Dissertations / Theses on the topic 'Thermosensitive copolymers'

Syntheses of biodegradable PLLA homopolymers and PLLA-mPEG diblock copolymers for the formation of thermo-sensitive gels were performed. The sol-gel transition temperature of the matrix was adjusted by altering the length of each PEG and LA component. PLLA-mPEG biocompatible copolymers, having appropriate length of each block component, showed sols at around 42-45 oC, suitable for the injection, then a gel with subsequent rapid cooling to body temperature. Topotecan and camptothecin were selected as anti-cancer drugs. Both drugs can easily hydrolyze at physiological conditions (pH=7.4). This causes the loss of its activity, and it turns into inactive toxic carboxylate form from active lactone state. To keep those anti cancer drugs in the lactone form, they were efficiently loaded into PLLA-mPEG gels in different loading ratios. Their stability in gel was fully examined with HPLC and fluorescence spectroscopy. It was found that both drugs were highly stable and in active form in the prepared gels (>
95 %). Then, both release profile of drugs at different loading ratios showed prolonged release over weeks. Mechanistic studies on the stabilization of CPT anti cancer drug with PLLA-mPEG gels were carried out using ATR-FTIR, confocal and optic microscopes. The cytotoxic efficacy of TPT in the PLLA-mPEG platform (PLLA-mPEG-TPT) was evaluated on LLC-1 and 4T1 cancer cell lines by MTT assay. In vivo, the administration of PLLA-mPEG-TPT to the mice bearing breast tumours established with 4T1 cells resulted in a significant reduction in tumour size and better survival percentages. Additionally, stabilization of CPT and TPT with gels may find another application on solid tumors in brain via local injection. A novel conducting polymer was successfully synthesized via electropolymerization of 1-(1H-pyrrol-1-yl)-2,5-di(thiophen-2-yl)-1H-pyrrole. The electrochemical and electro-optical properties of the corresponding polymer, which was the first example of polymer containing 1,1&rsquo
-bipyrrole units, were elaborated using electroanalytical and spectroscopic techniques. Cyclic voltammograms and electrooptical studies showed that the polymer has a stable and well-defined reversible redox process as well as electrochromic behavior. The processable polymer film also possessed a yellowish orange light emitter property.

Thesis (Ph.D.)--Boston University
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Chemotherapy requires the systemic administration of large doses of highly toxic antineoplastic agents in order to achieve therapeutically relevant concentrations at the tumor. These drugs typically act by impairing cell mitosis, effectively targeting rapidly-dividing cells that are the hallmarks of cancer. Non-cancerous cells that divide rapidly under normal circumstances are often damaged, leading to adverse side effects including myelosuppression, alopecia, and organ-specific toxicities. One potential means of reducing off-site toxicities is to encapsulate highly toxic chemotherapeutics into thermosensitive liposomes (TSL). These nanoscale structures are formed from temperature-sensitive lipids, and are designed to passively target the tumor by being large enough to avoid renal clearance while small enough to slip through leaky blood vessels characteristic of tumor vasculature. At the tumor, externally applied heating triggers a burst release of therapeutically relevant concentrations of drug. Current TSL formulations suffer from (i) approaches for heating that put healthy tissue surrounding the tumor at risk; (ii) lack of stability at physiological conditions (e.g. premature leakage of drug); and (iii) lack of noninvasive approaches for monitoring temperature elevation. This project presents a dual pH/thermosensitive liposome (PTSL) for the deliver of Doxorubicin (DOX), a commonly administered chemotherapeutic. Copolymers of temperature-responsive N-isopropylacrylamide (NIPAAm) and pH-responsive propylacrylic acid (PAA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, yielding copolymers with dual pH/temperaturedependent phase transition properties. When attached to liposomes, copolymers were membrane-disruptive m a pH/temperature-dependent manner, conferring pH/temperature-sensitive drug release properties to the liposome. These dual-sensitive properties can potentially exploit the slightly acidic environment of the tumor when PTSL are administered with externally applied heating. PTSL demonstrated enhanced release profile, significantly lower thermal dose threshold, and lower IC50 when compared to traditional TSL, and were stable in serum with minimal premature drug leakage. The application of MR-guided focused ultrasound (MRgFUS) as a noninvasive, highly controllable thermal source for triggering drug release and monitoring temperature elevations was demonstrated in vivo. PTSL combined with MRgFUS treatment resulted in delayed tumor growth when compared to PTSL alone and control treatments. This PTSL-MRgFUS delivery system thus addresses the limitations of existing TSL therapies and has potential applications in the clinic.
2031-01-01

Les travaux présentés dans ce manuscrit ont porté sur l'élaboration de nouveaux copolymères dibloc amphiphiles (poly(ε-caprolactone)-b-poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) biodégradables, thermostimulables et susceptibles d'être employés dans des applications respectueuses de l'environnement comme le traitement des eaux contaminées. La particularité de ces copolymères provient d'une part de la différence de solubilité des deux blocs et d'autre part de l'association d'un bloc hydrophobe biodégradable à un bloc thermostimulable hydrophile. Les propriétés de ces copolymères en milieu aqueux ont ainsi été évaluées en fonction de la température. Ces composés ont été obtenus par la combinaison de deux techniques de polymérisation contrôlée en utilisant un amorceur difonctionnel. Pour cela, deux stratégies ont été testées : i) la polymérisation par ouverture de cycle (POC) de l'ε-caprolactone à partir d'un macro-amorceur de poly(méthacrylate d'oligo(éthylène glycol) méthyl éther) à terminaison OH après avoir mis au point les conditions expérimentales de la POC en comparant plusieurs catalyseurs. ii) par polymérisation radicalaire par transfert d'atome (ATRP) du méthacrylate d'oligo(éthylène glycol) amorcée à partir d'une poly(ε-caprolactone) à extrémité bromée. Les températures critiques inférieures de solubilité (LCST) de ces copolymères ont été déterminées par UV visible. Leurs comportements micellaires ont été étudiés par mesures HPPS
The development of new biodegradable diblock copolymers poly(ε-caprolactone)-b-poly[oligo(ethylene glycol)methyl ether methacrylate], which could be used in environmental friendly applications such as treatment of contaminated water has been the main goal of this work. For the preparation these copolymers, the ring-opening polymerization (ROP) and the Atom Transfer Radical Polymerization (ATRP) were combined by using a bifunctional initiator. The two-step route for the synthesis of these copolymers was using either ATRP or ROP as first step and the other polymerization secondly. Each polymerization was studied carefully in order to control the macromolecular parameters of the copolymers. On the one hand, the ATRP of methacrylates bearing oligo(ethylene glycol) was carried out by using poly(ε-caprolactone) with bromide end-group as macroinitiator. On the other hand, the ring opening polymerization of ε-caprolactone was initiated by the hydroxyl end-group of the poly[oligo(ethylene glycol)methyl ether methacrylate], using tin octoate, tin tetrakis(phenylethynyl) or bismuth triflate as catalysts. The Low Critical Solution Temperature (LCST) of these amphiphilic diblock copolymers in aqueous medium have been determined by UV-visible spectroscopy. Their micellar behaviors were also studied by measuring size by HPPS

