The mechanism of hydroxide ion binding to nonionic surfaces is explored by variation of the properties of the water-aggregate interface and by variation of the type of the aggregate.
Sugar-based gemini surfactants (GSs) display rich pH-dependent phase diagrams and are considered to be promising candidates as gene- and drug-delivery vehicles for biomedical applications. Several sugar-based GSs form vesicles around neutral pH. The vesicular dispersions undergo transitions toward wormlike micelles and spherical micelles at acidic pH, whereas flocculation followed by redispersion upon charge reversal is observed at basic pH. The influence of various amounts of the double-tailed phospholipids DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and of the single-tailed surfactants lyso-PC (1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine) and OTAC (octadecyltrimethylammonium chloride) on the phase behavior of GS1 (1,8-bis(N-octadec-9-yl-1-deoxy-D-glucitol-1-ylamino)3,6-dioxaoctane) was determined as a function of pH, in water and in water at physiological ionic strength. The pH corresponding to the phase transitions and the characteristics of the aggregates were determined by means of a combination of physical techniques: static and dynamic light scattering (SLS and DLS), fluorescence spectroscopy, cryo-TEM and diffusion- and (31)P NMR. The results show that the additives affect the phase behavior of the GS1 dispersions in a pH-dependent fashion. In the presence of double-tailed phospholipids, a higher degree of protonation of GS1 must be reached to observe micelle formation, whereas single-tailed surfactants affect these transitions only slightly. In the presence of increasing amounts of lyso-PC, the pH range of flocculation becomes more narrow, indicating the increased hydration of the vesicles. The pH of redispersion after charge reversal is particularly sensitive to the presence of positively charged additives. It is suggested that the cationic headgroups disturb the hydrogen-bond structure of water at the vesicular surface, hampering OH(-) binding. The effect of an increase in ionic strength to physiological values is found to be modest, except for the dispersions containing the positively charged additives.
The present study aims at a better understanding of the mechanism of transfection mediated by two sugar-based gemini surfactants GS1 and GS2. Previously, these gemini surfactants have been shown to be efficient gene vectors for transfection both in vitro and in vivo. Here, using Nile Red, a solvatochromic fluorescent probe, we investigated the phase behavior of these gemini surfactants in complexes with plasmid DNA, so-called lipoplexes. We found that these lipoplexes undergo a lamellar-to-non-inverted micellar phase transition upon decreasing the pH from neutral to mildly acidic. This normal (non-inverted) phase at acidic pH is confirmed by the colloidal stability of the lipoplexes as shown by turbidity measurements. We therefore propose a normal hexagonal phase, H(I), for the gemini surfactant lipoplexes at acidic endosomal pH. Thus, we suggest that besides an inverted hexagonal (H(II)) phase as reported for several transfection-potent cationic lipid systems, another type of non-inverted non-bilayer structure, different from H(II), may destabilize the endosomal membrane, necessary for cytosolic DNA delivery and ultimately, cellular transfection.
The phase behavior of a series of carbohydrate-based gemini surfactants with varying spacer lengths was studied using static and dynamic light scattering between pH 2 and 12. Cryo-electron microscopy pictures provide evidence for the different morphologies present in solution. The spacer length of the gemini surfactants was varied from two to 12 methylene units. At near neutral pH, spherical vesicles were obtained for gemini surfactants with a spacer shorter than 10 methylene units, whereas nonspherical vesicles were obtained for spacer lengths of 10 and 12. Upon decreasing the pH, the vesicles underwent transitions toward worm-like micelles and spherical micelles for a spacer length of six and larger, whereas for shorter spacers, these transitions are not observed. For the shortest spacer at low pH, perforated vesicles are observed, and vesicles built from the gemini surfactant with a spacer of four methylene units only underwent a transition toward worm-like micelles. Upon increasing the pH to slightly basic values, flocculation followed by redispersion upon charge reversal was observed up to a spacer length of eight methylene units. The redispersal is explained by hydroxide-ion binding to the uncharged vesicular surface. By contrast, vesicles formed from the gemini surfactants with 10 and 12 methylene units only undergo a transition toward inverted phases. The observations can be understood in terms of the packing parameter.
