Gotowa bibliografia na temat „Dendritic Block Copolymers”

The design of nanoassemblies can be conveniently achieved by tuning the strength of the hydrophobic interactions of block copolymers in selective solvents. These block copolymer micelles form supramolecular aggregates, which have attracted great attention in the area of drug delivery and imaging in biomedicine due to their easy-to-tune properties and straightforward large-scale production. In the present work, we have investigated the micellization process of linear–dendritic block copolymers in order to elucidate the effect of branching on the micellar properties. We focus on block copolymers formed by linear hydrophobic blocks attached to either dendritic neutral or charged hydrophilic blocks. We have implemented a simple protocol for determining the equilibrium micellar size, which permits the study of linear–dendritic block copolymers in a wide range of block morphologies in an efficient and parallelizable manner. We have explored the impact of different topological and charge properties of the hydrophilic blocks on the equilibrium micellar properties and compared them to predictions from self-consistent field theory and scaling theory. We have found that, at higher degrees of branching in the corona and for short polymer chains, excluded volume interactions strongly influence the micellar aggregation as well as their effective charge.

This study describes the synthesis of novel amphiphilic linear-dendritic block copolymers and their self-assembly in water to form supramolecular nanoreactors capable of catalyzing Suzuki-Miyaura coupling reactions under “green” conditions. The block copolymers were formed through copper(I)-catalyzed alkyne-azide cycloaddition between azide functionalized poly(benzyl ether) dendrons as the perfectly branched blocks, as well as bis-alkyne modified poly(ethylene glycol), PEG, as the linear block. A first-generation poly(benzyl ether) dendron (G1) was coupled to a bis-alkyne modified PEG with molecular mass of 5 kDa, forming an ABA copolymer (G1)2-PEG5k-(G1)2 (yield 62%), while a second-generation dendron (G2) was coupled to a 11 kDa bis-alkyne modified PEG to produce (G2)2-PEG11k-(G2)2 (yield 49%). The structural purity and low dispersity of the linear-dendritic copolymers were verified by size-exclusion chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Their self-assembly was studied by dynamic light scattering, showing that (G1)2-PEG5k-(G1)2 and (G2)2-PEG11k-(G2)2 formed single populations of micelles (17 nm and 37 nm in diameter, respectively). The triazole rings located at the boundaries between the core and the corona are efficient chelating groups for transition metals. The ability of the micelles to complex Pd was confirmed by 1H NMR, transmission electron microscopy, and inductively coupled plasma. The catalytic activity of the supramolecular linear-dendritic/Pd complexes was tested in water by model Suzuki-Miyaura reactions in which quantitative yields were achieved within 3 h at 40 °C, while, at 17 °C, a yield of more than 70% was attained after 17 h.

In this study, we employed a polymer processing method based on solvent vapor annealing in a confined environment to swell-rich thin films of polybutadiene-b-poly(2-vinylpyridine)-b-poly(ethylene oxide) triblock copolymers and to promote their crystallization. As revealed by optical and atomic force microscopy, thin films of triblock copolymers containing a rather short crystalline poly(ethylene oxide) block that was massively obstructed by the other two blocks were unable to crystallize following the spin-casting process, and their further swelling in solvent vapors was necessary in order to produce polymeric crystals displaying a dendritic morphology. In comparison, thin films of triblock copolymers containing a much longer poly(ethylene oxide) block that was less obstructed by the other two blocks were shown to crystallize into dendritic structures right after the spin-casting procedure, as well as upon rich swelling in solvent vapors.

An in situ template fabrication of inorganic nanoparticles using carboxylated PEG-dendritic block copolymers of the GATG family is described as a function of the dendritic block generation, the metal (Au, CdSe) and metal molar ratio.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007.
Includes bibliographical references.
