Dissertations / Theses on the topic 'Amphiphilic graft copolymer'

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2010.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student submitted PDF version of thesis.
Includes bibliographical references (p. 99-106).
The throughput and efficiency of membrane separations make polymer filtration membranes an important resource for the pharmaceutical, food and wastewater treatment industries. Nanofiltration (NF) membranes fill an important niche between nonporous reverse osmosis membranes, which have comprehensive solute rejection and low solvent permeability, and porous sieving ultrafiltration membranes. However, challenges in NF membrane design remain outstanding. At the effective pore size of NF membranes (~0.5 nm-2 nm), both electrostatic and steric factors determine membrane selectivity. Most NF membranes are charged under a wide range of environmental conditions and thus preferentially exclude charged solutes. This charge selectivity precludes separation of molecules based solely on size. An additional limitation of NF membranes is the tendency to foul by adsorption of feed components. The purpose of this thesis is to demonstrate control of membrane selectivity in fouling resistant membranes via manipulation of the chemistry of a specific copolymer system, polyacrylonitrile (PAN)-based poly(ethylene oxide) (PEO) graft polymers. Previous work with amphiphilic graft copolymers as membrane materials has included PANg- PEO with an average graft length of 9 (PAN-g-PEO9). PAN-g-PEO9 was shown to have excellent fouling resistance as an antifouling additive in porous ultrafiltration membranes and as a dense selective layer coated onto a support base membrane-a thin-film composite (TFC) NF membrane. The comb morphology of the polymer imposes high interfacial area on the microphase-separated domains, resulting in a bicontinuous structure consisting of a glassy PAN matrix interpenetrated by PEO-filled "nanochannels" that can act as vias for water and small solutes (with a size cutoff of ~0.8 nm). It also presents a PEO brush on the comb surface which acts as a steric barrier to resist irreversible fouling of the membranes. The understanding from previous work on PEO comb NF membranes is that the pore size is determined by the nanochannel's size, i.e. the PEO domain size. Because the graft characteristics (spacing and length) of comb copolymers determine the domain size, it was expected that varying the graft length would allow broad, precise control of the size cutoff of the TFC membranes, a concept demonstrated previously with amphiphilic graft copolymer NF membranes of poly(vinylidene fluoride)-graft-poly(oxyethylene methacrylate) (PVDF-g-POEM). The first aim of this thesis was to tailor the retention properties of PAN-g-PEO TFC NF membranes by modifying the chemistry to tune the electrostatic and steric properties sufficiently to enable complex separations, particularly of solutes with high fouling potential. Comb copolymers incorporating ~40 weight % PEO with side chains varying from 5-40 EO units were synthesized by free radical methods and compared as selective-layer coatings on PAN UF membranes. 3 Membranes incorporating combs with 9 EO units or more were shown to resist irreversible fouling when challenged by a model protein feed solution (bovine serum albumin) for 24 hours. Fouling resistance was found to be compromised, however, upon exposure to acid (pH 2) solution, used to simulate chemical cleaning procedures in industry. Thickness-normalized permeabilities of these PAN-g-PEOn NF membranes exceeded those of commercially available NF membranes by approximately an order of magnitude. A systematic effect of side chain length on permeability was seen when varying temperature, ionic strength, and pressure. Contrary to expectations, the membrane size cutoff (~0.8 nm) for charged rigid molecular probes in deionized water was independent of the comb side chain length. This new finding can be explained by modeling the hydrophilic domains as opposing swollen polymer brushes of uniform density acting as a physical gel. The gel mesh size (distance between chains) is independent of side chain length, and controls the size cutoff in good solvent conditions matching those in which the membrane was equilibrated during fabrication. In poorer solvent conditions, a decrease in the brush height, progressing to complete collapse of the PEO gel, can be expected to create differentiation based on domain size (i.e. side chain length). This is consistent with the finding that retentions of dyes increased with decreasing side chain length in saline solution, as salt is known to reduce PEO-water miscibility. Fluorescently labeled peptides germane to proteomics research were filtered and both chromatographic and size-selective membrane behavior was observed-the first demonstration of size-based nanofiltration of peptides. Based on this finding, two different peptides of molecular weights 1.3kDa and 1.5kDa were fractionated to achieve a six-fold increase in the concentration of the larger peptide relative to the smaller peptide in two filtration steps. The electrostatic selectivity of the PEO comb membranes could also be varied. Terpolymers consisting of PAN-g-PEO with 1-2% charged sulfopropyl acrylate (SPA) or 5% N,Ndimethyl- N-(2-methacryloyloxyethyl-N-(3-sulfopropyl) ammonium betaine (SPE) were synthesized and coated onto PAN base membrane. The divalent salt (Na2SO4) retention of the resulting TFC membranes increased from ~20% for the PAN-g-PEO copolymer to ~45% and 82% for the SPE and SPA terpolymers, respectively. Retention of monovalent NaCl was substantially lower, characteristic of commercial NF membranes. The charged comb membranes did not completely resist fouling by a 1 g/L BSA solution, losing 2% of the initial flux after 24 h exposure. Forming a trilayer TFC, with a layer of PAN-g-PEO coated over a charged terpolymer, reduced membrane fouling compared to the charged layer alone. In summary, the goal of this study was to demonstrate control of membrane selectivity in fouling-resistant PAN-g-PEO NF membranes. An important finding was that the PEO gel created in the hydrophilic domains leads to similar size cutoffs over a wide range of side chain length. To access the desired spectrum of size cutoffs, the quality of solvent for the swollen PEO brush must be reduced. In spite of these limitations, the membrane was shown to have useful fractionating properties as demonstrated with labeled peptides of varying molecular weight. The retention of salts was enhanced by incorporating small amounts of charged monomer into the comb backbone, but at the expense of fouling resistance.
by Nathan Gary Lovell.
Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007.
Includes bibliographical references.
Amphiphilic comb-type graft copolymers comprising a poly(methyl methacrylate) (PMMA) backbone and short, polyethylene oxide (PEO) side chains, PMMA-g-PEO, are proposed to self-organize at the polymer/water interface, resulting in quasi-2D confinement of the backbone at the immediate surface. The branched architecture and amphiphilic chemistry of these polymers results in a dense PEO brush that resists cell adhesion. To facilitate specific cell-surface interactions, small biological molecules such as adhesion peptides can be selectively tethered to PEO chain ends. Quasi-2D confinement of the polymer backbone results in clustering of tethered epitopes on a length scale dictated by the backbone. The present work investigates two aspects of this polymer architecture on organization of tethered ligands: nanometer length-scale clustering through backbone 2D confinement, and tether length effects on the availability of tethered peptides for cell adhesion.
(cont.) To directly probe 2D confined polymer conformations, combs at the film/water interface were labeled with gold nanoparticles and observed by transmission electron microscopy. A 2D radius of gyration (Rg) was calculated by reconstructing nanoparticle-decorated chain trajectories, and compared with Monte Carlo simulations of a 2D melt of similarly broad length distribution. The 2D Rg calculated from observed conformations scaled with the number of backbone segments (N) as Rg - N.69-0.02 Monte Carlo simulations yielded a scaling exponent v = 0.67 + 0.03, suggesting that the deviation from classical 2D melt behavior (v= 0.5) arose from polydispersity. Tether length effects on cell adhesion to comb copolymer films functionalized with the adhesion peptide PHSRNGGGK(GGC)GGRGDSPY were further investigated by observing cell attachment and spreading on combs with long (22 EO unit) and short (10 EO unit) tethers. Lofiger tethers increased the rate of spreading and reduced the time required to form focal adhesions. Fluorescence resonance energy transfer (FRET) measurements suggest that the added mobility afforded by longer tethers allowed cells to reorganize tethered peptides.
(cont.) In addition, adhesion peptides were selectively coupled to short or long PEO tethers within a bimodal brush. Short peptide tethers in a bed of long inert chains did not promote cell attachment. Long peptide tethers with short inert chains resulted in cell attachment comparable to a monomodal brush of long chains. These findings may be of value in designing protein-resistant bioactive surfaces, where nanometer length-scale organization of ligands plays an important role in cell-surface interactions.
by William A. Kuhlman.
Ph.D.

