Characterization of fluorocarbon-in-water emulsions with added triglyceride

Fluorocarbon-in-water emulsions are being explored clinically as synthetic oxygen carriers in general surgery. Stabilizing fluorocarbon emulsions against coarsening is critical in maintaining the biocompatibility of the formulation following intravenous administration. It has been purported that the addition of a small percentage of long-chain triglyceride results in stabilization of fluorocarbon emulsions via formation of a three-phase emulsion. In a three-phase emulsion, the triglyceride forms a layer around the dispersed fluorocarbon, thereby improving the adhesion of the phospholipid surfactant to the dispersed phase. In the present study, we examined the effect of triglyceride addition on the physicochemical characteristics of the resulting complex dispersion. In particular, we examined the particle composition and stability of the dispersed particles using a method which first fractionates (classifies) the different particles prior to sizing (i.e., sedimentation field-flow fractionation). It was determined that the addition of a long-chain triglyceride (soybean oil) results in oil demixing and two distinct populations of emulsion droplets. The presence of the two types of emulsion droplets is not observed via light scattering techniques, since the triglyceride droplets dominate the scattering due to a large difference in the refractive index between the particles and the medium as compared to fluorocarbon droplets. The growth of the fractionated fluorocarbon emulsion droplets was followed over time, and it was found that there was no difference in growth rates with and without added triglyceride. In contrast, addition of medium-chain-triglyceride (MCT) oils results in a single population of emulsion droplets (i.e., a three-phase emulsion). These emulsions are not stable to droplet coalescence, however, as significant penetration of MCT into the phospholipid lipid interfacial layer results in a negative increment in the monolayer spontaneous curvature, thereby favoring water-in-oil emulsions and resulting in destabilization of the emulsion to the effects of terminal heat sterilization or mechanical stress.     

EVALUATION OF A SERIES OF PERFLUOROALKYLATED SURFACTANTS DERIVED FROM TERTIARY AMINES: SURFACE PROPERTIES AND EMULSIFICATION OF FLUOROCARBONS

In view of their easy preparation, the physicochemical properties of a series of highly fluorinated cationic (ammonium salts), zwitterionic (carboxybetaines) or nonionic (amine oxide) surfactants derived from perfluoroalkylated tertiary amines were investigated. Their solubility in water, interfacial properties and the exceptionally low hemolytic activity of the zwitterionic series mark them out as potential surfactants or co-surfactants for the preparation of fluorocarbon emulsions and other preparations for biomedical use. Fine and moderately concentrated fluorocarbon emulsions (50 w/w% in fluorocarbon) could be obtained in some cases when they were used as the sole surfactant. However, none was found suitable for preparing concentrated emulsions (90 w/v% in fluorocarbon) and no appreciable stabilization was found when they were used as co-surfactants with egg yolk phospholipids.     

The solubility of oxygen in aqueous fluorocarbon emulsions

The solubility of oxygen in aqueous fluorocarbon emulsions has been measured directly for several perfluorocarbons and monobromo or monoiodo-perfluorocarbons. The measured oxygen solubilities are consistent with results for the solubility of oxygen in neat liquid perfluorinated organic compounds.     

Impact of the structure of phospholipid dispersions on the stability of fluorocarbon/phospholipid emulsions for biomedical uses

The preparation of injectable fluorocarbon emulsions includes the dispersion of the phospholipids in the aqueous phase, then the admixing of the fluorocarbon to produce a crude premix; emulsification is then achieved using a high pressure mechanical procedure, followed by final heat-sterilization. In this work we report that, depending on the procedure used and energy applied, the dispersions of phospholipids consist of poorly organized unclosed “pre-liposomes”, multilamellar vesicles (MLV), or small unilamellar vesicles (SUV). This has a significant impact on the stability of the final fluorocarbon emulsions (90% (w/v) concentration), those prepared from “pre-liposomes” being more stable than those prepared from MLV or SUV. The first emulsion is shown to contain less fluorocarbon-free phospholipid vesicles than the other two. These free vesicles have previously been reported to have a detrimental effect on the stability of concentrated fluorocarbon emulsions.     