Polymeric drug delivery systems have been widely used in the pharmaceutical industry. Such systems can solubilize and sequester hydrophobic drugs from degradation, thereby increasing circulation half-life and efficacy. However, there are still challenges in the design of drug delivery vehicles to achieve efficient drug delivery in a site-specific manner. In this thesis, an amphiphilic linear-dendritic block copolymer was designed, synthesized, and applied as a new polymeric drug delivery platform. First, to develop the drug delivery vehicle, an ABA dendritic-linear-dendritic block copolymer consisting of poly(amidoamine) (PAMAM) and poly(propylene oxide) (PPO) was synthesized. In order to determine the viability of the linear-dendritic block copolymer as a drug delivery vehicle, the solution-phase self-assembly behavior and the self-assembled structures were characterized experimentally and through molecular dynamics simulations. The triblock self-assembles in aqueous media to form stable micelles with low CMC values. Dynamic light scattering results and TEM indicate the formation of particles ranging from 9 to 18 nm in diameter, with smaller diameters exhibited at higher generations. Static light scattering also confirmed the trend where the aggregation number decreased with higher generations. The experimental characterization results indicated that the physical characteristics of the PPO-PAMAM micelles were desirable and within the design specifications necessary for drug delivery. The experimental results were utilized to set up simulations where further knowledge of the microstructure of the micelles formed could be gained. It was found that the block copolymers simulated formed micelles in the same size range that was seen experimentally. However, the simulations indicated that the micelles displayed greater asphericity than dendrimers.
(cont) Backfolding of the terminal amine ends was encountered, which would have implications for the configuration and spacing of any additional targeting ligand attached to the dendritic ends. Further analysis revealed that with increasing generation, the porosity of the micelles increased, which could affect the diffusion rate of drugs released out of the system. Another important finding detailed the preferential localization of a model hydrophobid drug, triclosan, in an equilibrated micelle structure. Additional experiments were performed to assess the feasibility of the nanoparticles for drug delivery applications. Drug loading studies were performed with a model hydrophobic drug, triclosan, resulting in high loading efficiencies. In comparison, linear block copolymers were half as efficient in loading triclosan. It was determined that the dendritic block synergistically increased the drug loading due to either acting as an additional block capable of encapsulating drug or sterically favoring the seclusion of the drug in the core. The linear-dendritic block copolymer synthesized was found to be a promising candidate for drug delivery due to its relative stability in aqueous solution and its drug encapsulation and release properties. Overall, the linear-dendritic block copolymer displayed physical characteristics and self-assembly behavior that satisfied the design criteria for a viable drug delivery vehicle. As a further step, the potential benefits of the novel linear-dendritic architecture were explored in two different drug delivery applications. First, PPO-PAMAM was explored as a circulating nanoparticle with the capability of multivalently targeting to specific cells, due to the presence of the dense functional groups on the dendritic block forming the corona of the micelles. PPO-PAMAM was functionalized with galactose and targeted to hepatocellular carcinoma cells. It was found that the polymer was not cytotoxic and could bind to the asialoglycoprotein receptor.
(cont) The galactose-functionalized micelles were loaded with a chemotherapeutic, doxorubicin, and delivered to the carcinoma cells more efficiently than non-functionalized micelles and bare doxorubicin. The results from in vitro testing showed that PPO-PAMAM micelles with targeting capability are promising circulating drug delivery vehicles. In order to ensure success of subsequent testing in vivo of the targeted linear-dendritic block copolymer system, some improvements to the system were explored. First, PPO-PAMAM micelles were stabilized by physical entrapment of the hydrophobic core. An emulsion polymerization of hydrophobic methacrylate monomers created an interpenetrating polymer keeping the micelles intact at concentrations below the CMC and in a solubilizing solvent, methanol. This improvement would ensure that once injected into the bloodstream, the micelles would not destabilize and release high concentrations of drug. Another improvement that was explored was the synthesis of a new linear-dendritic block copolymer composed of a hydrophobic poly(amino acid) and a polyester dendron. Additionally, poly(ethyleneglycol) (PEG) groups were attached to the outer surface of the polyester dendron. The new system synthesized has a low CMC and is thermodynamically slow to break apart in the bloodstream. Furthermore, the micelles formed would be able to circulate for longer times with PEG aiding in evading the reticuloendothelial system. The second drug delivery application explored, which advantageously utilized the dendritic blocks on the outer surface of the block copolymer micelles was as a localized drug delivery coating created by the layer-by-layer (LbL) assembly approach. The electrostatic LbL assembly approach offers large potential in the area of drug delivery from thin films and surfaces; however, because the processing technique is aqueous-based, there have been few strategies proposed to incorporate hydrophobic molecules into these films.