Les gels d'alginate de calcium sont utilises en biotechnologie pour encapsuler divers biomatériaux. Les espèces séquestrées sont cependant insuffisamment retenues et tendent à fuir hors de leur support. L'objectif de notre travail a consiste à immobiliser sur l'alginate des chaines latérales a caractère hydrophobe doux des polyoxyalkylenes susceptibles de s'associer aux biosystèmes confinés et de minimiser ainsi ce relargage parasite. Deux stratégies de synthèse ont été adoptées: 1) d'une part, le polysaccharide a été oxydé par le periodate et un polyéther aminé modèle le -benzyloxy, -aminotetraethyleneglycol a été couplé par une réaction d'amination réductrice aux fonctions aldéhydes générées. Ce mode de synthèse conduit à des dérives fortement dégradés ne présentant plus de transition sol/gel; 2) d'autre part, le polyéther modèle a été greffe a l'alginate par l'intermédiaire d'une liaison amide. Les dérivés résultants, en dépit d'une modification profonde de leur comportement viscosimetrique, conservent leur capacité de gélification. Un polyoxyalkylene à caractère hydrophobe plus marque a ensuite été fixé. Les études physicochimiques des dérivés amphiphiles obtenus ainsi que les tests de gélification nous ont montré que les polyoxyalkylenes n'ont pas un caractère hydrophobe suffisamment prononcé pour permettre d'obtenir des dérivés à caractère associatif qui soient susceptibles d'améliorer les capacités de rétention des biomatériaux encapsulés

L’objectif de ce travail était de contrôler les propriétés rhéologiques de solutions aqueuses de copolymères amphiphiles. Dans l’eau, ces copolymères s’auto-associent et leurs propriétés peuvent être contrôlées en partie par leur dynamique d’échange. Il avait précédemment était montré que cette dynamique pouvait être contrôlée par le pH et la quantité d’unités acide acrylique dans des triblocs BAB (THx) où le bloc A est du poly(acide acrylique) (PAA) et les blocs B sont des copolymères statistiques (MHx) d’acrylate de n-butyle (nBA) et d’acide acrylique (AA). Tout d’abord, l’étude de l’auto-association en solution des blocs B seuls (MHx) a montré un lien fort entre leur agrégation et celle des diblocs de type BA (DHx). Cette agrégation est contrôlée par la quantité de charge des blocs B. Par la suite, des mélanges de triblocs (BAB) THx contenant différentes proportions (x) d’unités AA ont permis la formation de réseaux hybrides dont les propriétés rhéologiques sont maîtrisées par formulation plutôt que via la chimie. Des propriétés rhéologiques similaires aux triblocs BAB (THx) ont été obtenues avec des copolymères greffés possédant un squelette hydrophile PAA et des greffons B. Leurs propriétés rhéologiques sont principalement contrôlées par la structure chimique des blocs B, mais aussi par le taux de greffage. Ces copolymères greffés devraient être plus simples à obtenir à l’échelle industrielle que des triblocs. Pour finir, l’approche consistant à incorporer des unités hydrophiles dans les blocs hydrophobes de copolymères amphiphiles pour en contrôler la dynamique d’échange a été appliquée avec succès à des copolymères à base de méthacrylate de diméthylaminoéthyle et de méthacrylate de n-butyle. Leurs propriétés rhéologiques peuvent être contrôlées à nouveau par le pH, mais dans une gamme différente des polymères à base d’acide acrylique, et aussi dans une certaine mesure par la température
The aim of this work was to control the rheological properties of aqueous solutions of amphiphilic copolymers. In water, these copolymers self-assemble and part of their properties can be controlled by their dynamic of exchange. As previously reported, the exchange dynamics can be controlled by the pH and the acrylic acid (AA) content for BAB triblock copolymers (THx) consisting of a poly(acrylic acid) (PAA) A block and two statistical B blocks (MHx) of n-butyl acryle (nBA) and AA.First, the study of the self-association of B blocks (MHx) alone showed a strong relationship between their aggregation and the one of BA diblocks (DHx). This aggregation was mainly controlled by the amount of charges within the B blocks.Then, mixtures of BAB triblocks (THx) with different contents of AA units, x, formed hybrid networks the rheological properties of which were controlled by formulation rather than chemistry.Similar rheological properties were obtained using graft copolymers consisting of a PAA hydrophilic backbone and B grafts. Their rheological properties were mainly controlled by the chemical structure of the B grafts and by the grafting density. Such graft copolymers should be easier to produce at an industrial scale than triblock copolymers.To finish, the strategy consisting of incorporating hydrophilic units inside the hydrophobic blocks of amphiphilic copolymers to control their exchange dynamics was successfully applied to copolymers made of dimethylaminoethyl methacraylate and n-butyl methacrylate. Their rheological properties were controlled by the pH on a different pH-range than the AA based polymers, and, to some extent, by the temperature

1.Polymérisation par ouverture de cycle anionique contrôlée de carbamates cycliques à 5 chaînons en polyuréthanes. 2.Synthèse et auto-assemblage de copolymères diblocs linéaires amphiphiles à base de polyuréthane. 3.Synthèse et auto-assemblage de copolymères greffés amphiphiles à base de polyuréthane
1.Controlled anionic ring opening polymerization of 5-membered cyclic carbamates to polyurethanes. 2.Synthesis and self-assembly of polyurethane-based amphiphilic linear diblock copolymers. 3.Synthesis and self-assembly of polyurethane-based amphiphilic graft copolymers