Blood substitutes and other potential biomedical applications of fluorinated colloids

An oxygen carrying, heat-sterilized phospholipid-based emulsion of a fast excreted lipophilic fluorocarbon, perfluorooctyl bromide (perflubron), stabilized against molecular diffusion, has been developed to serve as a temporary blood substitute. It is expected to reduce exposure to donor blood and thereby help mitigate the pressure on our blood supply. A phase III clinical trial in Europe has demonstrated that use of the emulsion resulted in avoidance and reduction of donor blood transfusion in surgery patients. Further potential applications for fluorocarbon emulsions include use as a bridge to transfusion, treatment of myocardial ischemia and stroke, potentiation of radio and chemotherapy and preservation of organs destined for transplantation. Echogenic, injectable gaseous microbubbles, osmotically stabilized by perfluorohexane, provide an effective contrast agent for ultrasound imaging. Clinical trials have established improved imaging of the walls of the heart and, hence, assessment of cardiac function. The ability of improving detection of myocardial perfusion, blood flow abnormalities and solid tumors is also being investigated. Various families of fluorinated amphiphiles with modular molecular structures and polar heads derived from natural products have been synthesized. Due to their highly hydrophobic perfluoroalkylated tail chains, these amphiphiles readily self-assemble into stable fluorinated vesicles, tubules and other organized molecular systems with distinctive properties. Fluorosurfactants also allowed preparation of direct, reverse, apolar and multiple emulsions and gels. These fluorinated colloids have potential for the delivery of drugs and other bioactive materials, and provide unique tools in biomedical research.     

正、负离子碳氟-碳氢表面活性剂混合水溶液的表面活性

1　前言碳氟表面活性剂是目前所有表面活性剂中表面活性最高的一类 ,具有很多碳氢表面活性剂无法取代的特殊用途[1] 。但是碳氟表面活性剂由于合成困难 ,价格昂贵 ,实际应用受到限大限制。研究表明 ,通过碳氟表面活性剂与碳氢表面活性剂的复配 ,有可能减少碳氟表面活性剂的用量而保持其表面活性 [1] 。在所有表面活性剂混合体系中 ,正、负离子表面活性剂混合体系具有最强的协同效应 [2 ] 。但由于正、负离子表面活性剂混合溶液一般在很低浓度即形成沉淀 ,对碳氟表面活性剂更是如此。因此目前有关碳氟—碳氢混合表面活性剂的研究主要集中在同…     

Emulsions and microemulsions with a fluorocarbon phase

A phase III clinical study of a perfluorooctyl bromide emulsion demonstrated reduction and avoidance of donor blood transfusion in surgery. Novel fluorocarbon-in-water emulsions are being investigated, including emulsions highly stabilized by fluorocarbon–hydrocarbon diblocks and targeted emulsions for molecular imaging, diagnosis and drug delivery. Reverse water-in-fluorocarbon emulsions and microemulsions that have potential for pulmonary drug delivery are also being studied. Microemulsions with highly fluorinated components are being actively investigated, with applications in polymerization technology and as research tools.     

Ion pair catalysis of the autooxidation of pyridine and benzil in emulsion systems

It was found that the rates of absorption of oxygen by pyridine–aqueous sodium hydroxide emulsions and the same emulsions containing benzil were catalyzed by the addition of quaternary salts and followed the same rate law: . It was concluded that the autooxidation of benzil in pyridine-aqeuous sodium hydroxide emulsions has as its rate-determining step a step in the autooxidation of pyridine. Possibly the superoxide formed in the autooxidation of pyridine is the oxidizing agent in the oxidation of benzil.     