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

In this work new fluorinated and non-fluorinated mono- and bifunctional trithiocarbonates of the structure Z-C(=S)-S-R and Z-C(=S)-S-R-S-C(=S)-Z were synthesized for the use as chain transfer agents (CTAs) in the RAFT-process. All newly synthesized CTAs were tested for their efficiency to moderate the free radical polymerization process by polymerizing styrene (M3). Besides characterization of the homopolymers by GPC measurements, end- group analysis of the synthesized block copolymers via 1H-, 19F-NMR, and in some cases also UV-vis spectroscopy, were performed attaching suitable fluorinated moieties to the Z- and/or R-groups of the CTAs. Symmetric triblock copolymers of type BAB and non-symmetric fluorine end- capped polymers were accessible using the RAFT process in just two or one polymerization step. In particular, the RAFT-process enabled the controlled polymerization of hydrophilic monomers such as N-isopropylacrylamide (NIPAM) (M1) as well as N-acryloylpyrrolidine (NAP) (M2) for the A-blocks and of the hydrophobic monomers styrene (M3), 2-fluorostyrene (M4), 3-fluorostyrene (M5), 4-fluorostyrene (M6) and 2,3,4,5,6-pentafluorostyrene (M7) for the B-blocks. The properties of the BAB-triblock copolymers were investigated in dilute, concentrated and highly concentrated aqueous solutions using DLS, turbidimetry, 1H- and 19F-NMR, rheology, determination of the CMC, foam height- and surface tension measurements and microscopy. Furthermore, their ability to stabilize emulsions and microemulsions and the wetting behaviour of their aqueous solutions on different substrates was investigated. The behaviour of the fluorine end-functionalized polymers to form micelles was studied applying DLS measurements in diluted organic solution. All investigated BAB-triblock copolymers were able to form micelles and show surface activity at room temperature in dilute aqueous solution. The aqueous solutions displayed moderate foam formation. With different types and concentrations of oils, the formation of emulsions could be detected using a light microscope. A boosting effect in microemulsions could not be found adding BAB-triblock copolymers. At elevated polymer concentrations, the formation of hydrogels was proved applying rheology measurements.
Im Rahmen dieser Arbeit wurden neue fluorierte und unfluorierte mono- und bifunktionelle Trithiocarbonate der Typen Z-C(=S)-S-R und Z-C(=S)-S-R-S-C(=S)-Z zur Anwendung als CTAs (chain- transfer agents) im RAFT-Polymerisationsverfahren hergestellt. Alle CTAs wurden erfolgreich auf ihre Effizienz zur Steuerung des radikalischen Polymerisationsverfahrens hin durch Polymerisation von Styrol (M3) getestet. Neben GPC-Messungen wurden Endgruppenanalysen der synthetisierten Blockcopolymere mittels 1H-, 19F-NMR und in manchen Fällen auch UV-Vis Spektroskopie durchgeführt. Dazu wurden die Z- und/oder R-Gruppen der CTAs mit geeigneten fluorierten Gruppen versehen. Durch Anwendung des RAFT Verfahrens konnten symmetrische Triblockcopolymere vom Typ BAB bzw. mit einer Fluoralkylgruppe endgecappte unsymmetrische Polymere in nur zwei bzw. einem Polymerisationsschritt hergestellt werden. Das RAFT- Polymerisationsverfahren ermöglicht sowohl die Polymerisation hydrophiler Monomere wie N-Isopropylacrylamid (NIPAM) (M1) oder N-Acryloylpyrrolidin (NAP) (M2) für die A-Blöcke als auch der hydropoben Monomere Styrol (M3), 2-Fluorostyrol (M4), 3-Fluorostyrol (M5), 4- Fluorostyrol (M6) und 2,3,4,5,6- Pentafluorostyrol (M7) für die B-Blöcke. Die Eigenschaften der Blockcopolymere in verdünnten, konzentrierten und hochkonzentrierten wässrigen Lösungen wurden mittels DLS, Trübungsphotometrie, 1H- und 19F-NMR, Rheologie, CMC- sowie Schaumhöhen- und Oberflächenspannungsmessungen und Lichtmikroskopie untersucht. Weiterhin wurden ihre Eigenschaften als Emulgatoren und in Mikroemulsion untersucht. Das Micellbildungsverhalten der hydrophob endfunktionalisierten Polymere wurde mittels DLS Messungen in verdünnter organischer Lösung untersucht. Alle untersuchten BAB-Triblöcke bildeten Micellen und zeigten Oberflächenaktivität bei Raumtemperatur in verdünnter, wässriger Lösung. Weiterhin zeigen die wässrigen Lösungen der Polymere mäßige Schaumbildung. Mit verschiedenen Öltypen und Ölkonzentrationen wurden Emulsionen bzw. Mikroemulsionen gebildet. In Mikroemulsion wurde durch Zugabe von BAB-Triblockopolymeren kein Boosting-Effekt erzielt werden. Bei Untersuchung höherer Polymerkonzentrationen wurde die Bildung von Hydrogelen mittels rheologischer Messungen nachgewiesen. Verschiedene Substrate konnten benetzt werden. Die hydrophob endgecappten Polymere bilden in verdünnter organischer Lösung Micellen, die mittels DLS untersucht wurden, und zeigen somit Tensidverhalten in nichtwässriger Lösung.

Presented diploma thesis deals with drug encapsulation of Sulfathiazole (STA) in thermosensitive hydrogel composed of amphiphilic fibrous molecules of copolymer poly(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA). In the experimental part, the structure of the micelles which is dependent on the concentration of the default copolymer, was thoroughly described. The method of dynamic light scattering (DLS) was used to dimensionally characterize the micellar size in aqueous solution. At the same time, the Cryo-Transmission Electron Microscopy (Cryo-TEM) imaging technique confirmed the transition from spherical micelles to fibrous branched structures with a number of topological interactions. The change in viscoelastic properties of micellar hydrogel after addition of STA was studied by rheological analysis. The studied triblock copolymer appears to be a suitable tissue engineering material as a carrier in applications for targeted drug delivery and tissue regeneration.

Literární rešerše předložené dizertační práce shrnuje poznatky jak o současně používaných biomateriálech, tak i o tzv. „chytrých“ biomedicínských materiálech mezi které patří termocitlivé kopolymery. Mezi tyto kopolymery, jejichž vodné roztoky gelují při teplotě lidského těla (37 °C), řadíme amfifilní triblokové kopolymery skládající se z hydrofobního laktidu, glykolidu a hydrofilního polyethylen glykolu (PLGA PEG PLGA). Komerčně dostupné termocitlivé kopolymery známé pod názvem ReGel or OncoGel jsou v současné době využívány jako injekčně aplikovatelné nosiče s postupným uvolňováním léčiv, zejména při léčbě cukrovky nebo onkologického onemocnění. Nicméně PLGA PEG PLGA triblokový kopolymer může být použit I jako polymerní nosič anorganického léčiva případně jako biodegradabilní implantát v dentálních či ortopedickýchých aplikacích. Z toho důvodu byl vybrán anorganický biokompatibilní hydroxyapatit (HAp) pro své majoritní zastoupení v tvrdých tkáních. Experimentální část je zaměřena na přípravu HAp/PLGA PEG PLGA kompozitů, ve kterých je HAp buď ve formě nano- (n-HAp) nebo „core-shell“ částic (CS). Nové CS částice, připravené dvouemulzní metodou, jsou složeny z „tuhého“ HAp jádra obaleného termocitlivým kopolymerem, který je navíc funkcionalizován kyselinou itakonovou (ITA/PLGA PEG PLGA/ITA). Funkcionalizace pomocí ITA vnáší do původní struktury kopolymeru jak síťovatelné dvojné vazby, tak i koncové karboxylové skupiny. Volné karboxylové skupiny na koncích ITA/PLGA PEG PLGA/ITA kopolymerního obalu byly dále zesíťovány za vzniku 3D chemické sítě (CS-x), jejíž životnost je řízena a kontrolována. ATR-FTIR spektroskopie prokázala přítomnost „nových“ esterových vazeb vzniklých karbodiimidovou reakcí –OH a –COOH skupin, kterým náleží adsorpční pásy ve vlnové délce 1021 cm-1.. n-HAp a CS-x částice byly přidány do kopolymerní termocitlivé matrice (PLGA PEG PLGA) za účelem charakterizace jejich reologického chování. Bylo zjištěno, že pokud bylo do polymerní matrice přidáno méně než 10 hm. % CS-x částic a jen 5 hm.% n-HAp kompozit si zachoval své termocitlivé vlastnosti. Na druhou stranu, přídavek vyššího množství HAp částic do polymerní matrice zajistil změnu vodného polymerního solu v permanentní gel při teplotě nad 37 °C. Analýza ICP-OES prokázala rychlejší uvolňování CS-x částic z 10 hm/obj. % PLGA PEG PLGA polymerní matrice do inkubačního média (6 % 9. den) než tomu bylo u n-HAp částic (jen 3 %), které jsou vázány více v micelární struktuře kopolymeru. Proto, kompozit na bázi n-HAP částic tvořící tuhý trvalý gel při tělesné teplotě, je vhodný více jako biologicky rozložitelné kostní lepidlo, zatímco kompozit z CS-x částic a termocitlivého kopolymeru je vhodný jako nosič léčiv pro injekční aplikace.

