Cationic Porphyrin-Anionic Surfactant Mixtures for the Promotion of Self-Organized 1:4 Ion Pairs in Water with Strong Aggregation Properties.

We performed a systematic study on the spectroscopic and aggregation properties of stoichiometric mixtures (1:4) of the tetracationic meso-tetrakis(4-N-methylpyridinium)porphyrin (H2 TMPyP) and three sodium alkylsulfate surfactants (tetradecyl, hexadecyl, and octadecylsulfate) in an aqueous solution. The objective was to build a supramolecular aggregate, which would favor the internalization of tetracationic porphyrins in cells without chemical modification of the structure of the porphyrin. We show that stoichiometric H2 TMPyP/alkylsulfate (1:4) mixtures lead to the formation of large hollow spherical aggregates (60-160 nm). The TEM images show that the membrane of these aggregates are composed of smaller aggregates, which are probably rod-like micelles. These rod-like micelles have a hydrophobic core composed of the alkyl chains of the alkylsulfate surfactant, whereas the charged surface corresponds to the tetracationic porphyrins.

Versatile cellular uptake mediated by catanionic vesicles: simultaneous spontaneous membrane fusion and endocytosis.

Lactose-derived catanionic vesicles offer unique opportunities to overcome cellular barriers. These potential nanovectors, very easy to formulate as drug delivery systems, are able to encapsulate drugs of various hydrophilicity. This article highlights versatile interaction mechanisms between these catanionic vesicles, labeled with hydrophilic and amphiphilic fluorescent probes, and a mammalian cell line, Chinese Hamster Ovary. Confocal microscopy and flow cytometry techniques show that these vesicles are internalized by cells through cellular energy dependent processes, as endocytosis, but are simultaneously able to spontaneously fuse with cell plasma membranes and release their hydrophilic content directly inside the cytosol. Such innovative and polyvalent nanovectors, able to deliver their content via different internalization pathways, would positively be a great progress for the coadministration of drugs of complementary efficiency.

Electric Destabilization of Supramolecular Lipid Vesicles Subjected to Fast Electric Pulses.

Biological membranes are weakly permeable to hydrophilic molecules and ions and electric pulses can induce their transient permeabilization, but this process is not well characterized. We directly assay the electropermeabilization process, on the minimum model of lipid vesicles, by using a highly sensitive fluorescence method based on manganese ion transport. The approach gives access, at the single-lipid self-assembly level, to the transmembrane potential needed to detect divalent ion permeabilization on supramolecular giant unilamellar lipid vesicles. The critical values are strongly dependent on the lipid composition and are observed to vary from 10 to 150 mV. These values appear to be much lower than those previously reported in the literature for cells and vesicles. The detection method appears to be a decisive parameter as it is controlled by the transport of the reporter dye. We also provide evidence that the electropermeabilization process is a transient transition of the lipid self-organization due to the loss of assembly cohesion induced by bioelectrochemical perturbations of the zwitterionic interface with the solution.

Bioactive formulations with sugar-derived surfactants: a new approach for photoprotection and controlled release of promethazine.

Skin deep: A bioactive formulation for dermal delivery of antihistamines is obtained by using the original properties of catanionic associations towards self-assembly in water. The drug, which participates in its own transport, is preserved from photodegradation when solubilised in the bioactive formulation. The drug release through the skin is also delayed.

Functionalized vesicles based on amphiphilic boronic acids: a system for recognizing biologically important polyols.

We report on a new approach for creating water-soluble functionalized vesicles employing N-alkyl-3-boronopyridinium triflates (alkyl = Me, C12H25, C16H33) as sensors for monosaccharides. The nanoaggregate properties were studied by means of DLS, TEM, high-resolution (1)H NMR, and the solvatochromic dyes Reichardt's betaine and Methyl Orange. The vesicles were shown to have 30-200 nm diameters depending on the amphiphile chain length. Diol binding to the vesicles was studied by steady-state fluorescence and UV-vis using Alizarin Red S as a probe in the solution at pH 7.4 in the presence and in the absence of D-glucose and D-fructose. Strong sensing ability of boronic acid functional moieties in the order D-fructose > D-glucose was demonstrated, and apparent binding constants were estimated.

Multivalent catanionic GalCer analogs derived from first generation dendrimeric phosphonic acids.