Thesis (PhD)--Stellenbosch University, 2011.
ENGLISH ABSTRACT: Novel silicone nanocomposites were prepared using poly(acrylonitrile) (PAN) based reinforcing fibres as well as multi-walled carbon nanotubes (MWCNTs). Compatibility of the fibre fillers with the silicone matrix required the synthesis of novel amphiphilic, organic–inorganic graft copolymers of PAN and poly(dimethylsiloxane) (PAN-g-PDMS). These fibre precursor materials were synthesised via the “grafting through” technique using conventional free radical copolymerisation. The PDMS macromonomer content in the feed was varied from 5 wt% to 25 wt% and the molecular weights of the macromonomer were 1000 g.mol-1 and 5000 g.mol-1. The solvent medium of the precipitation reaction was optimised at a volume ratio of 98% benzene to 2% dimethylformamide (DMF). Successful incorporation of PDMS yielded graft copolymer blend materials of PAN-g-PDMS, blended with PAN homopolymer and unreacted PDMS macromonomer. A gradient elution profile was developed to track the successful removal of the PDMS macromonomer via hexane extraction. The gradient profile showed that as the PDMS content in the feed increased, the number of graft molecules in the blend increased relative to the number of PAN homopolymer molecules. The crystallisability of the PAN segments was shown to decrease as the PDMS content increased. The synthesised polymer was used as precursor material for the electrospinning of fibre fillers. The electrospinning of the precursor material was successfully achieved using 100% DMF as electrospinning solution medium. The amphiphilic nature of the precursor material in DMF resulted in self-assembled aggregate structures in the electrospinning solution. An increasing PDMS content was shown to affect the aggregation of the precursor material, and resulted in an increase in the solution viscosity. The “gel-like” solutions limited the achievable fibre morphological control when altering conventional electrospinning parameters such as voltage, tip-to-collector distance, and solution concentrations. The rapid evaporation and stretching of the solution during electrospinning, combined with the phase segregated amphiphilic molecules in solution and the crystallisation of the PAN segments resulted in (non-equilibrium morphology) fully porous fibres. The crystallinity was shown to decrease after electrospinning of the fibre precursor materials. Successful incorporation of surface oxidised MWCNTs into the electrospun fibres was achieved. The content of nanotubes was varied from 2 wt% to 32 wt%. The MWCNTs reduced the mean fibre diameters by acting as cross-linkers between the PAN segments and increasing the solution conductivity. The nanotubes dispersed well throughout the porous structure of the fibres and aligned in the direction of the fibre axis. Fabrication of silicone composites containing nonwoven and aligned fibre mats (with 8 wt% MWCNTs in the fibres, and without) was successfully achieved. The compatibilisation of the PDMS surface segregated domains allowed excellent dispersion and interaction of the PAN based fibre fillers with the silicone matrix. Mechanical analysis showed improved properties as the PDMS content in the fibre increased. The highest PDMS content fibres did, however, exhibit decreased properties. This was ascribed to increased PDMS (soft and weak) content, decreased crystallinity and increased fibre diameter (lower interfacial area). Dramatic improvements in strength, stiffness, strain and toughness were achieved. The most significant result was an increase in strain of 470%. The mechanical results correlated with results of SEM analysis of the fracture surfaces. The dramatic improvements in properties were a result of the fibre strength and ductility, as well as the mechanism of composite failure.
AFRIKAANSE OPSOMMING: Nuwe silikonnanosamestellings is berei deur gebruik te maak van poli(akrilonitriel) (PAN) gebaseerde versterkende vesels wat multi-ommuurde koolstof nanobuisies bevat het. Versoenbaarheid van die vesels met die silikonmatriks het die sintese van nuwe amfifiliese, organies–anorganiese ent-kopolimere van PAN en poli(dimetielsiloksaan) (PAN-g-PDMS) benodig. Die vesel voorlopermateriaal is deur middel van ‘n “ent-deur” vryeradikaalkopolimerisasie gesintetiseer. Die inhoud van die PDMS makromonomeer in die reaksie het gewissel vanaf 5% tot 25%. Die gebruik van twee verskillende molekulêre massas makromonomere is bestudeer (1000 en 5000 g.mol-1). Die optimale oplosmiddelmengsel vir die neerslagreaksie was 'n volume verhouding van 98% benseen tot 2% dimetielformamied (DMF). Suksesvolle insluiting van PDMS het versnitmateriale van PAN-g-PDMS kopolimere gemeng met PAN homopolimere en ongereageerde PDMS makromonomere gelewer. 'n Gradiënteluering- chromatografiese profiel is ontwikkel om die suksesvolle verwydering van die PDMS makromonomere via heksaanekstraksie te bepaal. Die gradiëntprofiel het aangetoon dat indien die PDMS inhoud in die reagense verhoog is, die aantal entmolekules relatief tot PAN homopolimeermolekules ook verhoog het. 'n Toename in PDMS inhoud het egter 'n afname in kristallisasie van die PAN segmente tot gevolg gehad. Die gesintetiseerde polimeer is gebruik as die beginmateriaal vir die elektrospin van veselvullers. Die elektrospin van die beginmateriaal was suksesvol wanneer 100% DMF as elektrospinoplosmiddel gebruik is. Die amfifiliese aard van die beginmateriaal in DMF lei tot outokonstruksie van aggregaatstrukture in die elektrospinoplossing. Toenemende PDMS inhoud beïnvloed die outokonstruksie van die molekules in oplossing en het gelei tot 'n toename in die oplossings se viskositeit. Die "gelagtige" oplossings beperk die haalbare vesel se morfologiese beheerbaarheid wanneer konvensionele elektrospin parameters soos elektriese spanning, punt-tot-versamelaar afstand, en oplossingkonsentrasies gewysig word. Die vinnige verdamping en strek van die oplossing tydens elektrospin, gekombineer met die fase-geskeide amfifiliese molekules in oplossing en die kristallisasie van die PAN segmente, het gelei tot (nie-ewewig morfologie) volledige poreuse vesels. Die kristalliniteit van die veselbeginmaterial het afgeneem nadat elektrospin toegepas is. Die insluiting van die oppervlak-geoksideerde multi-ommuurde koolstof nanobuisies in die elektrogespinde vesels was suksesvol. Die inhoud van die nanobuisies het gewissel van 2 wt% tot 32 wt%. Die MWCNTs het die gemiddelde veseldeursnit verminder deur op te tree as kruisbinders tussen die PAN segmente van die molekules. Die nanobuisies was goed versprei deur die poreuse struktuur van die vesels en dit was gerig in die rigting van die vesel-as. Bereiding van die silikonsamestellings bestaande uit nie-geweefde en gerigte veseloppervlakke (met en sonder 8 wt% multi-ommuurde koolstof nanobuisies in die vesel) was suksesvol. Die versoenbaarheid tussen die oppervlak van die PDMS-geskeide gebiede en die silikonmatriks laat uitstekende verspreiding en interaksie van die PAN-gebaseerde veselvullers met die silikonmatriks toe. Meganiese analise het aangetoon dat die fisiese eienskappe verbeter het namate die PDMS inhoud in die vesel vermeerder het. Die vesels met die hoogste PDMS inhoud het egter verswakte eienskappe getoon. Dit is toegeskryf aan ‘n verhoogde PDMS inhoud (sag en swak), ‘n afname in kristalliniteit en ‘n verhoogde veseldeursnit (laer grensoppervlakke). Dramatiese verbeterings in sterkte, styfheid, verlengbaarheid, vervorming en taaiheid is bereik. Die mees betekenisvolle gevolg was 'n toename in die verrekking van 470%. Die meganiese resultate is gekorreleer met SEM ontleding van die brekingsoppervlakke. Die veselkrag en vervormbaarheid, sowel as die meganisme van die splyting van die samestellings, het tot die dramatiese verbeterings in die meganiese eienskappe gelei.

Thesis (MSc)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Novel poly(methacrylic acid)-graft-poly(dimethylsiloxane) copolymers were synthesised by conventional free radical reactions using a poly(dimethylsiloxane) macromonomer. The polymers were electrospun to investigate how the fibre morphology can be modified by manipulating the electrospinning solution parameters, and to determine the possibility of using the polymers as new materials for the production of polymer nanofibre hydrogels. The electrospinning solution parameters were varied by electrospinning the highly amphiphilic copolymers in solvents with variable solvent qualities. Scanning Electron Microscopy (SEM) and Field Emission Scanning Electron Microscopy (FE–SEM) was used to investigate the fibre morphology. Internal morphology was studied using a freeze fracture technique prior to FE-SEM imaging. It is revealed that the polymers in this study does not form any fine structure or pores even when self-assembled structures are present in the solution. Attempts were made to visualise any self-assembled structures of films produced from dilute solutions using TEM. Further studies included investigating the fibres properties, primarily with regards to their rate and extent of moisture and water uptake. The fibres showed hydrogel behaviour and the PDMS content were found to have an impact on the hydrogel stability. Post electrospinning crosslinking of the nanofibres was also explored.
AFRIKAANSE OPSOMMING: Unieke ent-kopolimere wat bestaan uit poli(metielakrielsuur) (PMAS) en poli(dimetielsiloksaan) (PDMS) is gesintetiseer deur middel van 'n “ent-deur” vryeradikaalkopolimerisasie. 'n PDMS makromonomeer is vir hierdie doel gebruik. Die polimere is geëlektrospin om vesels te vorm. Die doel was om die invloed van verkillende strukture in oplossing op die veselmorfologie te bepaal. Die moontlikheid om hierdie nanovesels as gels te gebruik is ook ondersoek. Die amfifiliese kopolimere is geëlektrospin uit die oplossing waarin dit wisselende oplosbaarheid toon. Skandeer elektron mikroskopie (SEM) is gebruik om die morfologie te ondersoek. Die interne morfologie van die vesels is ondersoek deur die vesels te vries en in die gevriesde toestand te breek. Die studie het getoon dat geen strukture op, of binne, die vesels vorm nie, selfs al moes daar assosiasie tussen segmente van die polimere gewees het. Hierdie tipe assosiasies sou strukture in die oplossing tot gevolg gehad het. 'n Poging is aangewend om die strukture in oplossing te visualiseer deur transmissie elektron mikroskopie (TEM) van dun films te ondersoek. Films is vanaf verdunde oplossings gevorm. Ander studies het ingesluit om die eienskappe van die vesels te ondersoek, met die fokus op hoeveel en hoe vinnig die vesels waterdamp en water kon absorbeer. Die vesels het soos 'n gel reageer. Hierdie gedrag is beïnvloed deur die hoeveelheid PDMS wat 'n definitiewe invloed op die stabiliteit van die gel gehad het. Kruisverbindings van die vesels, nadat dit geëlektrospin is, is ook ondersoek.

