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The Langmuir-Blodgett technique is one of the most controlled methods to deposit monomolecular layers of floating or surface active materials but has lacked the ability to coat truly large-area substrates. In this work, by manipulating single-layer dispersions of graphene oxide (GO) and thermally exfoliated GO into water-immiscible spreading solvents, unlike traditional Langmuir-Blodgett deposition which requires densification achieved by compressing barriers, we demonstrate the ability to control the 2D aggregation and densification behavior of these floating materials using a barrier-free method. This is done by controlling the edge-to-edge interactions through modified subphase conditions and by utilizing the distance-dependent spreading pressure of the deposition solvent. These phenomena allow substrates to be coated by continuous deposition and substrate withdrawal-enabling roll-to-roll deposition and patterning of large-area substrates such as flexible polyethylene terephthalate. The aggregation and solvent-driven densification phenomena are examined by in situ Brewster angle video microscopy and by measuring the local spreading pressure induced by the spreading solvent acting on the floating materials using a Langmuir-Adam balance. As an example, the performance of films deposited in this way is assessed as passivation layers for Ag nanowire-based transparent conductors.
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The effect of variation in the length of surfactant hydrocarbon tail groups was tested in a series of dissymmetric gemini surfactants (N1-alkyl N1,N1,N3,N3-tetramethyl-N3-(6-pyren-6yl)-hexyl)propane-1,3-diammonium dibromide designated as CmC3CnBr, with m = hexyl pyrene, and n = 8, 12, 14, 16, and 18. The aggregation properties of these surfactants have been investigated by means of 1H NMR, fluorescence spectroscopy, surface tension and electrical conductivity measurements. The critical micelle concentration (CMC) was determined using surface tension and confirmed using the specific conductance method. Krafft temperatures and the degree of micelle ionization (α) were obtained from specific conductance measurements. With an increase of the dissymmetry (m/n) ratio, the CMC decreased linearly and an increase in the Krafft temperatures was observed for all of the gemini surfactants. α values for the dissymmetric GS were higher than those of the m-3-m counterparts, which may be attributed to enhanced micelle-micelle interactions that arise from increased hydrophobicity of the hydrocarbon chains. The introduction of the bulky pyrenyl tail group resulted in much lower CMC values compared to their symmetrical counterparts affecting the packing of these surfactants at the air/water interface, which resulted in high-ordered structures (lamellar and inverted micelles). This in turn affected the thermodynamic parameters of the micellization.
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The outermost layer of the skin, known as the stratum corneum (SC), is composed of dead corneocytes embedded in an intercellular lipid matrix consisting of ceramides, free fatty acids, and cholesterol. The high level of organization within this matrix protects the body by limiting the permeation of most compounds through the skin. While essential for its protective functions, the SC poses a significant barrier for the delivery of topically applied pharmaceutical agents. Chemical permeation enhancers (CPEs) can increase delivery of small drug compounds into the skin by interacting with the intercellular lipids through physical processes including extraction, fluidization, increased disorder, and phase separation. However, it is not clear whether these same mechanisms are involved in delivery of biotherapeutic macromolecules, such as proteins. Here we describe the effect of three categories of CPEs {solvents [ethanol, propylene glycol, diethylene glycol monoethyl ether (transcutol), oleic acid], terpenes [menthol, nerol, camphor, methyl salicylate], and surfactants [Tween 80, SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (Cremophor RH40), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB)]} on the lipid organizational structure of human SC as determined by X-ray scattering studies. Small- and wide-angle X-ray scattering studies were conducted to correlate the degree of structural changes and hydrocarbon chain packing in SC lipids caused by these various classes of CPEs to the extent of permeation of interferon alpha-2b (IFNα), a 19 kDa protein drug, into human skin. With the exception of solvents, propylene glycol and ethanol, all classes of CPEs caused increased disordering of lamellar and lateral packing of lipids. We observed that the highest degree of SC lipid disordering was caused by surfactants (especially SDS, DDAB, and DTAB) followed by terpenes, such as nerol. Interestingly, in vitro skin permeation studies indicated that, in most cases, absorption of IFNα was low and that an increase in SC lipid disorder does not correspond to an increase in IFNα absorption.