The synthesis and characterization of a new series of catanionic multivalent analogs of GalCer is described. These systems are based on phosphonic acid terminated dendrimers and N-hexadecylamino lactitol moieties. Despite important structural differences that affect the dendrimers' outer-shell, these supramolecular assemblies showed a fairly comparable anti-HIV-1 activity. All compounds have submicromolar IC(50) in a cell-based HIV-infection model but also a high general cytotoxicity.

Evaluation of biocompatible stabilised gelled soya bean oil nanoparticles as new hydrophobic reservoirs.

Based on the organogel concept, in which an oil is trapped in a network of low-molecular-mass organic gelator fibres creating a gel, a formulation of gelled soya bean oil nanoparticles was evaluated for its capacity to form biocompatible hydrophobic reservoirs. The aqueous dispersions of nanoparticles were prepared by hot emulsification (T° > Tgel) and cooling at room temperature in the presence of polyethyleneimine (PEI). The dispersions were stabilised by the electrostatic interactions between the positively charged amino groups of the PEI and the negatively charged carboxylates of the gelator fibres present at the surface of the particles. The aqueous dispersions were highly stable (several months) and the gelled particles were able to entrap a hydrophobic fluorescent model molecule (Nile red), allowing testing in cells. The gelled oil nanoparticles were found to be biocompatible with the tested cells (keratinocytes) and had the ability to become rapidly internalised. Thus, organogel-based nanoparticles are a promising hydrophobic drug delivery system.

Rheological characterization of a new type of colloidal dispersion based on nanoparticles of gelled oil.

The rheological properties of a new type of colloidal dispersion based on nanoparticles of gelled oil have been characterized. The nanoparticles (mean diameter approximately 250 nm) were viscoelastic droplets of dicaprylyl ether gelled by 12-hydroxystearic acid (HSA) and were stabilized in aqueous solutions by cetyltrimethylammonium bromide. The effects of the volume fraction of the dispersed organogel phase and of the organogelator concentration upon viscoelasticity of the dispersion were investigated and compared to the corresponding emulsion (without HSA). The shear viscosity of the dispersions of organogel droplets and the elastic and viscous moduli (G' and G'') were found to increase when the proportion of organogelator was increased. More surprisingly, the shear-thinning behavior was also more pronounced. The rheological behavior of the dispersions could be explained by strong interactions between some gelled particles. This hypothesis was supported by electron microscopy observations showing some particles bridged together by ribbons of HSA fibers.

Phosphonate terminated PPH dendrimers: influence of pendant alkyl chains on the in vitro anti-HIV-1 properties.

The synthesis, characterization and in vitro anti-HIV activity of a series of generation one dendrimers having phosphonate groups with pendant alkyl chains are described. The influence of the lateral alkyl chains on the biological properties was correlated to (1)H-(1)H NOESY experiments.

Ceramide production associated with retinal apoptosis after retinal detachment.

BACKGROUND: During retinal detachment, premature apoptosis of photoreceptors and a loss of optimally corrected visual acuity occur. We hypothesized that retinal cell death and generation of ceramide, a pro-apoptotic lipid, would progress as a function of time following experimental retinal detachment, and undertook to define the appropriate temporal window. METHODS: Unilateral retinal detachment was induced in white New Zealand rabbits by subretinal injection of sodium hyaluronate. In experimental animals, we injected sphingosine-1-P into the vitreous 2 hours before retinal detachment. Both eyes were removed on days 1, 3 and 6 for histological and biochemical examination. The number of photoreceptors was counted in section, the level of apoptosis was assessed using the TUNEL assay, and the production of ceramide was analyzed in situ with immunohistochemistry. The concentration of ceramide was also determined on retinal homogenates using a diacylglycerol kinase assay. RESULTS: We confirmed that the average number of live photoreceptors decreased gradually after retinal detachment. In eyes pre-treated with sphingosine-1-P the number of apoptotic photoreceptors was significantly lower. The proportion of apoptotic photoreceptors (14%) remained constant as a function of time in the window studied. As compared to controls, the detached retina showed intense ceramide immunostaining that was prominent in the photoreceptors, but also present to a lesser extent in other retinal layers. The total concentration of intra-retinal ceramide increased by 40% on the first day and continued augmenting through the sixth day after retinal detachment. CONCLUSIONS: Retinal apoptosis during experimental retinal detachment is associated with in vivo production of ceramide.