Medicínské aplikace tvoří z biodegradabilních alifatických polyesterů na bázi polylaktonů, polylaktidů a jejich kopolymerů velmi atraktivní skupinu materiálů. Metody přípravy těchto polymerů jsou založeny na polymeraci za otevření kruhu laktonů a laktidů. Mnoho organokovových sloučenin se vyznačují jako účinné a vysoce selektivní katalyzátory těchto polymerací, avšak je známo, že deriváty těžkých kovů jsou škodlivé pro lidský organismus. Z tohoto důvodu je v dnešní době rostoucí zájem o vývoj účinných „green“ polymeračních systémů pro syntézu biodegradabilních alifatických polyesterů. Předložená disertační práce se věnuje přípravě alifatických polyesterů založených na polykaprolaktonu, polylaktidu, polyglykolidu a zejména jejich kopolymeru pomocí organického katalyzátoru náležícího do skupiny N-heterocyklických karbenů (NHC) bez přítomnosti centrálního atomu těžkého kovu. Literární rešerše je zaměřená na pokroky v polymeraci za otevření kruhu (ROP) cyklických esterů (laktonů a laktidů) pomocí organických "metal-free" katalyzátorů. Nicméně, nebyly nalezeny žádné studie, kde se pro přípravu polyglykolidu nebo jeho kopolymerů využívá polymerace za otevření kruhu pomocí karbenových katalyzátorů. Experimentální část práce popisuje přípravu a vlastnosti 1,3-di-tert-butylimidazol-2-ylidenu (NHC-tBu) karbenu připraveného z jeho stabilní chloridové soli. Další část je zaměřena na přípravu polyesterů z cyklických monomerů, jmenovitě L-laktidu, D, L-laktidu, glykolidu a -kaprolaktonu pomocí NHC-tBu jako katalyzátoru. Byla zkoumána nová metoda přípravy termosenzitivního amfifilního triblokového kopolymeru na bázi biodegradabilního hydrofobního polylaktidu, polyglykolidu a biokompatibilního hydrofilního polyethylenglykolu (PLGA–PEG–PLGA) pomocí připraveného NHC-tBu. Dále byly studovány podmínky polymerace (například: přečištění monomeru, teploty polymerace, různé typy rozpouštědel, poměry rozpouštědla ku monomeru a nebo různé poměry iniciátoru ku katalyzátoru). Na závěr byl připravený PLGA–PEG–PLGA kopolymer srovnán s kopolymerem připraveným pomocí Sn(II)2-ethylhexanoátu. NHC-tBu se v přítomnosti PEG projevil jako účinný katalyzátor polymerace za otevření kruhu laktonu a laktidů. Připravené kopolymery dosahovaly vysoké konverze monomeru (70 – 85%) s polydisperzitou (Mw/Mn okolo 1,2). Byl připraven PLGA–PEG–PLGA kopolymer se dvěma fázovými přechody (sol-gel a gel suspenze) a gelační teplotou v rozmezí 35 – 43 °C. Změny polymeračních podmínek neměly ve většině případů zásadní vliv na chemické vlastnosti kopolymeru, jako jsou molekulová hmotnost nebo polydisperzita, ale měly významný vliv na visko-elastické vlastnosti.

Cette étude concerne le développement de nanoparticules hybrides offrant de nouvelles stratégies pour la thérapie et le diagnostic médical. Elles sont constituées d’un cœur magnétique jouant le rôle d’agent de contraste pour l’IRM et d’inducteur de chaleur par hyperthermie, d’une couronne de polymère thermosensible permettant d’encapsuler des principes actifs et de peptides de reconnaissance biologique. Une grande partie de l’étude a consisté à étudier les processus d'adsorption de copolymères poly(éther)-b-poly(L-lysine) de composition variable sur les particules magnétiques et à comprendre le rôle de la conformation des chaînes polymère à la surface des particules sur la stabilité des colloïdes en milieu physiologique. Un agent antitumoral a été encapsulé puis libéré de façon contrôlée sous l’effet d’un champ magnétique alternatif en exploitant le caractère thermosensible des blocs polyéthers. Des séquences peptidiques ciblant les zones d’inflammation de la barrière hémato-encéphalique ont été greffées sur les copolymères. L’efficacité du ciblage a été validée par IRM et fluorescence sur un modèle animal démontrant ainsi la multifonctionnalité des nanoparticules
This work deals with the development of hybrid nanoparticles that could offer new strategies for therapy and diagnostic. These are based on a magnetic core which can play the role of contrast agent for MRI as well as heat inductor in AC magnetic field. This inorganic core is surrounded by a thermo-responsive polymeric brush that controls the loading and the release of drugs, and can be functionalized by specific ligands ensuring the targeting specificity. A large part of this work consists in studying the adsorption mechanism of poly(ether)-b-poly(L-lysine) based block copolymers onto magnetic particle and to better understand the influence of the polymer chain conformation at particles surface on the colloidal stability under physiological conditions. An anticancer drug has been loaded and released in a controlled manner under alternative magnetic field by taking advantage from the thermosensitivity of the polyether block. Targeting peptides specific of inflammation sites at the blood brain barrier have been grafted onto copolymers. The targeting specificity has been demonstrated by MRI and fluorescence imaging in rats attesting the multifunctionality of such nanoparticles

Cette thèse présente le développement de nanoparticules hybrides avec un coeur inorganique et une couronne organique pour des applications médicales. Des nanoparticules d’oxyde de fer ont été obtenues par synthèse polyol, en contrôlant leurs cristallinités, leurs morphologies (monocoeur ou multicoeur) et leurs tailles (de 4 à 37 nm). Leurs propriétés ont été évaluées et comparées pour de possibles applications théranostiques : en thérapie pour le traitement du cancer par hyperthermie magnétique, pour le diagnostic en tant qu’agents de contraste pour l’IRM. Les surfaces des nanoparticules ont été modifiées par greffage de polymères/polypeptides pour apporter de la stabilité en milieux biologiques et de nouvelles fonctionnalités. Le poly(éthylène glycol) (PEG) a été greffé pour ses propriétés de furtivité, le poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) et des polypeptides dérivés de l’élastine (ELPs) pour leurs propriétés thermosensibles, et la sonde fluorescente DY700 pour permettre le suivi des nanoparticules in vitro et in vivo. Les propriétés magnétiques et thermosensibles de ces nanoparticules coeur-couronne ont été étudiées avec un instrument unique combinant l’hyperthermie magnétique et un système de diffusion dynamique de la lumière. Ainsi, les variations de température, de diamètre et d’intensité diffusée ont pu être mesurées simultanément. Les propriétés de nanoparticules monocoeur et multicoeur greffées avec du PEG, et des nanoparticules monocoeur greffées avec un ELP contenant un peptide pénétrant ont d’abord été évaluées in vitro. Leurs internalisations dans des cellules de tumeur cérébrale humaine (glioblastome) ont permis d’étudier leurs cytotoxicités après traitement par hyperthermie magnétique, et ont montré une baisse de viabilité cellulaire jusqu’à 90 %. In vivo, l’injection intraveineuse de ces nanoparticules dans des souris a abouti à une accumulation dans les tumeurs. L’injection intratumorale suivie du traitement par hyperthermie magnétique a conduit à des élévations de température locales d’environ 10 °C, avec un effet significatif sur l’activité des tumeurs
This thesis reports the development of hybrid nanoparticles made of an inorganic iron oxide core and an organic shell for medical applications. Iron oxide nanoparticles (IONPs) were produced by the polyol pathway, leading to a good control over their crystallinity and morphology (monocore or multicore). IONPs with diameters in the range of 4 to 37 nm were produced. Their properties as MRI contrast agents were assessed and compared, for possible theranostic applications. They can be used for treating cancer by magnetic hyperthermia, and as contrast agents for MR imaging. The surface of the IONPs was modified to bring stability in biological conditions, as well as new functionalities. Poly(ethylene glycol) was grafted for its stealth property, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) and elastin-like polypeptides (ELPs) for their thermosensitive capabilities, and a DY700 fluorescent probe was grafted for tracking nanoparticles in vitro and in vivo. The magnetic and thermosensitive properties of the nanoparticles were studied using a unique set-up combining magnetic hyperthermia with dynamic-light scattering. This set-up allowed measuring the elevations of temperature of the samples as well as variations in diameter and backscattered intensity. Monocore and multicore IONPs grafted with PEG, and monore IONPs grafted with a diblock ELP were tested in vitro. Their interactions with glioblastoma cells were studied, from the internalization pathway inside the cells to their cytotoxic effect (up to 90 %) under magnetic hyperthermia. In vivo, nanoparticles intravenously injected in mice accumulated in the tumors. Intratumoral administration followed by magnetic hyperthermia treatment led to elevations of temperature of up to 10 °C, with a significant effect on the tumor activity