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Interferon-alfa/metabolismo , Mama/metabolismo , Feminino , Humanos , Técnicas In Vitro , Microscopia Confocal , Absorção Cutânea/fisiologiaRESUMO
The metabolic pathways that are involved in regulating insulin secretion from pancreatic ß-cells are still incompletely understood. One potential regulator of the metabolic phenotype of ß-cells is the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1ß. ARNT/HIF-1ß levels are profoundly reduced in islets obtained from type 2 diabetic patients. However, no study to date has investigated key pathways involved in regulating insulin release in ß-cells that lack ARNT/HIF-1ß. In this study, we confirm that siRNA-mediated knockdown of ARNT/HIF-1ß inhibits glucose-stimulated insulin secretion. We next investigated the metabolic consequence of the loss of ARNT/HIF-1ß knockdown. We demonstrate that ß-cells with reduced ARNT/HIF-1ß expression levels exhibit a 31% reduction in glycolytic flux without significant changes in glucose oxidation or the ATP:ADP ratio. Metabolic profiling of ß-cells treated with siRNAs against the ARNT/HIF-1ß gene revealed that glycolysis, anaplerosis, and glucose-induced fatty acid production were down-regulated, and all are key events involved in glucose-stimulated insulin secretion. In addition, both first and second phase insulin secretion in islets were significantly reduced after ARNT/HIF-1ß knockdown. Together, our data suggest an important role for ARNT/HIF-1ß in anaplerosis, and it may play a critical role in maintaining normal secretion competence of ß-cells.
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Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico/fisiologia , Diabetes Mellitus Tipo 2/genética , Ácidos Graxos não Esterificados/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Perfilação da Expressão Gênica , Glucose/farmacologia , Células Secretoras de Insulina/citologia , Insulinoma , Metabolômica , Oxirredução , Neoplasias Pancreáticas , Via de Pentose Fosfato/fisiologia , RNA Interferente Pequeno , RatosRESUMO
Improvements in transfection efficiency are required in order to make the goal of cellular gene delivery by non-viral vectors realizable. Novel derivatives of gemini surfactants having dissymmetric tail groups have been designed specifically as a means to improve DNA transfection; the micelle and interfacial properties are reported herein. The effect of these substitutions on the aggregation properties of the gemini surfactants is discussed in the context of results for the m-3-m gemini series, previously reported in the literature. Phytanyl substitution results in lower cmc and higher micelle ionization. In addition, the phytanyl substituted gemini surfactants form vesicles at room temperature. Preliminary in vitro transfection assays showed the phytanyl substituted gemini surfactants to be more efficient transfection vectors as compared to symmetric gemini surfactants.
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Tensoativos/química , Transfecção , Calcitriol/análogos & derivados , Calcitriol/química , Linhagem Celular Tumoral , DNA/metabolismo , Vetores Genéticos/metabolismo , Humanos , Micelas , Fosfatidiletanolaminas/química , Tensoativos/síntese químicaRESUMO
Recently, the development of soft gelatin capsules (SGCs) dosage forms has attracted a great deal of interest in the oral delivery of poorly water-soluble drugs. This is attributed to the increased number of poorly soluble drugs in the pipeline, and hence the challenges of finding innovative ways of developing bioavailable and stable dosage forms. Encapsulation of these drugs into SGCs is one of the approaches that is utilized to deliver the active ingredients to the systemic circulation to overcome certain formulation hurdles. Once formulated, encapsulated drugs in the form of SGCs require suitable in vitro dissolution test methods to ensure drug product quality and performance. This review focuses on challenges facing dissolution test method development for SGCs. A brief discussion of the physicochemical and formulation factors that affect the dissolution properties of SGCs will be highlighted. Likewise, the influence of cross-linking of gelatin on the dissolution properties of SGCs will also be discussed.