Ce travail présente la synthèse de copolymères amphiphiles biocompatibles et biodégradables pour la formation de systèmes de libération d’agents anticancéreux. Ces copolymères sont composés d’une chaîne de poly-(ε-caprolactone) (PCL), un polyester hydrophobe biocompatible et biodégradable, sur laquelle sont greffés des chaînes hydrophiles d’oligomères de dextrane ou de chitosane. Ces nouvelles structures copolymères sont dites « inverses », les structures « classiques » étant constituées d’une chaîne polysaccharide avec des greffons PCL. La chaîne de PCL a été propargylée via une méthode anionique développée par notre équipe, tandis que les oligosaccharides ont été azoturés en extrémité de chaîne sur le dextrane, mais le long de sa chaîne sur le chitosane grâce à la présence de ses fonctions amines. Les copolymères ont été obtenus par couplage « clic » CuAAC entre PCL propargylée et oligosaccharides azoturés. Dans le cas du chitosane, les amines de la chaîne permettent i) le couplage de mannose squarate, un agent de ciblage de cellules cancéreuses et ii) une fonctionnalisation sous forme de thiol qui permet un couplage par réaction thiol-yne sur la PCL propargylée. Ces copolymères donnent des nano- objets en milieu aqueux qui, dans le cas du PCL-g-dextrane, sont sous forme de micelles qui encapsulent de la doxorubicine dont la libération est pH dépendante. Des études biologiques ont montré que ces micelles chargées sont toxiques essentiellement pour les cellules cancéreuses et qu’elles sont préférentiellement internalisées par les cellules cancéreuses. Ces résultats démontrent une grande sélectivité d’action vis-à-vis des cellules tumorales
This work presents the synthesis of biocompatible and biodegradable amphiphilic copolymers for the formation of anticancer drug delivery systems. These copolymers consist of a poly-(ε-caprolactone) (PCL) chain, a biocompatible and biodegradable hydrophobic polyester, on which hydrophilic oligomers of dextrane or chitosane are grafted. These new copolymer structures are called “reverse” structures, the “classic” ones being made of a polysaccharide chain with PCL grafts. The PCL chain was propargylated via an anionic method developed by our team, while azide functions were grafted on oligosaccharides at a chain end of dextrane, but along the chain in chitosan, thanks to its amine functions. Copolymers were obtained by CuAAC click coupling between the activated PCL and oligosaccharides. In the case of chitosan, the amines of the chain allowed the coupling of mannose squarate, a cancer cell targeting agent, as well as a functionalization in the form of thiols which allow coupling by thiol-yne reaction on propargylated PCL. These copolymers form nano objects in aqueous media which, in the case of the PCL-g-dextrane structure, are forming micelles that encapsulate doxorubicin, which is further released in a pH- dependent way. Biological studies have shown that these charged micelles are toxic to cancer cells and not to healthy cells and are preferentially internalized by cancer cells. These results demonstrate a high degree of selectivity of action against tumor cells

In this thesis I have dealt with the synthesis of different macromolecular structures in order to create innovative devices. The heart of the process of synthesis has been the RAFT polymerization, a recent polymerization technique which allows the compatibilization of various chemical systems. The aim of this work is the improvement of innovative devices already on the market with good performance, but that possess limitations both as what regards specific technical properties and commercial exploitation. The aspect which has to be improved isn’t related to the device’s functional materials, rather to the compatibilization between them. Often, materials with remarkable absolute performances are used in a device, but these state-of-the-art components suffer from a partial quenching of their properties when incorporated in the final device. For this reason, in recent years, many studies have focused on materials that compatibilize different chemicals structures. For example polymeric composite materials combine the various functional properties of inorganic materials (metals and metal oxides) with mechanical properties of structural polymers. The different chemical nature of these two classes of materials leads to incompatibility, un-mixing and then to the worsening of the final performance in the operating conditions of the device. So it is essential to find materials that allow the different structures to chemically recognize each other through their surfaces. The materials used in this context are the surfactants, namely compounds that possess both polar and non-polar moieties. The same mechanism is at the base of the natural world in which, for example, liposomes form cell membranes which are fundamental for life itself. With this in mind, I focused to the synthesis of amphiphilic materials that possess hydrophilic and hydrophobic parts, therefore affinity with inorganic materials, or water based, and organic materials. This type of structure can be found in macromolecular materials. Access to such complex polymer structures - and concomitantly access to carefully tunable polymer properties - has been greatly enhanced with the advent of living free radical polymerization (LFRP) protocols that allow for the synthesis of multifunctional “chain transfer” agents that can serve as molecular machinery for obtaining polymers with complex architecture. The most prominent among LFRP techniques are Reversible Addition–Fragmentation chain Transfer (RAFT), Atom Transfer Radical Polymerization (ATRP) , and Nitroxide-Mediated Polymerization (NMP). , In particular, the strength of RAFT chemistry lies in its high tolerance to functional monomers and the non-demanding reaction conditions (e.g. tolerance to oxygen and low temperatures) under which the polymerizations can be carried out. In addition, a wide range of monomers with varying reactivity can be used. RAFT polymerization offers substantial versatility when it comes to the synthesis of block copolymers, star polymers, polymer brushes, and other complex polymer systems. The critical key to their synthesis is the presence of chain transfer agent (RAFT agent or CTA) with a thiocarbonylthio end group. Undesired bimolecular termination reactions, high initiator concentrations, or chain transfer to monomer or solvent can reduce the amount of RAFT end capped polymer chains. If carefully designed, RAFT polymerization opens the door to a range of polymer architectures by variable approaches. Similar to other living radical polymerization techniques, block copolymers, star and comb polymers, as well as graft polymers are accessible by attaching the controlling moiety to a (multi)functional core linking moiety. In addition, block structures are obtained by chain extension of the RAFT moiety capped block. Unique to the RAFT process are the possible modes of attaching the RAFT group covalently to the (multi)functional moiety. The first aspect analyzed was the self-assembly of amphiphilic block copolymers into complex architectures. As known block copolymers in the solid state have a separation of phases in the order of nanometers . In addition, by varying the chemical composition of the blocks and their relationship, it is possible to generate a variety of morphologies (spherical, cylindrical, lamellar or gyroidal). This behavior is described by the diagram of Matsen and Schick (see Figure 1) and relates to polymers in their thermodynamic minimum. The introduction of a solvent in the system can be interpreted as a third dimension in the diagram. Thus, in addition to the variation of χN (Flory-Huggins interaction parameter times total number of monomer units) and fx (fraction of the monomeric units x), we can introduce the quantity of solvent. The interaction between the solvent and the chemistry of the block copolymer is a key parameter to determine in what way the self assembly occurs. In the case of complete solubility the polymer will be completely dissolved while selective (or partial) solubility occurs if a single block is dissolved. The latter leads to the formation of particular structures that depend on all previous parameters in addition to temperature and the environmental conditions. Therefore, amphiphilic block copolymers can self-assemble into structures such as micelles, spheres, worm-like assemblies, toroids and polymer gels, depending on the ratio of the selective solvent. With RAFT technique, I have synthesized diblock copolymers constituted by polystyrene and polydimethylacrylamide with different total block length and studied their self-assembly in different solvents and concentrations, with the aim of introducing functional molecules in incompatible matrices (Chapter 4). Also, I produced the triblock copolymer polystyrene-polyethylene oxide and used as a polymer gel for electrolyte in dye-sensitized solar cells (Chapter 5). The advantage of this technique is that the polymer is free from the contamination of metal catalyst. The second topic has been the functionalization of nanoparticles of metal oxides with different polymers. The surface chemistry has been modified by making it more similar to the host matrix, in this way a polymer nanocomposite is created with high performance limiting the de-mixing of the different components. Polymer grafting techniques provide a very versatile tool to tailor the surface of nanoparticles and thus the interfaces between nanoparticles and the matrix polymers. The RAFT technique provides control over the type of polymer to be grafted onto the particle surface, surface densities, and chain lengths at the nanometer scale. The technique of covalently grafting polymer chains onto particles can be categorized into “grafting from” and “grafting to”. The grafting to technique involves reacting the polymer, bearing an appropriate functional group, with the particles to chemically attach the polymer chains. Because of the steric hindrance imposed by the already grafted chains, it becomes increasingly difficult for the incoming polymer chains to diffuse to the surface against the concentration gradient of the existing grafted polymers, which intrinsically results in low graft densities. In contrast, the grafting from technique uses initiators that have been initially anchored to the particle surface, followed by the polymerization from the surface. Since the existing grafted polymers will not hinder the diffusion of the small-sized monomers, significantly higher graft densities can be achieved with this technique. In this study, I was involved in the growth of the polymer to the surface (grafting from) to ensure a high coating density. I have synthesized a polymer shell of polystyrene on nanoparticles of titania to create a nanocomposite TiO2/PS (Chapter 6), which has been tested as a material with high dielectric properties. I also polymerized isoprene on commercial SiO2 in order to introduce it in the production of compounds for tyres and thereby increase the dispersion and improve the dispersion of filler in the rubber matrix (Chapter 7).