(cont) Here we created an LbL film that is capable of incorporating hydrophobic drug at high loadings via encapsulation with linear-dendritic block copolymer micelles and demonstrate for the first time release times of a hydrophobic antibacterial agent over a period of several weeks--a significant improvement over reports of other micelle-encapsulated thin films with release times of several minutes. The PAMAM block, which is polycationic, enabled LbL deposition with negatively charged poly(acrylic acid) (PAA). The stable PPO-PAMAM micelles incorporated into the LbL films encapsulated a hydrophobic bactericide, triclosan. Film thickness and UV-vis measurements confirm the formation of the LbL film and incorporation of triclosan into the film. Fluorescence measurements of PPO-PAMAM/PAA films with pyrene indicated the presence of hydrophobic domains in the film. GISAXS revealed regular spacing of approximately 10.5 nm in the direction parallel to the film substrate, which is approximately the same size as the PPO-PAMAM micelles in aqueous solution. Volume fraction measurements based on elemental analysis and TGA confirm the GISAXS data. An in vitro release study revealed long release times of triclosan on the order of weeks, and a Kirby Bauer test was performed on Staphylococcus Aureus demonstrating that the drug released was still active to inhibit the growth of bacteria. Linear-dendritic block copolymer micelles were successfully used in two different drug delivery applications where the dendritic block could be fully utilized. It is hoped that with the research and results presented in this thesis further development of this drug delivery platform can result in a product successfully treating a serious disease.
by Phuong Nguyen.
Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007.
Vita.
Includes bibliographical references.
Linear-dendritic block copolymers consisting of a poly(styrene) linear block and poly(amidoamine) dendrimer block were synthesized and examined for their ability to self-assemble in both aqueous environments and organic/aqueous mixtures. These polymers were shown to assemble into vesicle structures under a variety of conditions. Furthermore, size measurements of the dendritic portion were taken by means of Langmuir-Blodgett isotherms, demonstrating both the steric area, as well as the electrostatic area occupied by the dendrimer in a monolayer. Further studies into the rapid synthesis of such systems were also undertaken, with a particular interest in use of the so-called "click" reaction to be used as a facile means toward block copolymer synthesis.
by Kristoffer Keith Stokes.
Ph.D.

L'objectif de cette thèse repose sur le développement de micelles de polymères polyioniques, vecteurs de molécules thérapeutiques en immunothérapie avec des cellules dendritiques (DCs). Elles sont préparées à partir d'un copolymère à blocs double-hydrophiles, l'acide polyméthacrylique-b-polyoxyde d'éthylène (PMAA-b-POE) et d'un contre ion de charge opposée. De taille nanométrique, elles sont capables d'encapsuler des molécules thérapeutiques selon une association tripartite originale et de se désassembler à pH acide pour permettre leur libération dans le milieu endosomal.Le premier axe de travail a porté sur l'évaluation de la propriété des copolymères à induire un échappement endosomal en fonction de leur masse molaire en utilisant deux modèles membranaires (liposomes et globules rouges). La complexation des copolymères de masses molaires différentes avec la poly-L-lysine comme contre-ion a permis l'obtention de micelles avec des propriétés d'échappement endosomal variables. Cette propriété est intéressante car en fonction de la stratégie thérapeutique adoptée, elle orientera le choix de la masse molaire du copolymère pour la formulation des micelles.Le second axe a consisté en l'application de ces micelles pour la vectorisation d'un peptide modèle (peptide OVA) dans les DCs. La capacité des micelles à encapsuler le peptide et à le libérer au niveau des compartiments endosomaux a été évaluée par des techniques de spectrofluorimétrie et de microscopie confocale. Enfin, l'efficacité de présentation du peptide formulé dans les différentes micelles a été mise en évidence et a