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Gemini surfactants have demonstrated significant potential for use in constructing non-viral transfection vectors for the delivery of genes into cells to induce protein expression. Previously, two asymmetric gemini surfactants containing pyrenyl groups in one of the alkyl tails of the surfactants were synthesized as fluorescence probes for use in mechanistic studies of the transfection process. Here we present the results of a thermodynamic investigation of the binding interaction(s) between the pyrenyl-modified surfactants and DNA. The thermodynamics of the interactions have been examined using isothermal titration calorimetry, light scattering, zeta potential, and circular dichroism measurements. Distinct differences are observed between the interaction of 12-s-12 vs. the pyrene modified py-s-12 surfactants with DNA; an intercalated binding is found for the py-s-12 surfactants that disrupts the typical interactions observed between DNA and gemini surfactants.
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DNA/metabolismo , Tensoativos/metabolismo , Animais , Calorimetria , Dicroísmo Circular , DNA/química , Modelos Moleculares , Conformação Molecular , Salmão , Tensoativos/química , TermodinâmicaRESUMO
Micelle formation enthalpies (Δmic H values) have been calorimetrically determined at 298 K for three sets of mixed zwitterionic/cationic gemini systems consisting of N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (ZW3-12) and a series of structurally related gemini surfactants, the N,N'-bis(dimethyldodecyl)-α,ω-alkanediammonium dibromide (12-s-12) systems. From the experimental and the estimated ideal micelle formation enthalpies, the excess enthalpies were obtained. The degrees of nonideality of the interaction in the mixed micelle (ß m) from our previous work was used along with the excess enthalpy values to determine excess thermodynamic quantities of the surfactants in the mixed system according to Regular Solution Theory (RST) and Motomura's theory. The excess enthalpies for the ZW3-12/12-4-12 were positive in magnitude and rose sharply when small amounts of the zwittergent were distributed into the gemini micelles. The excess enthalpies for the ZW3-12/12-5-12 and the ZW3-12/12-6-12 systems were also >0 kJ mol-1, and as a function of zwittergent composition, were quite different to those of the ZW3-12/12-4-12 mixed micelles. These results indicate that the heat of mixed micelle formation is strongly dependent on electrostatic interactions and the structure of the surfactants involved, specifically, the length of the tether group for the 12-s-12 gemini surfactants. From the calorimetric data and the application of RST and Motomura's theory, we have obtained estimates of the excess Gibbs energy and entropy of mixing. An analysis of the three thermodynamic properties suggests that the relative contributions of enthalpic and entropic effects to nonideal behavior for mixed micelles involving gemini surfactants are strongly dependent on the gemini structure.
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Avocado (Persea americana Mill.; Lauraceae) seed-derived polyhydroxylated fatty alcohols (PFAs) or polyols (i.e., avocadene and avocadyne) are metabolic modulators that selectively induce apoptosis of leukemia stem cells and reverse pathologies associated with diet-induced obesity. Delivery systems containing avocado polyols have not been described. Herein, natural surface active properties of these polyols are characterized and incorporated into self-emulsifying drug delivery systems (SEDDS) that rely on molecular self-assembly to form fine, transparent, oil-in-water (O/W) microemulsions as small as 20 nanometers in diameter. Mechanistically, a 1:1 molar ratio of avocadene and avocadyne (i.e., avocatin B or AVO was shown to be a eutectic mixture which can be employed as a novel, bioactive, co-surfactant that significantly reduces droplet size of medium-chain triglyceride O/W emulsions stabilized with polysorbate 80. In vitro cytotoxicity of avocado polyol-SEDDS in acute myeloid leukemia cell lines indicated significant increases in potency and bioactivity compared to conventional cell culture delivery systems. A pilot pharmacokinetic evaluation of AVO SEDDS in C57BL/6J mice revealed appreciable accumulation in whole blood and biodistribution in key target tissues. Lastly, incorporation of AVO in SEDDS significantly improved encapsulation of the poorly water-soluble drugs naproxen and curcumin.