碩士
國立臺灣科技大學
化學工程系
94
In this study, amphiphilic polymers comprising both PEG and distearin (or stearyl alcohol) side chains were synthesized and characterized. Grafting efficiency and relative average molecular weight were determined by 1H-NMR and GPC, respectively. Amphiphilic graft copolymer is capable of forming micelles in the aqueous solutions with different pH values. Characteristic properties of polymeric micelles were analyzed by fluorescence spectroscopy and dynamic light scattering (DLS). The colloidal system has lower CAC values (1.87~24.4 mg/l), higher partitioning coefficients (9588~8272), larger particle sizes (100~150 nm), higher rotational correlation time (2.46~3.09 × 10-10 s) and lower hyperfine coupling constant (15.42~15.48 G) in pH 4 buffer. On the other hand, these copolymers show opposite results in pH 7 buffer. For the copolymer-modified liposomes, the liposome complex shows good colloidal stability, as shown by the DLS data. Liposomes encapsulated by distearin side chains have higher encapsulation efficiency, higher crystallization temperature, lower fluorescence permeability and higher fluorescence intensity ratio (I3/I1). The copolymer with distearin side chains forms more compact and smaller micelles compared to the stearyl alcohol counterpart. These results indicate that the graft copolymers can effectively improve the colloidal stability of liposomes and are pH sensitive. These graft copolymers find potential application as the pH-sensitive drug delivery carrier.

碩士
高雄醫學大學
醫藥暨應用化學研究所
101
In this study, we designed a novel comb-shaped amphiphilic copolymer, poly(ethylene glycol)-b-poly(ε-caprolactone)-g-poly (methacrylic acid) (MPCL-g-pMAA), which was synthesized by atom transfer radical polymerization (ATRP). We controlled the molar ratio of pMAA and MPCL to form three copolymers with different hydrophilic/hydrophobic characteristics. The MPCL-g-pMAA could self-assemble into micelles in aqueous solution with hydrophobic PCL in the center and hydrophilic PEG and MAA on the surface to increase circulation time in the blood. The carboxylic groups of pMAA were used to coordinate with an anticancer agent, Cisplatin, and the formed polymer-metal complexes could be used for cancer therapy. We used dynamic light scattering (DLS) and transmission electron microscope (TEM) to observe sizes and morphologies of micelles with and without Cisplatin. The drug loading efficiency and the hydrodynamic diameter increased with increasing amount of the carboxylic groups of MPCL-g-pMAA. The MPCL-g-pMAA with the least hydrophilic block length of pMAA showed the highest drug release amount as well as the highest cytotoxicity. The cellular internalization was visualized using a confocal laser scanning microscopy (CLSM).

碩士
國立臺灣科技大學
化學工程系
87
In this study, a novel polymer modifier designed to improve the physical and biological stability of liposomes was proposed. A series of polymeric modifiers comprising monomeric units of stearyl methacrylate, acrylic acid, and PEG acrylate was synthesized using AIBN as initiator at 70 ℃. The compositions and molecular weights of these comb copolymers were determined by IR and 1H-NMR and GPC,respectively.The fluorimetric techniques were used to characterize the properties of the aqueous solutions of comb copolymer micelles. This method is based on the measurements of the ratio of intensities of the third and first vibrational bands, I3/I1, in the emission spectra of pyrene solubilized in a polymer solution as a function of micellar concentration. The strong perturbation of the vibronic band intensities was used as a probe to accurately determine the CMC of these comb copolymers. While stearyl methacrylate acts as an anchor by being dissolved in the phospholipid part of liposomes, the polymeric main chain further enhances the stability of liposomes by unlocalization of the PEG-grafted copolymer through liposomal surface area. PEG on the liposome surface exerts its aqueous repulsion effect on approaching macromolecules and/or cells and elevates the biological stability of the modified liposomes. In addition, the membrane structure of these polymer-coated liposomes, the dependence of liposome diameter versus time, and release behavior of water-insoluble and water-soluble model compounds were also investigated.

博士
國立清華大學
化學工程學系
98
The colorectal cancer is the third death reason of the cancer in Taiwan, and the second in the world. The greatest defects of the anticancer drug for chemotherapy are able to kill normal cells but also cause the damage of the normal tissues or organs at the same time. Furthermore, the cancer cells can resist anticancer drug by themselves or through gene mutation by chemotherapy, resulting in forming drug resistances and losing the effect of the drugs. The main goal of this research is to develop a novel method of polymerization using an anticancer drug as the initiator, which produces nano-scale micelles with two kinds of anticancer medicines to overcome above defects. These micelles will kill cancel cells effectively and improve healing efficiency. First, an anticancer drug (5’DFUR) is utilized directly to be an initiator in the polymerization, and ε-caprolactone or (lactide/glycolide) is polymerized to form the 5’DFUR-poly(ε-caprolactone) (5’DFUR-PCL) or 5’DFUR-poly (lactide-co-glycolide)(5’DFUR-PLGA) in this study. The 5’DFUR-PCL and 5’DFUR-PLGA are then grafted to Poly (glutamic acid) (γ-PGA) to form a comb-like amphiphilic copolymers respectively (5’DFUR-PCL-γ-PGA and 5’DFUR-PLGA-γ-PGA). The characteristics of the copolymers will be examined by FT-IR, NMR and GPC. Additionally, a second anticancer drug is coated on micelles of amphiphilic copolymers by self-assembly method in aqueous phase to from a micelle with two kinds of the anticancer medicines. The effects of drug delivery and cure of colorectal cancer in vitro will be investigated. We expect that this novel polymerization method is able to replace the present technique, which would decrease the steps of the preparation process and reduce the prime cost; on the other hand, the nano-micelles carriers are designed from the concept of the cocktail therapy, might provide a way to cure effectively the colorectal cancer.