Solubility of fluorocarbons in water as a key parameter determining fluorocarbon emulsion stability

The kinetics of particle size growth in emulsions of 14 fluorocarbons has been studied by means of photon correlation spectroscopy. It was assumed that Ostwald ripening is the mechanism of emulsion coarsening with time; solubility of fluorocarbons in water (about 10⁻⁶-10⁻¹⁰ml/ml) being the key parameter determining fluorocarbon emulsion stabilities. The solubilities of fluorocarbons in water were calculated from the Ostwald ripening kinetics data and a solubility-fluorocarbon structure relationship was established. In a homologous series of normal chain fluorocarbons the solubility in water decreased by a factor of 8.0 for each -CF₂ - group. For a given carbon number, ring formation and branching increased water solubility of the fluorocarbons. A correlation between fluorocarbon solubility in water and solvent cavity surface area was found which allows prediction of the fluorocarbon emulsion stability from the structure of the fluorocarbon.     

母核结构对三碳菁染料光氧化过程的影响

本文研究三种不同母核结构的三碳菁染料在乙醇溶剂中的光氧化反应,实验中采用了近红外区光谱能量分布平稳的光源,得出了母核结构对染料的光氧化稳定的影响,其影响次序:叮恶唑>硒唑>噻唑。同时本文还利用β值的测定,算出染料光氧化过程中敏化产生的单重态氧的浓度以及二者反应的速率常数。     

THE FLAVIN-SENSITIZED PHOTOOXIDATION OF NUCLEOTIDES — III. THE PARTICIPATION OF OXYGEN

Abstract— Quantum yields for the lumiflavin-sensitized oxidation of guanosine monophosphate and adenosine monophosphate in solution have been measured as functions of oxygen and nucleotide concentration. The quantum yield increases with oxygen concentration at low oxygen concentrations, but quenching of the excited flavin molecule by oxygen results in a fall in quantum yield at higher concentrations. It has also been established that the reciprocal of the quantum yield is linearly related to the reciprocal of the nucleotide concentration. A mechanism in which molecular oxygen reacts with an excited complex formed between triplet lumiflavin and the nucleotide is consistent with these observations.
A value for the second-order rate constant for the quenching of triplet lumifiavin by oxygen of 2·65 × 10⁹ M ^-1 sec^-1 has been obtained.     

Fluorocarbon- containing hydrophobically modified poly(N-isopropylacrylamide)

A fluorocarbon-modified poly(N-isopropylacrylamide) has been synthesized by copolymerization of N-isopropyl acrylamide with a small amount of acrylate or methacrylate containing a perfluoroalkyl group. It was found that the hydrophilicity of macromolecular backbone is an important factor to the solution properties of the copolymers and that hydrophobic association between fluorocarbon groups is stronger than that between the corresponding hydrocarbon analogies. The viscosity of some of the copolymer solutions was very sensitive to temperature. It was dilatant at higher fluorocarbon comonomer content ( > 0.20-1.0 mol%) and was Newtonian at very low fluorocarbon comonomer content (0.03-0.2 mol% ) . Evidence for hydrophobic association of the fluorocarbon groups was obtained from the effects of adding Nad and surfactants on the solution viscosity. The LC-ST properties of these copolymers were studied by DSC method and this was also found to be consistent with hydrophobic association between the fluorocarbo     

Prediction of conformational characteristics and micellar solution properties of fluorocarbon surfactants