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Emulsões/química , Persea/química , Polímeros/química , Tensoativos/química , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Feminino , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Polissorbatos/química , Solubilidade/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Água/químicaRESUMO
Gelatin nanoparticles (GNPs) are one of the most extensively used natural polymers for gene therapy. With advantages of being biodegradable, biocompatible, low cost and easily modified, gelatin holds great promise as a non-viral system for gene delivery. This review examines various methods of preparation of modified gelatin nanoparticles and considers how these modifications apply to gene delivery. The article discusses cationic gelatin, PEGylated gelatin, thiolated gelatin, alendronate gelatin, and EGFR gelatin nanoparticles. This article also considers several advantages of these modifications and their contribution to the improvement in the efficiency of these systems, resulting in superior transfection and enhanced gene delivery in general.
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Gelatina/química , Técnicas de Transferência de Genes , Nanopartículas , Animais , Terapia Genética/métodos , Humanos , TransfecçãoRESUMO
Phyto-phospholipid complexes have been developed as a common way of improving the oral bioavailability of poorly absorbable phyto-pharmaceuticals; however, the complexation with phospholipids can induce positive or negative effects on the bioaccessibility of such plant-derived active ingredients in different parts of the gastrointestinal tract (GIT). The purpose of this study was to investigate the effects of phospholipid complexation on the bioaccessibility of a rosmarinic acid-phospholipid complex (RA-PLC) using the TNO dynamic intestinal model-1 (TIM-1). Preparation of RA-PLC was confirmed using X-ray diffraction, Fourier-transform infrared spectroscopy, partition coefficient measurement, and Caco-2 monolayer permeation test. Bioaccessibility parameters in different GIT compartments were investigated. Complexation by phospholipids reduced the bioaccessibility of RA in jejunum compartment, while maintaining the ileum bioaccessibility. The overall bioaccessibility of RA-PLC was lower than the unformulated drug, suggesting that the improved oral absorption from a previous animal study could be considered as a net result of decreased bioaccessibility overwhelmed by enhanced intestinal permeability. This study provides insights into the effects of phospholipid on the bioaccessibility of hydrophilic compounds, and analyzes them based on the relationship between bioaccessibility, membrane permeability, and bioavailability. Additionally, TIM-1 shows promise in the evaluation of dosage forms containing materials with complicated effects on bioaccessibility.
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Gemini surfactants provide a significant opportunity in the development of new non-viral delivery systems designed for gene therapy applications. This review summarizes the wide range of gemini surfactant structures that have been employed for DNA transfection in vitro. A general observation is that those structures capable of inducing a wide variety of polymorphic structures (lamellar, hexagonal, or cubic phases) demonstrate higher transfection efficiencies. Those compounds whose structures result in pH-dependent changes in aggregate structure similarly show higher levels of transfection. In vivo transfection using gemini surfactants has been demonstrated in only three cases, and in a recent study the transfection was linked to a specific therapeutic response.
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Técnicas de Transferência de Genes , Terapia Genética , Nanopartículas , Plasmídeos/genética , Tensoativos/química , Animais , Humanos , Plasmídeos/administração & dosagemRESUMO
A critical aggregate concentration for the surfactant-DNA "complex" or "condensate" consisting of the 16-3-16 gemini surfactant and circular plasmid DNA was determined using surface tensiometry, dynamic light scattering, and conductometry. This surfactant-DNA complex acts as an amphiphile itself, for example, decreasing the surface tension of water until a critical concentration is reached. The evidence presented here introduces a new way of considering these surfactant-DNA condensates, not simply as aggregates in solution but as surface-active agents in their own right. At concentrations below the critical aggregate concentration, there is some dissociation of surfactant molecules from the condensate, creating a more "loose" or "relaxed" complex; however, at and above the critical aggregate concentration, the surfactant-DNA system forms smaller and more uniformly distributed condensates once again. This behavior is analogous to demicellization/micellization that occurs in typical surfactant systems.