Le travail de thèse présenté dans ce manuscrit a pour objectif la synthèse de copolymères thermosensibles complexants innovants pour la mise en place d'un nouveau procédé de traitement des effluents aqueux chargés en métaux. Ce procédé original est en effet basé sur l'utilisation de copolymères porteurs de groupements phosphonés permettant la sorption des métaux en solution aqueuse et possédant un caractère thermosensible de sorte à contrôler la solubilité du copolymère et à faciliter les étapes de sorption et de séparation. Dans un premier temps, la synthèse de copolymères thermosensibles phosphonés a été réalisée par polymérisation radicalaire conventionnelle puis par polymérisation radicalaire contrôlée (PRC) ce qui a conduit à différentes architectures. Parmi les composés préparés, le P(NnPAAm-stat-hMAPC1) a été sélectionné car il présente une basse température critique de solution proche de la température des effluents industriels chargés en métaux. Les propriétés de sorption de ces copolymères ont ensuite été déterminées en réacteur statique afin de mettre en évidence les facteurs influents (temps de contact, température, pH, composition de l'effluent). Ces différents essais ont également permis d'étudier les mécanismes de sorption intervenant entre les groupements acide phosphonique et les différents cations métalliques évalués (Ni2+, Ca2+, Cd2+, Al3+). Enfin, les étapes de séparation post-sorption et de régénération ont également fait l'objet d'études approfondies, permettant de proposer à l'issue de ce travail un procédé innovant de traitement de la pollution métallique, appelé procédé TEMF (Thermosensitive polymer Enhanced Microfiltration). L'efficacité des différentes étapes constituant ce procédé a été évaluée en batch à l'échelle du laboratoire et en semi-continu sur un pilote de laboratoire conçu dans le cadre du projet
This Ph-D work aims at synthetizing thermosensitive and complexing polymers for the implementation of an innovative process targeting the removal of metallic cations from wastewater. This process is based on the use of copolymers bearing phosphonic acid groups as sorption moieties whereas thermoresponsiveness allows adjusting the solubility of the polymeric sorbent according to the process step considered. First, the synthesis of various thermosensitive copolymers bearing phosphonated moieties is reported. The use of free radical polymerization or Reversible Addition Fragmentation Transfer (RAFT) polymerization allowed synthesizing copolymers with different architectures. Among all macromolecular compounds, the P(NnPAAm-stat-hMAPC1) copolymer was chosen as the most relevant polymeric sorbent for the process. Sorption properties of this copolymer were then evaluated and results highlighted that the contact time, the temperature, the pH and more generally the effluent composition were the main influencing parameters. These studies also enable to figure out the sorption mechanisms involved between phosphonic acid and the cationic metals studied (Ni2+, Ca2+, Cd2+, Al3+).The studies carried on the separation and regeneration steps of the process allowed the development of an innovative process for the removal of metallic pollution from wastewaters named Thermosensitive polymer Enhanced Microfiltration (TEMF) process. Finally, the conception of a pilot plant permitted the study of the TEMF process at larger scale

Biodegradabilné syntetické polyméry nesú vlastnosti, ktoré ich zvýhodňujú oproti iným materiálom používaným na poli regeneratívnej medicíny a tkanivového inžinierstva. Najdôležitejšie výhody zahŕňajú schopnosť prispôsobovať mechanické a chemické vlastnosti aj kinetiku degradácie. Obzvlášť polyestery sú zaujímavé z pohľadu na ich biodegradáciu. Podliehajú hydrolýze, počas ktorej dochádza k štiepeniu esterových väzieb a degradačné produkty sú metabolizované bez akýchkoľvek škodlivých účinkov. Diplomová práca je zameraná na syntetické biodegradabilné triblokové kopolyméry PLGA-PEG-PLGA s obsahom kyseliny polymliečnej (PLA), kyseliny polyglykolovej (PGA) a polyetylénglykolu (PEG), ktoré patria do skupiny biodegradabilných polyesterov. Obsah hydrofilnej a hydrofóbnej zložky polymérneho reťazca spôsobuje amfifilný charakter kopolyméru. Pripravené triblokové kopolyméry sú schopné tvoriť hydrogél pomocou fyzikálneho sieťovania v dôsledku ich amfifilného charakteru. Tieto materiály zaznamenali významný záujem vo vedeckej oblasti. Teoretická časť diplomovej práce všeobecne popisuje hydrogély, bližšie sa venuje fyzikálnemu sieťovaniu amfifilných blokových kopolymérov a mechanizmom degradácie. Podrobný popis triblokového kopolyméru PLGA-PEG-PLGA je rozdelený na PLGA kopolyméry, PEG a ich fyzikálno-chemické vlastnosti. Zahrnuté sú aj poznatky o chemickej funkcionalizácii anhydridom kyseliny jantárovej, anhydridom kyseliny itakonovej a kyselinou listovou. Dopamín je prezentovaný ako spájací faktor a spomenuté sú taktiež najdôležitejšie bioaktívne látky. Experimentálna časť sa zaoberá konkrétnymi metódami syntézy, ktoré viedli k funkcionalizácii a modifikácii triblokových kopolymérov PLGA-PEG-PLGA. Funkcionalizáciou anhydridom kyseliny itakonovej bol získaný kopolymér s oboma koncami obohatenými o reaktívne dvojité väzby a karboxylové funkčné skupiny. Dvojité väzby umožňujú chemické sieťovanie a koncové karboxylové skupiny ponúkajú možnosť modifikácie kopolyméru biologicky aktívnymi látkami. Modifikácia bioaktívnymi látkami L-lyzínom a butylamínom obohacuje polymérnu sieť a dopamín v roli spojovacieho faktoru poskytuje univerzálnosť v naväzovaní bioaktívnych látok, stabilizuje ich a zabezpečuje zachovanie biologickej aktivity naviazaných bioaktívnych látok predĺžením reťazca. Výsledné produkty boli charakterizované pomocou 1H NMR, FTIR a DRA analýz. Funkcionalizácia anhydridom kyseliny itakonovej bola prevádzaná v tavenine. Podarilo sa dosiahnuť vyššieho množstva naviazanej kyseliny itakovovej s hodnotou 79,4 mol % a následné modifikácie boli prevádzané vo vodnom roztoku, organickom roztoku a taktiež v tavenine. Bolo zistené, že najefektívnejšia metóda modifikácie bola syntéza v organickom roztoku s rozpúšťadlom N,N-dimetylformamidom a aktivačným systémom dicyklohexylkarbodiimid/4-(dimetylamino)pyridínom. Najvyššie množstvo naviazaného dopamínu bolo 18,6 mol %, najvyššie množstvo naviazaného butylamínu bolo 7,8 mol % a L-lyzín sa naviazať nepodarilo.