博士
國立清華大學
化學工程學系
94
In this investigation, new biodegradable brush-like amphiphilic copolymers were synthesized by ring opening polymerization. Poly(L-lactide) (PLLA) was grafted onto chondroitin sulfate (CS), which is one of the physiologically significant specific glycosaminoglycans (GAGs), using a tin octanoate [Sn(Oct)2] catalyst in DMSO. The hydroxyl groups of the chondroitin sulfate were used as initiating groups. These functional groups enable specific mucoadhesion or receptor recognition. The degree of substitution (DS), the degree of polymerization (DP) and the chondroitin sulfate content (from 1.1% to 15.4%) were analyzed by 1H-NMR. The characteristics of these grafted copolymers, including the structure, the thermal properties and biodegradability etc., were examined with respect to CS content. Meanwhile, the amphiphilic core (PLLA) - corona (CS) nanoparticles, with size smaller than 200 nm, was examined by dynamic light scattering (DLS). Zeta potential analysis exhibited the value in the range -18.3 to -49.4 mV. The morphologies of the nanoparticles were observed by field-emission scanning electron microscopy (FE-SEM). The nanoparticles with lower cytotoxicity were examined by MTT assay. Furthermore, the in vitro BSA release kinetics of those CSn-PLLA nanoparticles was also determined in this study. Novel polymeric amphiphilic copolymers were synthesized using chondroitin sulfate (CS) as a hydrophilic segment and poly(L-lactide) (PLLA) as a hydrophobic segment. Micelles of those copolymers were formed in an aqueous phase and were characterized by 1H NMR spectra, fluorescence techniques, dynamic light scattering (DLS), atomic force microscopy (AFM) and confocal microscopy. Their critical aggregation concentrations (CAC) are in the range of 0.0043 to 0.0091 mg/mL at 25oC. The partition equilibrium constants, Kv, of the pyrene probe in the aqueous solution were from 3.65×105 to 1.41×106 at 25 oC. The mean diameters of the micelles were below 200 nm, and their sizes were narrowly distributed. The AFM images revealed that the self-aggregates were spherical. Additionally, the CSn-PLLA micelles can efficiently transport within the cells via endocytosis as observed from confocal microscopy. In cartilage tissue engineering, the graft copolymer was blended with poly(L-lactide) (PLLA) to form biomimic porous scaffolds. Natural CS was introduced into the polyester matrix to promote the proliferation of cells. Three-dimensional sponge-like scaffolds were fabricated by a combination of salt leaching and solvent casting methods. The morphology of the scaffolds was observed with scanning electron microscopy (SEM) with average pore size between 50~250 μm and its porosity was high (>85%). Compression analysis indicated that the mechanical properties of the scaffold were adequate to support the proliferation of cells. The hydrophilicity increased with increasing the copolymer content in the blend, as determined by measuring the contact angle. H&E, Masson and Safranin-O staining showed that cells formed a chondro-tissue gradually. Histological results revealed that abundant cartilaginous matrices surrounded spherical chondrocytes in the center of the explants. Chondrocytes cultured in this ECM-like scaffold maintained a round morphology phenotype, characterized by a significant quantity of extracellular matrix of sulfated glycosaminoglycans and collagens. Additionally, phenotypic gene expression (RT-PCR) indicated that chondrocytes expressed transcripts that encoded type II collagen and aggrecan, and generated sulfated glycosaminoglycans.

碩士
國立臺灣科技大學
化學工程系
95
Amphiphilic copolymers comprising poly(acrylic acid) (PAAc) as the backbone and monomethoxy poly(ethylene glycol) (mPEG) as the grafts were synthesized and characterized. The functional group, grafting efficiency and relative average molecular weight were determined by FTIR, 1H-NMR and GPC, respectively. This copolymer as a carrier is capable of immobilizing chymotrypsin (ChT) in alkaline aqueous phase. GPC and SDS-PAGE were used to whether ChT was success fully attached on to the amphiphilic polymer carrier. Characteristic properties of polymer-protein conjugate system were analyzed by fluorescence spectroscopy, dynamic light scattering (DLS) and quartz crystal microbalance (QCM). The carrier system has lower CAC values (0.831~2.072 g/l), lower λmax (416~422 nm) of 2-AN spectrum, smaller particle sizes (only for P5-ChT (53.6 nm)) and higher frequency (only for P10-ChT (148.77 Hz)) in pH 4 buffer solutions. On the other hand, this carrier system show opposite results in pH 7.5 buffer solutions. In activity assay, residual activity increased with increasing the mPEG amounts and pH values. This carrier system has obviously high activity in pH 9 buffer solution.

The goal of this thesis, funded by the European Union’s Horizon 2020 research and innovation programme under the SAMCAPS project (grant agreement no. 814100), is to address the current need for bio-degradable materials and efficient encapsulating agents for home and beauty care products. To this aim, this work focuses on the liquid-liquid phase separation (LLPS) of an amphiphilic thermoresponsive copolymer that leads to the formation of micron-sized domains, known as simple coacervates, at room temperature and in surfactant-rich media, where control of liquid-liquid phase separation is particularly challenging. Additionally, these microstructures can entrap hydrophobic active principles from the medium and release them in a triggered way, rendering them as suitable encapsulating agents.

Living anionic polymerization techniques were applied to the synthesis of arborescent (dendritic) well-defined graft polymers having core-shell morphologies, with a hydrophobic core and a hydrophilic shell. Cycles of polystyrene substrate acetylation and anionic grafting yielded successive generations of arborescent polystyrenes. The anionic polymerization of styrene with sec-butyllithium provided polystyryllithium serving as side chains. These were coupled with a linear acetylated polystyrene substrate to obtain a generation zero (G0) arborescent polymer. An analogous G0 hydroxyl-functionalized polystyrene substrate with hydroxyl end groups was also obtained by a variation of the same technique, using a bifunctional organolithium initiator containing a hydroxyl functionality protected by a silyl ether group to generate the polystyrene side chains. These were coupled with the linear acetylated polystyrene substrate and subjected to a deprotection reaction to give the G0 polymer functionalized with hydroxyl groups at the chain ends. A similar procedure was used to generate a hydroxyl-functionalized arborescent G1 polymer from the corresponding G0 acetylated polystyrene substrate. The growth of polyglycidol chain segments was attempted from the hydroxyl-functionalized cores, to form a hydrophilic shell around the hydrophobic cores, but led to extensive degradation. A click reaction was also developed to synthesize the amphiphilic copolymers and was much more successful. In this case alkyne-functionalized arborescent polystyrene substrates, obtained by a modification of the hydroxyl-functionalized arborescent polystyrenes, were coupled with azide-functionalized polyglycidol side chains.

碩士
國立臺灣科技大學
化學工程系
97
Amphiphilic copolymers comprising poly(acrylic acid) (PAAc) as the backbone and monomethoxy poly(ethylene glycol) (mPEG) as the grafts were synthesized and characterized. The copolymers were used for conjugation with different amounts of α - chymotrypsin immobilized enzyme system. In this study, it was intended to investigate the activity of enzyme after grafting toward high and low molecular weight substrates. N-Benzoyl-L-Tyrosine ethyl ether was used as a low molecular weight substrate whereas bovine serum albumin and Azocasein was used as a high molecular substrate. Residual activity increased with increasing the mPEG amount when a low molecular weight substrate was used. But enzyme's residual activity was reduced along with temperature increment. The cleavage rate of bovin serum albumin and Azocasein was reduced due to the excess amounts of mPEG that would induce steric effect, there by leading to slow cleavage rate. When the enzyme was under the low pH environment, it was not easy for enzyme to undergo thermal deactivation.