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Emulsion technology has been utilized extensively in the pharmaceutical industry. This article presents a comprehensive review of the literature on an important subcategory of emulsions, microemulsions. Microemulsions are optically transparent, thermodynamically stable colloidal systems, 10-100nm diameter, that form spontaneously upon mixing of oil, water and emulsifier. This review is the first to address advantages and disadvantages, as well as considerations and challenges in multi-drug delivery. For the period 1 January 2011-30 April 2016, 431 publications related to microemulsion drug delivery were identified and screened according to microemulsion, drug classification, and surfactant types. Results indicate the use of microemulsions predominantly in lipophilic drug delivery (79.4%) via oil-in-water microemulsions and non-ionic surfactants (90%) for oral or topical administration. Cancer is the disease state most targeted followed by inflammatory diseases, microbial infections and cardiovascular disease. Key generalizations from this analysis include: 1) microemulsion formulation is largely based on trial-and-error despite over 1200 publications related to microemulsion drug delivery since their discovery in 1943; 2) characterization using methods including interfacial tension, droplet size, electrical conductivity, turbidity and viscosity may provide additional information for greater predictability; 3) microemulsion drug delivery publications arise primarily from China (27%) and India (21%) suggesting additional research opportunities elsewhere.
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Sistemas de Liberação de Medicamentos , Emulsões/química , Administração Oral , Administração Tópica , Química Farmacêutica , Humanos , TensoativosRESUMO
Nonviral gene delivery, provides distinct treatment modalities for the inherited and acquired diseases, relies upon the encapsulation of a gene of interest, which is then ideally delivered to the target cells. Variations in the chemical structure of gemini surfactants and subsequent physicochemical characteristics of the gemini-based lipoplexes and their impact on efficient gene transfection were assessed in part I, which was published in first March 2016 issue of Nanomedicine (1103). In order to design an efficient vector using gemini surfactants, the interaction of the surfactant with DNA and other components of the delivery system must be characterized, and more critically, well understood. Such studies will help to understand how nonviral transfection complexes, in general, overcome various cellular barriers. The Langmuir-Blodgett monolayer studies, atomic force microscopy, differential scanning calorimetry, isothermal titration calorimetry, small-angle x-ray scattering, are extensively used to evaluate the interaction behavior of gemini surfactants with DNA and other vector components. Part II of this review focuses on the use of these unique techniques to understand their interaction with DNA.
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DNA/química , Terapia Genética , Compostos de Amônio Quaternário/química , Tensoativos/química , Calorimetria , DNA/genética , Microscopia de Força Atômica , Propriedades de Superfície , TermodinâmicaRESUMO
Nonviral gene therapy using gemini surfactants is a unique approach to medicine that can be adapted toward the treatment of various diseases. Recently, gemini surfactants have been utilized as candidates for the formation of nonviral vectors. The chemical structure of the surfactant (variations in the alkyl tail length and spacer/head group) and the resulting physicochemical properties of the lipoplexes are critical parameters for efficient gene transfection. Moreover, studying the interaction of the surfactant with DNA can help in designing an efficient vector and understanding how transfection complexes overcome various cellular barriers. Part I of this review provides an overview of various types of gemini surfactants designed for gene therapy and their transfection efficiency; and Part II will focus on different novel methods utilized to understand the interactions between the gemini and DNA in a lipoplex.
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DNA/química , Terapia Genética , Tensoativos/químicaRESUMO
AIM: To synthesize an osteotropic alendronate functionalized gelatin (ALN-gelatin) biopolymer for nanoparticle preparation and targeted delivery of DNA to osteoblasts for gene therapy applications. MATERIALS & METHODS: Alendronate coupling to gelatin was confirmed using Fourier transform IR, (31)PNMR, x-ray diffraction (XRD) and differential scanning calorimetry. ALN-gelatin biopolymers prepared at various alendronate/gelatin ratios were utilized to prepare nanoparticles and were optimized in combination with DNA and gemini surfactant for transfecting both HEK-293 and MG-63 cell lines. RESULTS: Gelatin functionalization was confirmed using the above methods. Uniform nanoparticles were obtained from a nanoprecipitation technique. ALN-gelatin/gemini/DNA complexes exhibited higher transfection efficiency in MG-63 osteosarcoma cell line compared with the positive control. CONCLUSION: ALN-gelatin is a promising biopolymer for bone targeting of either small molecules or gene therapy applications.