碩士
國立成功大學
臨床藥學研究所
92
Introduction. Novel thermosensitive copolymers with a specific composition are a free flowing sol at low temperature, but become a transparent semi-solid gel at body temperature and they can be both biodegradable and biocompatible. These safety materials have been applied to the formulation of pharmaceuticals, generally as the excipients or surfactants. In recent years, efforts have been made to try utilizing such thermosensitive characteristics on drug delivery system, local drug delivery or delay-release dosage forms. Noteablely, previous studies have demonstrated that some of the amphiphilic thermosensitive block copolymers can improve the transport of rhodamine, digoxin and danounrubcin…etc., across the MDR/MRP overexpression cell lines, such as Caco-2, Chinese hamster ovary cells, BBMECs, human ovarian carcinoma cells. 　　Purpose. The aim of this study was to evaluate the effects of thermosensitive biodegradable copolymer on drug delivery and transport. Methods. A new PEG/PLGA amphiphilic thermosensitive block copolymer, developed and synthesized by the Industrial Technology Research Institute of Taiwan, was used to evaluate its local delivery effect for paclitaxel in the isolated perfused rat liver and for irinotecan in rats following intra-liver and intra-peritoneal administration, respectively. To investigate the effects of amphiphilic thermosensitive block copolymers on Mdr/Mrp transporters, the biliary secretion of ciprofloxacin and digoxin was characterized in the absence and presence of Pluronic F-127. 　　Results. The new PEG/PLGA copolymer showed favorable local delivery effects by limiting the anticancer drugs in the local tissues and reducing their systemic exposure. The biliary secretion of both ciprofloxacin and digoxin was significantly reduced by Pluronic F-127, suggesting an inhibitory effect of Pluronic F-127 on Mdr/Mrp transporters. 　　Conclusion. In summary, the new PEG/PLGA amphiphilic thermosensitive block copolymer from the Industrial Technology Research Institute of Taiwan can be used for local drug delivery. And Pluronic F-127 may alter drug dispositions through its inhibition on Mdr/Mrp transporters.

Antivascular targeting is a promising strategy for tumor therapy. This strategy overcomes many of the transport barriers and has shown efficacy in many preclinical models, but targeting epitopes on tumor vasculature can also promote accumulation in healthy tissues. We used Elastin-like Polypeptide (ELP) to form block copolymers (BCs) consisting of two separate ELP blocks seamlessly fused at the genetic level. ELPBCs self-assemble into spherical micelles at a critical micelle temperature (CMT), allowing external control over monovalent unimer and multivalent micelle forms. We hypothesized that thermal self-assembly could trigger specific binding of ligand-ELPBC to target receptors via the multivalency effect as a method to spatially restrict high-avidity interactions. We termed this approach Dynamic Affinity Modulation (DAM). The objectives of this study were to design, identify, and evaluate protein-based drug carriers that specifically bind to target receptors through static or dynamic multivalent ligand presentation.

ELPBCs were modified to include a low-affinity GRGDS or GNGRG ligand and a unique conjugation site for hydrophobic compounds. This addition did not disrupt micelle self-assembly and facilitated thermally-controlled multivalency. The ability of ligand-ELPBC to specifically interact with isolated AvB3 or CD13 was tested using an in vitro binding assay incorporating an engineered cell line. RGD-ELPBC promoted specific receptor binding in response to multivalent presentation but NGR-ELPBC did not. Enhanced binding with multivalent presentation was also observed only with constructs exhibiting CMT < body temperature. This study establishes proof-of-principle of DAM, but ELPBC requires thermal optimization for use with applied hyperthermia. Static affinity targeting of fluorescent ligand-ELPBC was then analyzed in vivo using intravital microscopy (IM), immunohistochemistry (IHC), and custom image processing algorithms. IM showed increased accumulation of NGR-ELPBC in tumor tissue relative to normal tissue while RGD-ELPBC and non-ligand ELPBC did not, and IHC verified these observations. This study shows (1) multivalent NGR presentation is suitable for static multivalent targeting of tumors and tumor vasculature, (2) multivalent RGD presentation may be suitable for DAM with thermal optimization, and (3) ELPBC micelles may selectively target proteins at the tumor margin.

Dissertation

This dissertation presents the synthesis of stimuli-sensitive hydrophilic polymers, particularly doubly responsive hydrophilic block copolymers, by controlled radical polymerizations and the study of their solution behavior in water. By incorporating a small amount of stimuli-responsive groups into the thermosensitive block of a hydrophilic block copolymer, the lower critical solution temperature (LCST) of the thermosensitive block can be tuned by a stimulus and multiple micellization/dissociation transitions can be achieved by combining two external triggers. Chapter 1 describes the synthesis and thermosensitive properties of two new watersoluble polystyrenics with a short oligo(ethyl glycol) pendant from each repeat unit and the study of hydrophobic end group effects on cloud points of thermosensitive polystyrenics. Well-defined polymers were prepared from monomer-based initiators via nitroxide-mediated polymerization and the alkoxyamine end groups were removed by tri(n-butyl)tin hydride, yielding thermoresponsive polystyrenics with essentially no end groups. The results showed that hydrophobic end groups could significantly change the cloud points and the molecular weight dependences of cloud points of polystyrenics. Chapter 2 presents the synthesis of thermo- and light-sensitive hydrophilic block copolymers, poly(ethylene oxide)-b-poly(ethoxytri(ethylene glycol) acrylate-co-onitrobenzyl acrylate), and their responsive behavior in dilute aqueous solutions. Dynamic light scattering and fluorescence spectroscopy studies showed that these copolymers were molecularly dissolved in water at lower temperatures and self-assembled into micelles at temperatures above the LCST of the thermosensitive block. Upon UV irradiation, the oiv nitrobenzyl group was cleaved and the LCST of the thermosensitive block was increased, causing the dissociation of micelles into unimers. The resultant copolymers underwent thermo-induced reversible micellization at higher temperatures. Chapter 3 describes multiple micellization/dissociation transitions of thermo- and pH-sensitive hydrophilic block copolymers, poly(ethylene oxide)-b-poly(methoxydi(ethylene glycol) methacrylate-co-methacrylic acid), in response to temperature and pH changes. The LCST of the thermosensitive block can be reversibly tuned and precisely controlled by solution pH. Chapter 4 presents the study on multiple sol-gel-sol transitions of a 20.0 wt % aqueous solution of poly(ethylene oxide)-b-poly(ethoxytri(ethylene glycol) acrylate-co-o-nitrobenzyl acrylate) induced by temperature changes and UV irradiation. The solution underwent thermo-induced sol-gel-sol transitions. Upon UV irradiation to dissociate micelles, the gel was transformed into a free-flowing liquid, which upon heating underwent sol-gel-sol transitions again.

碩士
大同大學
化學工程學系(所)
97
ABSTRACT In this study, a series of biodegradable triblock amphiphilic and thermosensitive PLGA-PEG-PLGA copolymers were prepared by using hydrophilic poly(ethylene glycol) (PEG) as macro-initiator and stannous octoate as a catalyst, lactide (LA) and glycolide (GA) via ring opening polymerization where the used PEG was equally weight ratio mixed with PEG1000 and PEG1500. This research was subdivided into three parts. In first part, a series of biodegradable triblock amphiphilic and thermosensitive PLGA-PEG-PLGA copolymers were prepared. Their molecular weight ratios of hydrophobic PLGA(X) and hydrophilic PEG (Y) were fixed at 2.5 and 3.0. In addition, the various molar ratios of LA and GA were designed. The effect of the different molar ratios of LA/GA on the aqueous properties, such as critical micellization temperature (CMT), critical micellization concentration (CMC), and sol-gel phase diagram etc, of the present triblock copolymers was investigated. In second part, a series of biodegradable triblock amphiphilic and thermosensitive PLGA-PEG-PLGA copolymers were prepared. Their molar ratio of LA and GA in the triblock copolymer was fixed at 75/25. The effect of different hydrophobic chain lengths in the PLGA-PEG-PLGA copolymers on the aqueous properties, such as critical micellization temperature (CMT), critical micellization concentration (CMC), and sol-gel phase diagram etc, of the present triblock copolymers was investigated. In third part, a series of biodegradable triblock amphiphilic and thermosensitive PLGA-PEG-PLGA copolymers were prepared. Their molar ratio of LA and GA in the triblock copolymer was fixed at 75/25 and hydrophobic chain length PLGA(X) and hydrophilic chain length PEG (Y) were fixed at 2.5. Then, these triblock copolymers was chain-end blocked with monomethoxy poly(ethylene glycol) (mPEG) to form mPEG-PLGA-PEG-PLGA-mPEG block copolymer and their aqueous properties and biodegradation behavior was investigated.