This thesis describes the synthesis and application of a new series of amphiphilic graft copolymers with a hydrophobic polyolefin backbone and pendent hydrophilic poly(ethylene glycol) (PEG) grafts. These copolymers are synthesized by ruthenium benzylidene-catalyzed ring-opening metathesis polymerization (ROMP) of PEG-functionalized cyclic olefin macromonomers to afford polycyclooctene- graft-PEG (PCOE-g-PEG) copolymers with a number of tunable features, such as PEG graft density and length, crystallinity, and amphiphilicity. Macromonomers of this type were prepared first by coupling chemistry using commercially available PEG monomethyl ether derivatives and a carboxylic acid-functionalized cycloctene. In a second approach, macromonomers possessing a variety of PEG lengths were prepared by anionic polymerization of ethylene oxide initiated by cyclooctene alkoxide. This methodology affords a number of benefits compared to coupling chemistry including an expanded PEG molecular weight range, improved hydrolytic stability of the PEG-polycyclooctene linkage, and a reactive hydroxyl end-group functionality for optional attachment of biomolecules and probes. The amphiphilic nature of these graft copolymers was exploited in oil-water interfacial assembly, and the unsaturation present in the polycyclooctene backbone was utilized in covalent cross-linking reactions to afford hollow polymer capsules. In one approach, a bis-cyclooctene PEG derivative was synthesized and co-assembled with PCOE-g-PEG at the oil-water interface. Upon addition of a ruthenium benzylidene catalyst, a cross-linked polymer shell is formed through ring-opening cross-metathesis between the bis-cyclooctene cross-linker and the residual olefins in the graft copolymer. By incorporating a fluorescent-labeled cyclooctene into the graft copolymer, both oil-water interfacial segregation and effective cross-linking were confirmed using confocal laser scanning microscopy (CLSM). In a second approach, reactive functionality capable of chemical cross-linking was incorporated directly into the polymer backbone by synthesis and copolymerization of phenyl azide and acyl hydrazine-functional cyclooctene derivatives. Upon assembly, these reactive polymers were cross-linked by photolysis (in the phenyl azide case) or by addition of glutaraldehyde (in the acyl hydrazine case) to form mechanically robust polymer capsules with tunable degradability (i.e. non-degradable or pH-dependent degradability). This process permits the preparation of both oil-in-water and water-in-oil capsules, thus enabling the encapsulation of hydrophobic or hydrophilic reagents in the capsule core. Furthermore, the assemblies can be sized from tens of microns to the 150 nm - 1 µm size range by either membrane extrusion or ultrasonication techniques. These novel capsules may be well-suited for a number of controlled release applications, where the transport of encapsulated compounds can be regulated by factors such as cross-link density, hydrolytic stability, and environmental triggers such as changes in pH.

碩士
國立臺灣科技大學
化學工程系
96
Enzyme immobilization is one of the most important techniques for increasing the stability of enzyme and recycling. In this study, it is intended to investigate the activity of enzyme after immobilization toward high and low molecular weight substrates. Amphiphilic copolymer comprising poly(acrylic acid)(PAAc) as the backbone and monomethoxy poly(ethylene glycol)(mPEG) as the grafts were synthesized and characterized. The copolymers were used for conjugation with different amounts of α- chymotrypsin as a pH-sensitive immobilized enzyme system. N-Benzoyl-L-Tyrosin ethyl ether was used as a low molecular weight substrate whereas bovine serum albumin was used as a high molecular substrate. Residual activity increased with increasing the mPEG amount and pH. The cleavage rate of bovin serum albumin was accelerated obviously for the experiments carried out in the pH 7 buffer solution. However, the excess amounts of mPEG would induce steric effect, thereby leading to slow cleavage rate.

碩士
國立臺灣科技大學
化學工程系
98
Amphiphilic copolymers comprising poly(acrylic acid)(PAAc) as the backbone and monomethyl poly(ethylene glycol)(mPEG) as the grafts were synthesized and characterized. The copolymers were used for conjugation with different amounts of α-chymotrypsin. The activities of α-chymotrypsin before and after incorporating into the graft copolymers toward high and low molecular weight substrates were studied. N- Benzoyl-L-Tyrosine ethyl ether (BTEE) was used as a low molecular weight substrate and Azocasein was used as a high molecular substrate. Residual activity increased with increasing the pH and the mPEG content when BTEE was used, but it decreased with increasing the temperature and the mPEG amount when Azocasein was used due to the steric effect associated with the excessive amounts of mPEG. In addition, enzyme’s residual activity was reduced with temperature increment.

