBM nanoclusters. The amount and physico‐chemical state of the phase separated PCBM is quantified by solid‐state NMR relaxation times experiments. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Studies on the encapsulation of diclofenac in small unilamellar liposomes of soya phosphatidylcholine

The encapsulation of acid (AD) and sodium diclofenac (SD) in small unilamellar liposomes (SUV) as well as the interactions of the drug with the bilayer was studied. SUV was prepared by sonication from multilamellar liposomes containing soya phosphatidylcholine and diclofenac at various proportions. The size distribution obtained from dynamic light scattering showed that the incorporation of SD decreases significantly the size of the liposomes suggesting that the drug interacts with the bilayer of the liposomes. This size decrease is related with the phase transition of liposomes to mixed micelar solution. The encapsulation of the hydrophilic dye indocyanine green in the aqueous compartment of liposomes showed that the rate of captured dye decreases with SD concentration suggesting the transition of liposomes to mixed micelles. The (31)P NMR analysis indicates that SD interacts with the phosphate of phosphatidylcholine head groups. A schematic model for interaction of SD with phosphatidylcholine of the liposomes in which the diclofenac anion interacts with the ammonium group of the phospholipid and the dichlorophenyl ring occupies a more internal site of bilayer near phosphate group was proposed.     

Contact angle measurements as a tool to investigate the filler-matrix interactions in polyurethane-clay nanocomposites from blocked prepolymer

Optically transparent polyurethane-clay nanocomposite films were prepared by dispersing 5 wt% of various commercial organo-clays in a mixture of cycloaliphatic amines used as chain extender-cross-linker of a blocked prepolymer. For the first time, vibration-induced equilibrium contact angle measurements were successfully employed to rank the selected organo-clays accordingly to their hydrophobicity order. Polymer-clay intercalation degree in the nanocomposites, as assessed from X-ray diffraction, was strongly correlated to the water-clay equilibrium contact angle. Moreover, as the clay intercalation degree increased, a decrease of the cross-linking degree of the polyurethane matrix occured.Uniaxial tensile tests under quasi-static and impact conditions, and isothermal thermogravimetric analysis were performed on both unfilled polyurethane matrix and nanocomposites. Secant tensile modulus, tensile energy to break, and thermal lifetime showed a non monotonic trend with a maximum as a function of the intercalation degree. This behaviour is discussed considering that two concomitant and contrasting effects develop as the polymer-clay intercalation degree increases: a positive improvement of the filler matrix interactions, and a negative reduction of the matrix cross-linking degree.     

Kerr effect as a tool for the investigation of dynamic heterogeneities

We propose a dynamic Kerr effect experiment for the distinction between dynamic heterogeneous and homogeneous relaxations in glassy systems. The possibility of this distinction is due to the inherent nonlinearity of the Kerr effect signal. We model the slow reorientational molecular motion in supercooled liquids in terms of noninertial rotational diffusion. The Kerr effect response, consisting of two terms, is calculated for heterogeneous and for homogeneous variants of the stochastic model. It turns out that the experiment is able to distinguish between the two scenarios. We furthermore show that exchange between relatively "slow" and "fast" environments does not affect the possibility of frequency-selective modifications. It is demonstrated how information about changes in the width of the relaxation-time distribution can be obtained from experimental results.