碩士
淡江大學
化學工程與材料工程學系碩士班
98
In this study, we synthesized thermosensitive poly(N-isopropylacrylamide，PNIPAAm) homoolymer and PNIPAAm/poly(2-Acrylamido-2-methyl-1-propanesulfonic acid，PAMPS) copolymer by photo-polymerization. We hope the sulfonic acid group of AMPS to increase the swelling ratio, volume phase transition temperature and glass transition temperature of copolymer. We use the N,N’-methylenebisacrylamide(MBA) as crosslinker and 2-Hydroxy-2-methyl-1-phenyl-propanone(Darocure 1173) as photo-initiator. Because the Darocure 1173 is hydrophobic initiator, we use water/ethanol as mixture solvent. In the first part of this study, we synthesize the PNIPAAm by changing the ratio of crosslinker and the volume ratio of water and ethanol. When we increase the ratio of crosslinker and the volume ratio of water and ethanol, the conversion of PNIPAAm would increase, but the swelling ratio (SR) and Volume phase transition temperature (VPTT) would decrease. The second part of this study, we regulate the ratio of water and ethanol for 1/1, and synthesize the P(NIPAAm-co-AMPS) copolymer by changing the ratio of crosslinker and the ratio of AMPS monomer. When increasing the ratio of AMPS monomer, the sweling ratio, VPTT and water retension capability of the copolymer would increse. Then reason is the strong hydrophilicy of the sofonic acid group of the AMPS. Finally, we study the drug relaese kinetic with PNIPAAm and P(NIPAAm-co-AMPS) copolymer.

碩士
國立臺北科技大學
有機高分子研究所
100
In this study, we used Nitroxide-mediated Controlled Radical Polymerization (NMCRP; NMRP) to prepare the active polymer - PNTBA-TEMPO. NMCRP; NMCRP;NMRP is a Stable Free Radical Polymerization (SFRP) of Control/Living Free Radical Polymerization method. The monomers we proceeded for the series of polymerization are N-tert-butylacrylamide (NTBA), N-isopropylacrylamide (NIPAAm), stable nitroxide free radical, 2,2,6,6-tetramethyl-1-piperdinyloxy nitroxide (TEMPO). The initiator is 2,2’-Azobis(isobutyronitrile) (AIBN). This method can effectively control the formation polymers to have low polydispersity (PDI) property, and it can also maintain the active of polymer in order to facilitate the second polymerization. By NMCRP method, we set the ratio of NTBA / AIBN / TEMPO equal to 20 mmol/0.24 mmol/0.216 mmol. In nitrogen condition and constant temperature at 125℃ to proceed first polymerization, and we obtained white active polymer – Poly(N-tert-butylacrylamide) (PNTBA-TEMPO). From 1H-NMR spectrum, the double bond signal at δ=5.5-6.2 ppm (-CH=CH2) is disappeared. It shows that the double bond of NTBA monomers were broken to use for polymerization. According to the analysis from GPC (Gel Permeation Chromatography), the molecular weight (Mw = 11667 to 16854) will slightly increased with increase of reaction time (10 min to 24 hr). The samples’ PDI degree all below 2. Otherwise, using Free Radical Polymerization Techniques. Under same reaction time (24 hr), the samples’ molecular weight is 48700; PDI ratio is 4.7. Measuring by light transmission instrument, we had discovered that under different concentration (1% - 30%), the UCST (Upper Critical Solution Temperature) transition temperature region of PNTBA-TEMPO was between 27.5℃ to 33.13 ℃. In the secondary copolymerization, we selected the ratio for NIPAAm / AIBN / TEMPO equal to 20 mmol / 0.24 mmol / 0.216 mmol. In nitrogen condition and temperature at 125℃ to proceed 24 hr, we added different percentage of NTBA (0.2826 g (2.22 mmol) and 2.5438 g (20 mmole) ). We raised the temperature to 135℃ and repeated reaction for 24 hr, then we obtained the white polymer of PNIPAAm-block-PNTBA. Measuring by 1H-NMR spectrum, the double bond signal at δ=5.5-6.2 ppm (-CH=CH2, NTBA and NIPAAm) is disappeared and there is another methyl group signal at δ=1.2 ppm (CH3, NTBA). As a conclusion, we had proved that PNIPAAm-block-PNTBA polymer was successfully created. Based on the testing from light transmission instrument, we had figured out the LCST (Lower Critical Solution Temperature) temperature of PNIPAAm-block-PNTBA (mole ratio = 1:1) is 27.69℃. Furthermore, if we added 5% of PNIPAAm-block-PNTBA (mole ratio = 9:1) in solution, the phase transition temperature was close to human body temperature (37.43℃).

碩士
大同大學
化學工程學系(所)
99
Part I In this study, stannous octoate (Sn(Oct)2) as catalyst, methoxy polyethylene glycol or polyethylene glycol as co-catalyst to ring-opening lactide (LA) and glycolide (GA) to synthesize a series of non-toxic, non-solvent, and injectable thermosensitive methoxy polyethylene glycol (mPEG) and poly(lactide-co-glycolide) di-block copolymer (mPEG-PLGA), then this copolymer was end-blocked with 2, 2-bis (2-oxazoline) (Box). The effect of the Box structure in the di-block copolymer on the lower critical transition temperature (LCST), gel stability, phase transition temperature, and cell cytotoxicity of the copolymer was investigated in this study. The results showed that the copolymer’s LCST increased and their critical gelation concentrations (cgc) reduced when the copolymer dissolved in different solutes for the copolymer chain en-capped with Box. The range of gel formation temperature increase when they dissolved in different solutions, such as saline, Bovine Serum Albumin (BSA), or glucose (10 wt%), but their degradation rate would slow down. The stability of storage of the copolymers in different temperatures was measured, in which the commercial products, Macro Med, was referred as its product shelf life duration 18 months when storage in -20 oC of temperature. Part II This research is focus on synthesis of the shape-memory materials based on [polyethylene glycol (PEG) / polycaprolactone (PCL)]-polyurethane (PU) which is biodegradable. Because biodegradable PCL is hydrophobic when we use it as a soft-chain, then combine it with a hard-chain PU which is made from 2, 4-toluene diisocyanate (TDI) and chain-extend agent to synthesize a shape-memory polyurethane, the products will also exhibit hydrophobic. In this article, , we try to change the molecular weight of PEG in the polyethylene glycol (PEG) / polycaprolactone (PCL) to improve the their hydrophilicity and let the products become more biocompatible. Besides, we also compared the properties of polyurethane by changing the composition of soft-chain and hard-chain. The structure and properties and molecular weight of the copolymers were measured with FT-IR, DSC, and GPC. The results showed that when the composition of hard-chain increases, the crystallinity of PCL will decrease because of the physical-crosslink formed by hard-chain in the structure, and then the melting point will be decreased. In addition, the water contact angles of the [(PEG-PCL)-PU] di-block copolymers decrease with increase of the hydrophilic PEG. PCE20 series copolymers have better shape-memory recovered ratio because the amount of hard-chain can effectively form enough physical-crosslink.

碩士
國立臺北科技大學
有機高分子研究所
100
Temperature sensitive hydrogels were synthesized using N-isopropylacrylamide (NIPAAm) and Acrylicamide acid(AIM) via nitroxide-mediated radical polymerization. The use of a stable rical such as 2,2,6,6-rwreamwthyl-1-piperi-nylxy(TEMPO) as reversible terminating agent to control the eadical polymerization of a monomer has been extensively studied. With a view to expanding the possivlities of nitroxide moderators,much attention has been focoused on how to weaken the C-O-N bond in the alkoxylamine which os formed upon reverisible termination . Recent studies have shown that specific electronic effects are likely to weaken the C-O-N bond (thus enabling the polymerization to proceed in a faster way in the case of casee of nitroxide-mediated eadical reactions),and to ensure the control of reactions which concern other types of monomers,such as the acrylic monomers.