Block copolymers can self-assemble into a variety of periodic nanostructures and therefore, are promising candidates for a diverse range of applications. While self-assembly of block copolymers has been widely studied and exploited, graft copolymers have remained far less explored in this context. One of the primary reasons for this is that the most commonly used methods to prepare graft copolymers leads to polymers that do not have precisely defined structures; specifically, controlling the precise location of the grafted segments is a synthetically difficult challenge. In typical chain polymerization processes, statistically random incorporation of monomers takes place and consequently, the periodicity of the grafted segment along the backbone is very difficult to control precisely; therefore, such methods cannot be utilized to prepare periodically grafted copolymers. Some recent efforts towards the preparation of sequence regulated copolymers using controlled radical polymerization in conjunction with periodic dosing of a commoner could provide an alternative to better regulate the periodicity, although this will also not be perfectly periodic. The only approach to control the periodicity perfectly is to utilize condensation polymerization approaches, wherein one of the monomers serve as a spacer whereas the other provides the opportunity to install the graft segment, as depicted in Scheme 1. One of the earliest examples of the utilization of a condensation approach to locate desired units at periodic intervals was reported by Wagener and co-workers using Acrylic Diene Metathesis (ADMET) process.1 ]n periodicity ]n graft segment Scheme 1. Synthetic scheme for the preparation of periodically grafted copolymers using condensation polymerization. From our lab, Roy et al. developed periodically grafted amphiphilic copolymers (PGAC), based on a readily available starting material, diethyl malonate;2 melt trans-esterification between diethyl malonate, containing a pendant hexaethylene glycol monomethyl ether (HEG) segment and 1,22-docosane diol resulted in PGAC wherein the hydrophilic oligo ethylene glycol units were placed on every 27th atom along the backbone (Scheme 2). Such PGAC underwent self-segregation and adopted a folded zigzag conformation, which was driven by the intrinsic immiscibility of the alkylene and HEG segments and was reinforced by the strong tendency for long chain alkylene segments to crystallize in a paraffinic lattice. However, one of the drawbacks of the above approach was that the hydrophilic pendant unit was installed at the monomer stage and consequently, the synthetic approach does not allow easy variation of the hydrophilic grafted segment; this limits the flexibility and any structural variation of the pendant segment would be synthetically tedious. 150 oC DBTDL 5 20 DBTDL = Dibutyltin dilaurate Scheme 2. Synthesis of PGAC, based on diethyl malonate, and immiscibility-driven folding of such PGACs. Mandal et al. developed a more general strategy for the synthesis of such periodically grafted systems; they prepared periodically clickable polyesters carrying propargyl groups at regular intervals, by the solution polycondensation of 2-propargyl-1,3-propanediol or 2,2-dipropargyl-1,3-propanediol and the acid chloride of 1,20-eicosanedioic acid. Such periodically clickable polyesters were shown to react quantitatively with a fluoroalkyl azide3 and PEG 350 azide4, thus allowing them to place different kinds of functionalities precisely along the backbone, as shown in Scheme 3. The immiscibility of the alkylene and fluoroalkyl/PEG segments caused the polymer chains to fold in a zigzag fashion, thereby facilitating the segregation of these segments, as observed earlier in the study by Roy et al.2 The objective of this study was to place various desired functionalities along the polymer backbone and examine their effect on the self-assembly behaviour and morphology of such periodically clicked systems. Scheme 3. Synthetic scheme for the generation of periodically clickable polyesters and their subsequent functionalization via Cu-catalysed click chemistry. In Chapter 2, we describe an alternative general strategy for the scalable synthesis of periodically graftable polyesters and their subsequent functionalization to generate a wide variety of periodically grafted systems. The importance of our approach lies in our choice of the monomer, which is based on itaconic acid, an inexpensive and bio-sourced molecule. We demonstrated that dibutyl itaconate can be melt-condensed with aliphatic diols to generate unsaturated polyesters (Scheme 4); importantly, we showed that the double bonds in the itaconate moiety remain unaffected during the melt polymerization. A particularly useful attribute of these polyesters is that the exo-chain double bonds are conjugated to the ester carbonyl and therefore, can serve as excellent Michael acceptors. A variety of organic thiols, such as alkane thiols, MPEG thiol, thioglycerol, derivative cysteine etc., were shown to quantitatively Michael-add to the exo-chain double bonds and generate interesting functionalized polyesters; similarly, organic amines, such as N-methylbenzylamine, diallyl amine and proline also underwent Michael addition across the double bond (Scheme 4). Thus, such poly(alkylene itaconate)s could be utilized to place diverse functionalities at regular intervals along the polymer backbone. Scheme 4. Preparation of periodically graftable polyesters, based on itaconic acid, and their subsequent modification by Michael addition. In Chapter 3, we examined a series of periodically grafted polyesters carrying long crystallizable alkylene (C-20) segments along the backbone and pendant polyethylene glycol monomethyl ether (MPEG) segments grafted at periodic intervals. Such periodically grafted amphiphilic copolymers (PGAC) having MPEG graft segments of varying lengths were prepared by utilizing the activated exo-chain double bonds in poly(icosyl itaconate) (PII) that carries a 20-carbon alkylene segment; MPEG thiols of varying lengths (TREG, 350, 550 and 750) were quantitatively grafted under standard Michael addition conditions to yield the required graft copolymers, as shown in Scheme 5. Scheme 5. Synthesis of a series of periodically grafted amphiphilic copolymers (PGAC) utilizing post-polymerization modification via Michael addition with MPEG thiols of varying lengths. The immiscibility of the backbone alkylene and pendant MPEG segments, and the strong propensity of the alkylene segments to crystallize in a paraffinic lattice, drive these systems to fold in a zigzag fashion and subsequently organize into a lamellar morphology, as shown in Scheme 6. Interestingly, all the graft copolymers exhibited a clear and invariant melting transition at ~44°C that suggested the crystallization of the backbone C-20 segment; the MPEG segments were, however, amorphous except in the case of polymers carrying MPEG 550/MPEG-750 segments, wherein a second melting transition corresponding to the independent crystallization of the PEG segment was also seen. SAXS studies indicated that all of the samples exhibited lamellar morphologies wherein more importantly, the inter-lamellar spacing was seen to increase linearly with the MPEG length (Scheme 6). This study provides a new design for controlling the dimensions of the microphase-separated nanostructures at significantly smaller length scales (sub-10 nm) than is typically possible using block copolymers. Scheme 6. Schematic representation of formation of lamellar morphology in PGACs and control of interlamellar spacing in such systems. In order to understand the influence of having a mixture of MPEG lengths on the self-assembled morphology, in Chapter 4 we prepared a series of PGACs by co-grafting the parent poly(icosyl itaconate) with a mixture of two different MPEG thiols, namely MPEG-350 and MPEG-750; the mole-ratios of these two PEGs were varied to generate co-grafted PGACs, carrying different amounts of the two MPEG segments randomly distributed along the chain (Scheme 7). Parallely, we also examined the behaviour of physical mixtures of two different PGACs, one bearing MPEG-350 and the other MPEG-750 grafts; keeping the total MPEG content constant, we sought to examine the differences in the behaviour of randomly co-grafted polymers and physical mixtures. Scheme 7. Preparation of co-grafted PGACs and physical mixtures of two different PGACs. The co-grafted PGACs also exhibited a lamellar morphology; interestingly, the inter- lamellar spacing increased linearly with the total volume of PEG domain. This suggested that despite the presence of MPEG segments of two different lengths in the co-grafted samples, there occurred a reorganization of the PEG chains within the amorphous domain ensuring that the condition of incompressibility is not violated, thereby giving rise to a weighted average interlamellar spacing, as shown in Scheme 8. In contrast, the SAXS patterns of the physical mixtures revealed the presence of two distinct lamellar domains in the sample; this indicated that the two homo-grafted samples do not mix and form separate lamellar domains. The self- segregation induced folding and subsequent crystallization of the central alkylene segments clearly appeared to dominate the final morphology. Scheme 8. Schematic depiction of the possible scenarios that could arise when MPEG segments of two different lengths, namely MPEG350 and MPEG750, are present in the PGACs; top panel depicts the co-grafted PGACs, whereas the bottom panel shows the case of mixtures of PGACs with two different MPEG lengths. In Chapter 5, we have dealt with the design and synthesis of chain-end functionalizable polyalkylene itaconates. Changing the monomer from dibutyl itaconate to dipropargyl itaconate and using it in controlled excess allowed us to generate chain-end functionalizable polymers containing propargyl groups at the chain ends, in addition to the exo-chain double bonds along the backbone, thereby providing the opportunity for orthogonal functionalization. In order to obtain three different telechelic polymers with target DPs (degree of polymerization) of 5, 10 and 20 respectively, 3 different mole ratios of the two monomers (dipropargyl itaconate and 1,20-eicosanediol) were used (Scheme 9). Scheme 9. Synthetic scheme for the generation of chain-end functionalizable polyalkylene itaconates. Orthogonal functionalization of the resultant polymers was carried out using thiol-Michael addition and Cu(I)-catalysed alkyne-azide cycloaddition (AAC), without interference between the functional handles present along the polymer backbone and the chain-end, respectively. Michael addition with triethylene glycol thiol and subsequent Cu-catalysed click reaction with MPEG 750 azide led to the generation of ABA type triblock copolymers where the middle block is a periodically grafted amphiphilic block and the two linear end blocks are hydrophilic in nature. Furthermore, such propargyl-terminated polyalkylene itaconates were used as macromonomers to prepare multiblock copolymers. The telechelic polymers were first treated with PEG 600 diazide, resulting in the formation of alternating multiblock copolymers; these multiblock copolymers were further reacted with thioglycerol to generate amphiphilic multiblock copolymers where one of the blocks is a periodically functionalized amphiphilc block, as depicted in Scheme 10. In both these amphiphilic block copolymer systems, a key feature is that the periodically functionalized amphiphilic block folds into a zigzag form, as evident from the presence of a nearly invariant melting peak corresponding to the crystallization of the alkylene segment. Scheme 10. Preparation of multiblock copolymers utilizing propargyl-terminated polyalkylene itaconates as a macromonomer. In summary, the thesis has demonstrated the design and synthesis of a series of novel amphiphilic copolymers using a bio-sourced monomer, wherein the driving theme is the immiscibility driven self-segregation that leads to the folding of the chain; these have been thoroughly examined using DSC, SAXS, WAXS, variable temperature FT-IR and AFM measurements. References (1) Berda, E. B.; Lande, R. E.; Wagener, K. B. Macromolecules 2007, 40, 8547. (2) Roy, R. K.; Gowd, E. B.; Ramakrishnan, S. Macromolecules 2012, 45, 3063. (3) Mandal, J.; Krishna Prasad, S.; Rao, D. S. S.; Ramakrishnan, S. Journal of the American Chemical Society 2014, 136, 2538. (4) Mandal, J.; Ramakrishnan, S. Langmuir 2015, 31, 6035.