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Alendronato/análogos & derivados , Conservadores da Densidade Óssea/química , DNA/administração & dosagem , Gelatina/química , Nanopartículas/química , Transfecção/métodos , Linhagem Celular Tumoral , DNA/genética , Terapia Genética , Células HEK293 , HumanosRESUMO
M-DNA, a complex formed in solution between divalent metal ions (M) and duplex DNA, has been studied extensively using fluorescence quenching. This review examines the methods used to examine the formation of M-DNA, and its ability to serve as a pathway for electron transfer between donor and acceptor chromaphores. A mass action model for M-DNA formation is presented based upon the results of fluorescence quenching studies using fluorescein/QSY-7 labeled duplexes. From the mass action analysis, it was determined that approximately 1.4 protons are released per base pair, with k(eq) on the order of 10(-8), indicative of a strong interaction. As resonance energy transfer is shown to be unlikely over the distances involved in this work, the observed quenching in M-DNA is discussed in terms of an electron hopping mechanism for electron transfer, with k(hop)=2.5 x 10(11)s(-1).
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DNA/química , DNA/metabolismo , Metais/química , Metais/metabolismo , Animais , Humanos , Espectrometria de FluorescênciaRESUMO
The interactions between triblock copolymers of poly(ethylene oxide) and poly(propylene oxide), P103 and F108, EO(n)PO(m)EO(n), m=56 and n=17 and 132, respectively, and m-s-m type gemini surfactants, m=8, 10, 12, and 18, and s = 3, 6, 12, and 16, have been studied in aqueous solution using isothermal titration calorimetry and dynamic light scattering techniques. The enthalpograms of F108 as a function of surfactant concentration show one broad peak at polymer concentrations C(p) < or = 0.50 wt%, below the cmc of the copolymer at 25 degrees C. It is attributed to interactions between the surfactant and the triblock copolymer monomer. DLS results show hydrodynamic radii (R(h)) initially consistent with copolymer monomers that change to values consistent with gemini surfactant micelles as the surfactant concentration is increased. In P103 solutions at C(p) > or = 0.05 wt%, two peaks appear in the enthalpograms, and they are attributed to the interactions between the gemini surfactant and the micelle or monomer forms of the copolymer. An origin-based nonlinear fitting program was employed to deconvolute the two peaks and to obtain estimates of peak properties. An estimate of the fraction of copolymer in aggregated form was also obtained. The enthalpy change due to interactions between the surfactants and P103 aggregates is very large compared to values obtained for traditional surfactants. This suggests that extensive reorganization of copolymer aggregates and surrounding solvent occurs during the interaction. DLS results for the P103 systems containing C(p) > or = 0.05% show evidence of very large aggregates in solution, likely P103 micelle clusters. The transitions observed in the hydrodynamic radii are consistent with a breakdown of micelle clusters with addition of gemini surfactant, followed by mixed micelle formation and/or deaggregation into monomer P103. This is followed by interactions similar to those typically observed in surfactant-nonionic polymer systems. Mechanisms for the interaction and the observed structural changes are discussed.
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Calorimetria/métodos , Química Farmacêutica/métodos , Polímeros/química , Biofísica/métodos , Luz , Micelas , Modelos Químicos , Espalhamento de Radiação , Tensoativos/química , Termodinâmica , Fatores de Tempo , TitulometriaRESUMO
M-DNA is a complex of metal ions such as Zn(2+) with duplex DNA. Previous results showed that the fluorescence of a donor fluorophore was quenched when an acceptor fluorophore was placed at the opposite end of a short M-DNA duplex. In order to investigate further the molecular wire behaviour of M-DNA, 30-mer duplexes were constructed with fluorescein as donor and rhodamine, pyrene and the cyanine dyes, Cy5 and Cy5.5 as acceptors. Good quenching was observed in all cases even though the efficiency of resonance energy transfer was calculated to be < 5%. The distance dependence of quenching was investigated by preparing doubly-labelled duplexes ranging in length from 20 to 1,000 base pairs. Upon formation of M-DNA significant quenching of the fluorescence of the donor fluorophore was observed in duplexes up to 500 base pairs in length. The amount of quenching decreased with increasing length of the duplexes with a shallow distance dependence. The results are consistent with an electron transfer mechanism in which the electron hops between metal centers. This process can occur efficiently over long distances.