碩士
國立清華大學
奈米工程與微系統研究所
99
The objective of this study is to discuss the thermo responsiveness properties of methoxy poly(ethylene glycol)-polyesters (mPEG-PLGA, mPEG-PCLA) diblock copolymers. Without changing the hydrophilic/hydrophobic segment ratio of the copolymer, the molar ratio of ester monomers was adjusted to obtain better formulation for a thermal-sensitive hydrogel. Diblock copolymers were synthesized using ring-opening polymerization. For the mPEG-PLGA series, L10, L8G2, L6G4, L4G6, L2G8, and G10 were prepared corresponding to LA/GA ratios of 100/0, 80/20, 60/40, 20/80, and 0/100, respectively. For the mPEG-PCLA series, L10, L8C2,L6C4, L4C6, L2C8, and C10 were prepared corresponding to LA/CL ratios of 100/0, 80/20, 60/40, 20/80, and 0/100 respectively. Results showed that L10, L4G6, L2G8, L2C8, C10 and G10 were insoluble in water due to high crystallinity and hydrophobicity. L8G2, L6G4, L8C2, L6C4, and L4C6 formed nanoparticles with sizes under 100 nm and critical micelle concentrations below 0.1 mg/mL in aqueous solution. Also, it was observed that 15 wt% (w/v) mPEG-PLGA displayed a wide gelation window in water. Adjusting the molar ratio of monomers in mPEG-PLGA did not significantly alter the gelation window while decreasing the LA units in mPEG-PCLA narrowed the gelation window. In degradation test, mPEG-PCLA series showed slower degradation rate, L4C6 and L6C4 both degraded less than 40% of their original weight after 30 days. In brief, L6C4 hydrogel has optimal ratio, which shows good biocompatibility in cytotoxicity test. Also, L6C4 is a promising drug delivery carrier in cartilage defect regeneration model. These results demonstrate some diblock copolymers of mPEG-PLGA and mPEG-PCLA can be used as in situ gelling drug delivery systems.

碩士
國立臺北科技大學
生物科技研究所
100
Poly(NIPAAm-PEGMEA) copolymers were prepared via free radical polymerization of various mole ratios of monomers initialized by H2O2-vitamin C redox initiators. The synthesized copolymers were further mixed with chitosan particles in phosphate buffered saline (PBS). The temperature dependences of flow property and cloud point of the solution with chitosan particles were investigated by the tube-invert, DSC, and light transmission tests. It was found that the poly(NIPAAm) could flow at 25oC, and formed a gel at higher temperature. The cloud point of the Poly(NIPAAm-PEGMEA) could increased to about 36.4oC with increasing of PEGMEA unit, but there had almost no change with addition of chitosan particles. The thickness of the poly(NIPAAm), and poly(NIPAAm-PEGMEA) hydrogels could increased to 40% and 80%, respectively, higher than that before swelling in PBS at 37oC. The ratio became only 50% for the poly(NIPAAm-PEGMEA)/chitosan particle system. The MTT assay indicated the biocompatibility could be improved by adding the chitosan particles into the copolymer hydrogel.

碩士
國立高雄大學
生物科技研究所
101
We employed magnetic nanoparticles incorporated with thermosensitive polymers to prepare intelligent gel. The chosen thermosensitive polymer was biocompatible Pluronic F127, which could be attached with caprolactone as a thermosensitive block-copolymer under investigation for its structure by FT-IR and,1H-NMR. The transition temperature could be controlled with added quantity of caprolactone. Based on the same solid content in polymer solutions, the phase transition range of PCL-Pluronic-PCL polymer is smaller than that of of Pluronic F127 polymer. As for the magnetic nanoparticles, we used superparamagnetic CoFe2O4 nanoparticles, prepared via a solid-state grinding method and characterized by FTIR, STEM, XRD, and SQUID. It was shown that nanoparticles had saturated flux of 78.7emu/g, and diameter of 10.6±4.0 nm. There were two polymers used to modify nanoparticle surfaces in order to improve nanoparticle dispersion: poly(acrylic acid) (PAA), and thermosensitive block copolymer, respectively. The modified nanoparticles were then blended with the thermosensitive block polymers in a certain ratios to fabricate intelligent gel. PAA was coated on the nanoparticle surfaces to enhance dispersity in water and prevent agglomeration. However, the PAA-coated nanoparticles was not dispersed in thick block copolymer aqueous solution, apparently leading to adverse effect on gelation. The other method was adopted to modify nanoparticle surfaces with the similar block-copolymer. Pluronic F127 and PCL-Pluronic-PCL were modified at the chain ends to introduce catechol groups, which could be then attached on magnetic nanoparticle surfaces. The similar thermosensitive polymer-coated nanoparticles could be dispersed into polymer sol system without precipitation. From experimental results, And then the polymer have OH group, can binding stably on the surface of magnetic nanoparticles. The lowest critical gelation temperature for 20wt% F127 solution changed from 23℃ to 20℃ with addition of CoFe2O4@Dopamine-F127-Dopamine; and the highest critical solution temperature of F127 solution also changed from 57℃ to 55℃. The transition temperature of F127 solution could be reduced due to nanoparticle addition. the magnetic thermosensitive hydrogel can be injected at a lower temperature in a sol state, and then the gel formation happens in situ at 37 ℃ suitable for storage in human body. The hydrogel can be dissolved again after initiation of hyperthermia process, showing a promising magnet-driven and thermosensitive drug carrier.

碩士
國立臺灣大學
醫學工程學研究所
97
In this study, we use a biodegradable monomer (ε-Caprolactone) to combine with a biodegradable polymer (polyehylene glycol) and a biodegradable triblock copolymer (PCL-PEG-PCL) was synthesis. The triblock copolymer (PCL–PEG–PCL) is thermosensitive when weights of those monomers were combined at some special ratio and its aqueous solution can undergo the sol–gel–sol transition as the temperature increases. The hydrogel was fully biodegradable and biocompatible. GPC and NMR 1H are used for characterizing the polymer. Thermal stability was tested by TGA. Chemotherapy drugs：CPT-11 and SN-38 were loaded into hydrogel made by triblock copolymers at several concentrations. Then, a scanning electron microscope was used to observe morphology of hydrgel loaded with chemotherapy drugs. The morphology of hydrogel loaded with hydrophilic drug CPT-11 is different from the polymer concentrations and hydrogel loaded with hydrophobic drug SN-38 show another appearance under the same polymer concentration with CPT-11. In vitro drug release from thermosensitive hydrogel was investigated. CPT-11 was released within two days from hydrgel when they are loaded at a high concentration (5mg/ml). The releasing curve of hydrogel loaded with SN-38 at the same concentration shows a slowly stable and linear trend within 10 days. In vivo experiments of CPT-11 indicated that the treatment using hydrogel loaded with 5 doses (inject once) for suppressing tumor growth is the same effective as five injections and the toxicity is lower. In the experiments of SN-38, hydrogel loaded with 5 doses also shows a lower toxicity than five injections. Thus, they can be used as a suitable drug - polymer implant for local release of chemotherapeutic drug like irinotecan or SN-38.