A molecular-thermodynamic theory is developed to model the micellization of fluorocarbon surfactants in aqueous solutions, by combining a molecular model that evaluates the free energy of micellization of fluorocarbon surfactant micelles with a previously developed thermodynamic framework describing the free energy of the micellar solution. In the molecular model of micellization developed, a single-chain mean-field theory is combined with an appropriate rotational isomeric state model of fluorocarbon chains to describe the packing of the fluorocarbon surfactant tails inside the micelle core. Utilizing this single-chain mean-field theory, the packing free energies of fluorocarbon surfactants are evaluated and compared with those of their hydrocarbon analogues. We find that the greater rigidity of the fluorocarbon chain promotes its packing in micellar aggregates of low curvatures, such as bilayers. In addition, the mean-field approach is utilized to predict the average conformational characteristics (specifically, the bond order parameters) of fluorocarbon and hydrocarbon surfactant tails within the micelle core, and the predictions are found to agree well with the available experimental results. The electrostatic effects in fluorocarbon ionic surfactant micelles are modeled by allowing for counterion binding onto the charged micelle surface, which accounts explicitly for the effect of the counterion type on the micellar solution properties. In addition, a theoretical formulation is developed to evaluate the free energy of micellization and the size distribution of finite disklike micelles, which often form in the case of fluorocarbon surfactants. We find that, compared to their hydrocarbon analogues, fluorocarbon surfactants exhibit a greater tendency to form cylindrical or disklike micelles, as a result of their larger molecular volume as well as due to the greater conformational rigidity of the fluorocarbon tails. The molecular-thermodynamic theory developed is then applied to several ionic fluorocarbon surfactant-electrolyte systems, including perfluoroalkanoates and perfluorosulfonates with added LiCl or NH(4)Cl, and various micellar solution properties, including critical micelle concentrations (cmc's), optimal micelle shapes, and average micelle aggregation numbers, are predicted. The predicted micellar solution properties agree reasonably well with the available experimental results.     

A dynamic light scattering study of the influence of the phospholipid concentration in a model perfluorocarbon emulsion

Perfluorohexyl iodide in water emulsions stabilised by phospholipids were prepared by microfluidisation. Photon correlation spectroscopy revealed that the particle size distributions of these emulsions were bimodal. Centrifugation experiments indicated that the larger mode was caused by the emulsion droplets, whereas the smaller mode was due to phospholipid vesicles formed from the excess amount of phospholipid emulsifier. Comparing the particle size distributions of perfluorocarbon emulsions containing different amounts of phospholipids, it could be concluded that emulsions with a phospholipid/fluorocarbon ratio of 2% at the most were emulsifier limited, whereas those with a ratio of at least 5% were energy input limited.     

Cosurfactant effect of a semifluorinated alkane at a fluorocarbon/water interface: impact on the stabilization of fluorocarbon-in-water emulsions

Previous work has demonstrated that semifluorinated alkanes CnF2n+1CmH2m+1 (FnHm diblocks), when used in conjunction with phospholipids, strongly stabilize fluorocarbon (FC)-in-water emulsions destined to be used as oxygen carriers. Although the presence of FnHm diblocks in the emulsion's interfacial phospholipid film was suggested to account for the observed stabilization, no direct proof of the diblock's location has been provided so far. We now report definite experimental evidence of the diblock's presence at the interfacial film, both on a macroscopic level by investigating the FC/water interface using the pendant drop method and directly on emulsions by monitoring their stability for various phospholipid chain lengths. We first establish that F8H16 has a strong cosurfactant effect with phospholipids [dimyristoylphosphatidylcholine (DMPC), dilaurylphosphatidylcholine (DLPC), dioctanoylphosphatidylcholine (PCL8)] at a perfluorooctyl bromide (PFOB)/water interface, as evidenced by a dramatic F8H16-concentration-dependent decrease of the interfacial tension. Where FC emulsions are concerned, we show that the stabilization effect, which consists of a decrease of the rate of molecular diffusion of the FC, depends strongly on the length of the phospholipid's fatty chain as compared to the length of the hydrocarbon segment, Hm, of the diblock. Stabilization is maximized when the Hm length is similar to that of the phospholipid's fatty chains. A strong mismatch between Hm and the phospholipid chain length can actually destabilize the emulsion. A different destabilization mechanism is then at work: coalescence. The presence of F8H16 at the interfacial film is further supported by the fact that perfluorodecyl bromide, a heavy analogue of PFOB that stabilizes PFOB emulsions by lowering the solubility and diffusibility of the emulsion's dispersed FC phase, exercises its stabilizing effect similarly for all the phospholipids investigated.     