Drug delivery by soft matter: matrix and vesicular carriers.

The increasing need for drug delivery systems that improve specificity and activity and at the same time reduce toxicity to ensure maximum treatment safety has led to the development of a great variety of drug vectors. Carriers based on soft matter have particularly interesting characteristics. Herein we present the current standing of the research in this area, and focus on two main families, namely matrix systems and vesicles. We outline the structure, properties, and potential applications of these vectors, and discuss their main advantages and drawbacks in their synthesis.

Preparation and characterization of new hybrid organic/inorganic systems derived from calcium (alpha-aminoalkyl)-phosphonates and -phosphonocarboxylates.

We have studied the phenomenon of calcium complexation by lab synthesized amphiphilic (alpha-aminoalkyl)-phosphonocarboxylic or -phosphonic acids. The electrical conductivity of aqueous solutions of sodium salts of all these acids was measured versus the volume of a calcium salt solution added. It appeared that calcium complexes are formed in a Ca/P atomic ratio close to 1. Calcium phosphonocarboxylates and calcium phosphonates were also precipitated by mixing aqueous solutions of disodium salts of phosphorus amphiphiles and calcium nitrate solutions. Before chemical analysis, these complexes were calcined to remove the organic part. In the mineralized products, calcium and phosphate were assayed: the Ca/P atomic ratio was equal to 1. X-ray diffraction and IR spectroscopy showed that they are made entirely of beta pyrophosphate (Ca2P2O7), a result in agreement with previous chemical analysis. The chemical formula of the starting calcium complexes could be written as CaL2H2O (L=ligand). The SEM micrographs of these complexes show plate-like structures. XRD patterns are characteristic of layered structures. These facts suggest that calcium complexes are composed of alternating bimolecular layers of calcium alkylphosphonocarboxylates or calcium alkylphosphonates, the chains being tilted and partially interdigitated.

Asymmetric synthesis of (alpha-amino)phosphonic acid amphiphiles using chiral P-H spirophosphoranes.

Chiral P-H spirophosphoranes reacted with long-chain prochiral aldimines and, after selective hydrolysis, afforded (alpha-amino)phosphonic acid amphiphiles in both enantiopure forms.

Correlation between structure, aggregation behaviour and cellular toxicity of anti-HIV catanionic analogues of galactosylceramide.

The self-association process of catanionic analogues of galactosylceramide and in particular the arrangement of their hydrophobic part seems to play a key role in their cellular toxicity

Phosphorus-containing dendrimers bearing galactosylceramide analogs: self-assembly properties.

We report the synthesis and the supramolecular auto-assembly of catanionic phosphorus-containing dendrimers mimicking multisite analogs of galactosylceramide.

Photochemical behavior of a new long-chain UV absorber derived from 4-tert-butyl-4'-methoxydibenzoylmethane.

A new UV filter, the 1-(4-tert-butylphenyl)-2-decanyl-3-(4'-methoxyphenyl)-propane-1,3-dione, called C10-DBM, was prepared by grafting a 10-carbon aliphatic chain to the alpha-carbonyl position of 4-tert-butyl-4'-methoxydibenzoylmethane (BM-DBM), a well-known and often used UV filter. The UV-A absorption efficiency of organic solutions containing the new filter was tested and compared with identical solutions containing BM-DBM with or without irradiation (xenon lamp). The originality of this new filter is that its UV-A absorbance appeared during irradiation of the molecule. Although the molar absorption coefficient of C10-DBM in the UV-A domain was lower than that of BM-DBM, the solutions absorption exhibited a much more photostable behavior under irradiation. In this study, we first demonstrated that C10-DBM was a precursor of BM-DBM (enol isomer) by means of high-performance liquid chromatography followed by mass spectrometry. Indeed, we showed that the UV-A absorption of C10-DBM solutions appearing during the irradiation of the molecule was due to a Norrish-II reaction (beta-cleavage), which induced the release of the BM-DBM enol form and 1-decene. Then, we established a kinetic model for the photochemistry of C10-DBM and fitted the variation of UV absorption spectra to confirm the proposed mechanism.

Crystal structure of the dimeric beta-cyclodextrin complex with 1,12-dodecanediol.