montré l'amélioration de la présentation par les DCs du peptide formulé dans les micelles comparé au peptide non formulé. Cette présentation est nettement supérieure en utilisant les micelles composées de copolymères de masse molaire élevée qui n'entraînent pas d'échappement endosomal.Le troisième axe de recherche a reposé sur la transfection des DCs avec des micelles de siRNA dirigés contre la protéine de surface CD86. Seules les micelles composées de copolymères de faible masse molaire ont permis l'encapsulation du siRNA et la baisse de l'expression de la protéine CD86 à la surface des DCs. Afin d'optimiser la capacité des micelles à encapsuler et transfecter les DCs, la formulation des micelles a été optimisée en remplaçant la PLL par un autre polycation la polyethylene imine PEI. Ces micelles polyioniques à base de copolymère PMAA-b-POE apparaissent donc comme des vecteurs de molécules d'intérêt thérapeutique prometteurs pour les cellules dendritiques en immunothérapie ou en thérapie génique
The aim of the thesis work is based on the development of polymeric micelles vectors of therapeutic molecules in immunotherapy with dendritic cells (DCs). They are composed of a double hydrophilic blocks copolymers, poly(methacrylic acid)-b-poly(ethylene oxide) (PMAA-b-PEO) and an oppositely charged polyion. They are caracterized by a nanometric size, a capacity to encapsulate therapeutic molecules according to a tripartite association and are able to disassemble at acidic pH allowing the release of their cargo.The first part of this work has focused on the evaluation of the endosomal escape property of copolymers based on their molecular weight by using two membrane models (liposomes and red blood cells). Complexation of different molecular weight copolymers with poly- L- lysine as counter ion allowed the formation of micelles with variable endosomal escape properties. This property is interesting because according to the adopted therapeutic strategy, it will guide the choice of the copolymer micelles for formulation.The second part consisted of the application of these micelles for the vectorization of a model peptide (OVA peptide) in DCs. The ability of micelles to encapsulate and release this peptide in the endosomal compartments was assessed by fluorescence spectroscopy and confocal microscopy techniques. Finally, the effectiveness of the OVA presentation formulated in the different type of micelles has been demonstrated and shown that the peptide presentation by DCs was improved when it was formulated in micelles compared to unformulated peptide. This presentation was much higher using micelles composed of high molecular weight copolymers that do not involve endosomal escape.The third part of the research was based on the transfection of DCs with siRNA directed against CD86 protein surface. Only micelles composed of low molecular weight copolymers allowed the encapsulation of siRNA molecules and decreased the expression of CD86 protein on DCs surface. To increase the ability of micelles to encapsulate and transfect DCs, the micelle formulation was optimized by changing the PLL with another polycation PEI.These polyion micelles based PMAA-b-PEO copolymers appear as vectors of therapeutic molecules for promising strategies with dendritic cells such as vaccination and gene therapy

La technologie Lithium-air développée par EDF utilise une électrode à air qui fonctionne avec un électrolyte aqueux ce qui empêche l’utilisation de lithium métal non protégé comme électrode négative. Une membrane céramique (LATP:Li1+xAlxTi2-x(PO4)3) conductrice d’ion Li+ est utilisée pour séparer le milieu aqueux de l’électrode négative. Cependant, cette céramique n'est pas stable au contact du lithium, il est donc nécessaire d'intercaler entre le lithium et la céramique un matériau conducteur des ions Li+. Celui-ci devant être stable au contact du lithium et empêcher ou fortement limiter la croissance dendritique. Ainsi, ce projet s'est intéressé à l'étude d'électrolytes copolymères à blocs (BCE).Tout d'abord, l'étude des propriétés physico-chimiques spécifiques de ces BCEs en cellule lithium-lithium symétrique a été réalisée notamment les propriétés de transport (conductivités, nombre de transport), et la