苯并三氮唑对硫增感溴化银乳剂的过增感效应

采用在曝光前后用苯并三氮唑溶液对未增感的和硫增感的立方体溴化银乳剂涂层的处理方法,考察了苯并三氮唑在溴化银成像过程的两个阶段:曝光潜影的形成阶段和潜影中心得以放大的显影阶段的作用.有意义地发现苯并三氮唑对硫增感溴化银乳剂有明显的过增感效应.实验结果表明:1)对于未增感的立方体溴化银乳剂涂层,在曝光前吸附了苯并三氮唑后会抑制潜影的形成,但曝光后吸附了苯并三氮唑对显影有十分明显的促进作用;2)对于硫增感的立方体溴化银乳剂涂层,曝光前用苯并三氮唑溶液处理后,产生显著的过增感效应,相对感光度可提高4倍左右,在曝光后用苯并三氮唑溶液处理,随着苯并三氮唑浓度的增加对显影也有一定程度的促进作用;3)对于硫增感的溴化银涂层,先经过388 mV的氧化还原缓冲液处理,再经苯并三氮唑溶液处理过的样片的感光度都要较未经缓冲液处理的提高4倍左右,这说明苯并三氮唑对硫增感乳剂产生的过增感效应只与硫敏化中心内(Ag₂S)_n的存在有关,与(Ag)_m是否存在无关.     

Effect of lateral heterogeneity in mixed surfactant-stabilized interfaces on the oxidation of unsaturated lipids in oil-in-water emulsions

The development of lipid oxidation in oil-in-water (O/W) emulsions is widely influenced by the properties of the interfacial layer, which separates the oil and water phases. In this work, the effect of the structure of the interface on the oxidative stability of surfactant stabilized O/W emulsions was investigated. Emulsions were prepared with either single Tween 20 or Tween 20/co-surfactant mixtures in limiting amounts. The co-surfactants, Span 20 and monolauroyl glycerol have the same hydrophobic tail as Tween 20 but differ by the size and composition of their polar headgroup. Metal-initiated lipid oxidation, monitored through the measurement of oxygen uptake, formation of conjugated dienes and volatile compounds, developed more rapidly in the emulsions stabilized by the surfactant mixture than in the single Tween 20-stabilized emulsion. The reconstitution of Tween 20/co-surfactant films at the air-water interface and their surface-pressure isotherms highlighted that, contrary to single Tween 20 molecules, Tween 20/co-surfactant mixtures exhibited an heterogeneous distribution within the interfacial layer, offering probably easier access of water-soluble pro-oxidants to the oil phase. These observations provide direct information about the link between the homogeneity of the interface layer and the oxidative stability of emulsions.     

Investigation in monolayers of double-chain fluorocarbon amphiphiles Effect of headgroups on molecular packing and interaction between hydrocarbon and fluorocarbon monolayers

The surface pressure-area diagrams of double-chain fluorocarbon amphiphiles with different headgroup compositions show that the amphiphiles arrange almost perpendicularly to the water subphase and the structure of headgroups exerts significant influence on the amphiphile packing. Strong hydrogen bonding and weak electrostatic interaction favor the formation of stable monolayers. Perfluorooctanoic acid (FOA) cannot form monolayer at water/air interface and can only form liquid monolayer in subphase of calcium nitrate solution. Complete phase separation of palmitic acid and a fluorocarbon amphiphile with shorter hydrocarbon spacer group, 1, could be demonstrated in monolayers by using the phase rule of Crisp. The creation of phase-separated monolayers is possible when the monolayer is composed of a mixture of palmitic acid and a fluorocarbon amphiphile with longer hydrocarbon spacer group, 2. It can be suggested that the miscibility of hydrocarbon amphiphiles with fluorocarbon amphiphiles is determined by the hydrocarbon fraction of fluorocarbon amphiphiles.     

铜(Ⅱ)及其配合物催化胆红素氧化动力学的研究

本文用电化学，吸收光谱等方法对Ｃｕ（２＋）及其配合物与胆红素在碱性（ｐＨ１０）条件下的作用规律进行了研究．发现Ｃｕ（２＋）及其配合物对胆红素的氧化的催化作用依配合物的稳定性和配体齿数不同而异．在胆红素的氧化过程中，真正起氧化作用的是溶解氧．