The structure of the complex of beta-cyclodextrin (beta-CD) with 1,12-dodecanediol has been determined at 173 K and refined to a final R=0.0615 based on 22,386 independent reflections. The complex crystallizes in the triclinic space group P1; with a=17.926(4), b=15.399(3), c=15.416(3) A, alpha=103.425(4), beta=113.404(4), gamma=98.858(4) degrees, D(c)=1.362 Mg cm(-3) and V=3651.4(13) A(3) for Z=1. One molecule of the diol is located as a guest in the hydrophobic cavity of a beta-CD-dimer, forming a [3]pseudorotaxane. The guest molecule shows a disorder over two positions. The hydroxyl groups of the diol emerge from the primary faces of the beta-CD dimer and form several hydrogen bonds with water molecules lying in the interstitial space, similarly to dimeric complexes of beta-CD with other alpha,omega-bifunctional guests.

Polynorbornene polycationic polymers as gene transfer agents. Influence of the counterion for in vitro transfection.

Polycationic derivatives of polynorbornene with different non-cytotoxic counterions, have been prepared by organometallic polymerization of methyleneammonium norbornene and subsequent exchange of the counterion. In this paper the effect of the counterion on the polycationic polymer binding onto plasmid DNA was studied via different ethidium bromide assays, heparin displacement and protection against degradation by DNAse. According to the nature of the counterions and consequently the size of the polymer particles, their complexation with the DNA led to aggregates with variable binding affinity for the plasmid. The relative transfection efficiency of each polyplex was compared, on the basis of reporter gene expression, in cells in culture. The nature of the counterion was seen to affect gene delivery. The order of transfection efficiency of the counterions studied at equivalent charge ratios (NH3+/PO4-) is lactobionate, acetate, chloride. The results obtained with the polynorbornene methyleneammonium lactobionate and acetate are particularly encouraging.

Langmuir films of (alpha-amino) phosphorus amphiphiles on various ion-containing subphases.

Monolayers of amphiphilic (alpha-amino)phosphonocarboxylic and (alpha-amino)phosphonic acids have been formed by adsorption at the air/water interface. The influence of both the ionic strength and the pH of the subphase on the stability and compactness of the monolayers have been studied. The stability and the compactness of the Langmuir films are enhanced by introduction of metallic ions such as Ca(2+) or Mg(2+) in the subphases. These effects are more pronounced with Ca(2+). These metal ions can form dimeric complexes with the phosphorus moieties of the surfactant polar heads and therefore bring the amphiphiles closer. For the less hydrophobic derivative, complexation with Ca(2+) or Mg(2+) is required to ensure the formation of a stable monomolecular film. For both phosphonocarboxylic and phosphonic compounds, models have been proposed to represent the complexation phenomenon at the air/water interface.

Gelled oil particles: a new approach to encapsulate a hydrophobic metallophthalocyanine.

Chloroaluminum phthalocyanine (ClAlPc) is a promising sensitizer molecule for photodynamic therapy, but its hydrophobicity makes it difficult to formulate. In this study, we have efficiently encapsulated ClAlPc into gelled soybean oil particles dispersed in water. 12-Hydroxystearic acid (HSA) and polyethyleneimine (PEI) were the gelling and stabilizing agents, respectively. The preparation process involved hot emulsification above the gelation temperature (Tgel), followed by cooling to room temperature, which gave a colloidal dispersion of gelled particles of oil in aqueous medium. The gelled particles containing ClAlPc had a medium diameter of 280 nm, homogeneous size distribution (polydispersity index ≈0.3) and large positive zeta potential (about +50 mV) and showed a spherical morphology. The gelled oil particle formulations exhibited good physical stability over a 6-month period. ClAlPc interfered with the HSA self-assembly only slightly, and decreased the gelation temperature to a small extent; however it did not affect gelation process of the oil droplets. The amounts of PEI and HSA employed during the preparation allowed us to control particle size and the dispersion stability, a phenomenon that results from complex electrostatic interactions between the positively charged PEI and the negatively charged HSA fibers present on the gelled particles surface. In summary, by using the right ClAlPc, HSA, and PEI proportions, we prepared very stable dispersions of gelled soybean oil particles with excellent ClAlPc encapsulation efficiency. The obtained colloidal formulation of gelled oil particles loaded with ClAlPc shall be very useful for photodynamic therapy protocols.