résistance à la croissance dendritique du lithium. Puis dans un second temps, l'étude des composites BCE-céramique a été mise en place. Nous nous sommes en particulier focalisés sur l'analyse du transfert ionique polymère-céramique.Plusieurs techniques de caractérisation ont été utilisées telles que la spectroscopie d'impédance électrochimique (transport et interface), le SAXS (morphologies des BCEs), la micro-tomographie par rayons X (morphologies des interfaces et des dendrites).Pour des électrolytes possédant un nombre de transport unitaire (single-ion), nous avons obtenus des résultats remarquables concernant la limitation à la croissance dendritique. La micro-tomographie des rayons X a permis de montrer que le mécanisme de croissance hétérogène dans le cas des single-ion est très différent de celui des BCEs neutres (t+ < 0.2)
The lithium-air (Li-air) technology developed by EDF uses an air electrode which works with an aqueous electrolyte, which prevents the use of unprotected lithium metal electrode as a negative electrode. A Li+ ionic conductor glass ceramic (LATP:Li1+xAlxTi2-x(PO4)3) has been used to separate the aqueous electrolyte compartment from the negative electrode. However, this glass-ceramic is not stable in contact with lithium, it is thus necessary to add between the lithium and the ceramic a buffer layer. In another hand, this protection should ideally resist to lithium dendritic growth. Thus, this project has been focused on the study of block copolymer electrolytes (BCE).In a first part, the study of the physical and chemical properties of these BCEs in lithium symmetric cells has been realized especially transport properties (ionic conductivities, transference number), and resistance to dendritic growth. Then, in a second part, the composites BCE-ceramic have been studied.Several characterization techniques have been employed and especially the electrochemical impedance spectroscopy (for the transport and the interface properties), the small angle X-ray scattering (for the BCE morphologies) and the hard X-ray micro-tomography (for the interfaces and the dendrites morphologies). For single-ion BCE, we have obtained interesting results concerning the mitigation of the dendritic growth. The hard X-ray micro-tomography has permitted to show that the mechanism involved in the heterogeneous lithium growth in the case of the single-ion is very different from the one involved for the neutral BCEs (t+ < 0.2)

博士
國立臺灣大學
高分子科學與工程學研究所
102
This work consists of the synthesis of dendritic block copolymers (DBCs) with various flexible chain lengths, architectures and numbers of branching generations, and the effects of these structural factors on the morphologies. A series of poly(urethane/malonamide)dendrons were synthesized first based on the reactive building block, 4-isocyanate-4-(3,3-dimethyl-2,4-dioxo-azetidine)-diphenylmethane (IDD) with different numbers of branching generations. All the dendrons were confirmed by FT-IR, 1H-NMR, EA and Mass. Subsequently, the flexible poly(oxyalkylene) reacted with the reactive dendrons with different numbers of branching generations. Hence, several series of DBCs were synthesized and confirmed by FT-IR, 1H-NMR and GPC. Because the high branching generations of dendrons were difficult to self-assemble, a soft segment was incorporated to enhance the x values of DBCs. As a result, the presence of microphase separation between the interface would certainly induce a pattern of the architecture of dendrons with high branching generations to self-assemble. In addition, two melting transitions, pertaining to the partial micro-separation were observed as measured by DSC. In the L1DBC system, Tm1 and Tm2 were increased from 20 oC, 60 oC to 37 oC, 86 oC, respectively, when a dendron of higher generation was incorporated onto a DBC. The TEM image of L1DBC showed the morphologies were lamellar, worm-like and sphere, dependent on increasing generation of dendrons in L1DBCs accordingly. Furthermore, the morpholgy of L2D0BC and D2D0BC were cylinder and lamellar by the extension of flexible chain lengths and architecture conformation, respectively. All the DBCs were confirmed by Small angle x-ray scattering (SAXS) and Igor software curve fitting.