Two double-tailed pyridinium cationic amphiphiles, differing only in the degree of unsaturation of the alkyl chains, have been selected for a detailed study of their aggregation behavior, under conditions employed for transfection experiments. The transfection efficiencies of the two molecules are remarkably different, especially when combined with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as helper lipid. The phase behavior of the cationic amphiphile/DOPE mixtures have been studied using (31)P- and (2)H-NMR (on deuterated cationic amphiphiles) as main techniques, to monitor independently the behavior of the two components. In water, the lamellar organization is dominant for both the surfactants in their mixtures with the helper lipid. In HEPES saline buffer (HBS), the mixtures of the unsaturated surfactant form inverted phases and, in particular, stable H(II) phases for DOPE contents > or =30 mol %. By contrast, the saturated surfactant does not form homogeneously mixed inverted phases in mixtures with DOPE at room temperature. However, mixed inverted phases are observed for this system at higher temperatures and, after mixing has been achieved by heating, the metastable mixed phases remain present for several hours at 5 degrees C. At 35 degrees C the dominant phase is the cubic phase. The lipoplex composed of equimolar mixtures of the unsaturated surfactant with DOPE and plasmid DNA was found to be organized in highly curved bilayers.
A detailed physicochemical study is presented on a new class of cationic amphiphiles, Sunfish amphiphiles, recently designed, synthesized, and tested for gene delivery. These materials have two hydrophobic tails, connected to the cationic pyridinium headgroup at the 1- and 4-positions. Two extreme morphologies can be visualized, i.e. one by back-folding involving association of both tails at one side of the pyridinium ring and one by independent unfolding of the tails, the two molecular geometries leading to considerable differences in the aggregate morphology. The behavior of six members of the Sunfish family in mixtures with DOPE, applying different conditions relevant for transfection, has been studied by a combination of techniques (DLS, DSC, NMR, SAXS, Cryo-TEM, fluorescence, etc.). The effects of structural parameters such as the presence of unsaturation in the tails and length of the alkyl chains on the properties of the aggregates have been assessed. A correlation of these structural data with cellular transfection efficiencies reveals that the highest transfection efficiency is obtained with those amphiphiles that are easily hydrated, form fluid aggregates, and undergo a transition to the inverted hexagonal phase in the presence of plasmid DNA (p-DNA) at physiological ionic strength.
The pH-dependent phase behavior and hydroxide-ion adsorption ability of a series of (reduced) carbohydrate-based gemini surfactants were studied between pH 2 and 12. Static and dynamic light scattering were employed to address transitions in the aggregate morphologies and cryo-electron microscopy was used to provide further evidence for the morphologies present in solution. Changes in aggregate structure as a result of a change in solution pH and an accompanying change in protonation state or a change in molecular structure can be rationalized in terms of the variations in the packing parameter. In this paper we have focused our attention on the size of the carbohydrate moiety, the carbohydrate stereochemistry and the nature of the spacer (hydrophobic vs hydrophilic). At near neutral pH, most of the gemini surfactants form vesicles. Upon lowering of the pH, the vesicles undergo a transition toward wormlike micelles followed by a transition to spherical micelles. Upon increasing the solution pH, flocculation occurs due to charge neutralization followed at still higher pH by redispersion and charge reversal of the vesicles through the specific adsorption of hydroxide ions to the vesicular surface. Upon decreasing head group size at constant, but low, degrees of protonation, the packing parameter has a tendency to become larger than one resulting in the formation of inverted phases. Upon further decrease in the head group size, oil droplets are observed. In case of a hydrophobic spacer, the carbohydrate stereochemistry affects the pH of the transitions, but not the type of the transitions. By contrast, for a hydrophilic spacer, the pH of the transitions remains unaffected. Adsorption of hydroxide ions at basic pH follows similar trends, but was only found for vesicles and oil droplets. The large range of structural variations that we have examined allows a better understanding of the requirements for the phase transitions for carbohydrate-based gemini surfactants as well as for the physisorption of hydroxide ions to interfaces in general.
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