碩士
大同大學
化學工程研究所
89
A series of copolymeric hydrogels were prepared from various molar ratios of N-isopropylacrylamide (NIPAAm), trimethyl acrylamidopropyl ammonium iodide (TMAAI), and 3-dimethyl (methacryloxy-ethyl) ammonium propane sulfonate (DMAPS). The swelling behaviors of these copolymeric hydrogels were investigated in various saline solutions. The result showed that the phase transition temperatures of these gels changed insignificantly, and the thermosensitivity, in contrast, diminished. In the saline solution, results showed that the swelling ratio of pure NIPAAm gel had not significantly change with an increase of the salt concentration until the salt concentration was larger than 0.5M. In addition, the copolymer gels exhibited polyelectrolytic behavior under lower salt concentration (10-4~10-1 M)；exhibited a nonionic gel (like NIPAAm) behavior at the salt concentration from 0.1 to 0.5 M；and showed an antipolyelectrolytic behavior (polyzwitterionic effect ) at the concentration of salt over 0.5 M. The drug release behavior of the ionic thermosensitive hydrogels related to their ionicity and drug types. Results show that the release ratio of caffeine in the hydrogels is not affected by the ionicity of hydrogels. But it increased with increasing of the swelling ratio. The anionic solute (phenol red) strongly interacted with cationic hydrogel (very large Kd), so the phenol red release ratio in cationic gels is very low. On the other hand, CV is only adsorbed on the skin layer of the cationic hydrogel due to the charge repulsion, and releases rapidly. Therefore the release ratio is the highest for cationic hydrogel to cationic drug. In addition, the partition coefficients (Kd) and the drug delivery behavior of the present gels were also investigated. Porous ionic thermosensitive hydrogels were prepared from N-isopropylacrylamide（NIPAAm）and cationic monomer, trimethyl acrylamidopropyl ammonium iodide（TMAAI) or anionic monomer, acrylic acid（AA) or zwitterionic monomer, N’, N’-dimethyl (acrylamido propyl) ammonium propane sulfonate（DMAAPS) or nonionic monomer, Poly(ethylene glycol) methylether acrylate (PEGMEA), and pore forming agent, poly(ethylene glycol) with different molecular weights. Some fundamental properties and dynamic swelling kinetic parameters and solute permeation from these porous gels were investigated. Results show that the gel with cationic monomer, TMAAI has higher equilibrium swelling ratio. The results from diffusion coefficients, D show that the swelling rates of the gels with anionic monomer AA, and PEG having larger molecular weight (MW=20000) are faster. The results exhibit that the fast swelling-deswelling behavior for the porous structure gels is more available than the gels with long hydrophilic side chains. In addition, the interactive force between solutes and gels, and the solute permeation through the porous gel were also investigated. The influence of various drugs with different charges on the drug release behavior in the porous ionic thermosensitive hydrogels was investigated. The present hydrogels were prepared from N-isopropylacrylamide (NIPAAm) and cationic monomer, trimethyl acrylamidopropyl ammonium iodide (TMAAI), or anionic monomer, acrylic acid (AA), or zwitterionic monomer, N’, N’-dimethyl (acrylamido propyl) ammonium propane sulfonate (DMAAPS), or nonionic monomer, poly (ethylene glycol) methylether acrylate (PEGMEA), and pore forming agent, poly(ethylene glycol) with different molecular weights. Caffeine as a nonionic drug, crystal violet (CV) as a cationic drug solute, and phenol red as an anionic drug solute were chosen as model drugs to perform the drug release experiment. Results show that the release ratio of caffeine in the hydrogels is not affected by the ionicity of hydrogels. The CV strongly interacted with the anionic hydrogel, so the CV release ratio is very low. CV is only adsorbed on the skin layer of the cationic hydrogel due to charge repulsion, and releases rapidly. The result of phenol red (anionic solute) release in the gels is contrary to CV. In addition, the partition coefficients and the drug delivery behavior of the gels were also investigated.

碩士
國立清華大學
化學工程學系
98
The purpose of this study is to understand the effect of copolymer composition on the drug delivery system. A series of biodegradable mPEG-PLGA diblock copolymers, [PLGA]/[mPEG] ratio from 1.46 to 3.01, were synthesized by ring-opening polymerization. Methoxy poly(ethylene glycol)(mPEG) of 350, 550 and 750, were used as the hydrophilic segment. Our results showed that copolymers of mPEG350 series and [PLGA]/[mPEG] at 3.01 were insoluble in water. The other copolymers in aqueous solution formed nanoparticles with critical micelle concentrations below 1×10-2 mg/ml. mPEG550 and mPEG750 series copolymers had thermosensitive properties with mPEG-PLGA(550-1405) having a wider gelation window. However, the gelation temperatures of mPEG750 series copolymers were above body temperature. Initially, hydrolysis occurred at the ester linkage of mPEG, which was followed by PLGA degradation occurring preferentially in GA unit rather than LA unit due to their hydrophobicity. Cytotoxicity and hemolysis test indicated that mPEG-PLGA diblock copolymers were biocompatible. Drug release study showed no initial burst and 15 wt% mPEG-PLGA(550-1405) hydrogel had the optimal drug release behavior. Before day9, drug release rate decreased as the concentration of copolymer aqueous solution increased. But this relationship inverted after day9. We inferred that this was due to the crystallization of degraded oligomer in the hydrogel. In vivo study showed that implantation of the mPEG-PLGA hydrogel containing Teicoplanin was effective in treating osteomyelitis in rabbits. The effect of copolymer composition on the drug delivery system was elucidated in this study. The use of mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for osteomyelitis.

碩士
國立清華大學
化學工程學系
101
The objective of this study was to discuss the thermoresponsive properties of a novel poly(ester-amide) polymer, i.e. methoxy poly(ethylene glycol)-poly(pyrrolidone-co-lactide)(mPDLA) diblock copolymers and evaluate its capability of chondrocyte encapsulation for cartilage tissue engineering. A series of amphiphilic diblock copolymers were synthesized by ring-opening polymerization of mPEG550, D,L-lactide and 2-pyrrolidone. The initial ratio of monomers in mPDLA was [PD]/[LA]=30/70 and the target molecular weight of hydrophobic segment were 1105, 1405, 1705 respectively. The copolymers were characterized via1H-NMR,FT-IR spectroscopy, and GPC. The results indicated that the diblock copolymers formed nano-micelles at low concentrations in aqueous phase. The micelle properties were also measured. The critical micelle concentration(CMC) was ranged from 0.1 to 0.3 mg/ml.As the temperature increased, micelles aggregation was observed by DLS. The diblock copolymer P3L7-1405 solution underwent a sol-to-gel phase transition, which was confirmed by test tube inverting method. Rheology results showed that viscoelastic properties of the copolymer solution varied with temperature, indicative of the formation of a gel. The mPDLA diblock copolymer solutions exhibited sol-gel transition behavior as a function of temperature. In vitro degradation test showed that the acidity of degradation was effectively reduced by introducing the monomer PD into polyester hydrogel. mPDLA alsoexhibited higher water content from swelling ratio. It would provide an environment that is preferred by cells; therefore, mPDLA diblock copolymer exhibited better biocompatibility in vitro. As an injectable scaffold, the viability, cell proliferation and chondrogenesis of chondrocytes encapsulated in mPDLA hydrogel were investigated. MTT and DNA quantification showed proliferation of cells within 2 weeks. By Live/Dead stain we can confirm that the morphology of cells in hydrogel was typical sphere which mature chondrocytes supposed to be. Also, ECM content was significant increased within 2 weeks compared with initial amount. In vivo test showed the repair of cartilage defect treated with 15% mPDLA hydrogel. From above results, we deduced that this thermosensitive hydrogel was sutible as an injectable scaffold for cartilage tissue engineering.

碩士
國立臺灣科技大學
材料科學與工程系
101
Monomethoxy poly(ethylene glycol)-Poly(D,L-lactic-co-glycolic acid) (mPEG-PLGA) diblock copolymers with fixed mPEG length (degree of polymerization =12.50) and various PLGA lengths (degree of polymerization = 17.59 to 23.75) were synthesized. The molar ratio of DLLA and GA is 58:42 to 55:45 . Phase diagrams were determined by the tube inverting method and rheometry. The critical micelle concentrations (CMC) and micellar radius were determined by UV/Vis spectroscopy with dye solubilization and dynamic light scattering, respectively . Based on Leibler theory for CMC, we calculated the Flory-Huggins interaction parameter between hydrophobic segments and water, χmPEG-PLGA .Using the mPEG- PLGA as the drug loading carrier for the drug that was aminoguanidine hydrochloride.The drug release experiment was performed at 37℃, the drug release amount was determined by UV/Vis spectroscopy. It was aimed at investigating how the drug release amount was affected by structure of hydrophobic blocks in mPEG-PLGA and mPEG-PLGA concentration in solution. Rheomety showed three phases (sol, gel and precipitate) in copolymer solutions, whereas the tube inverting method two phases (sol and gel). Relative difference between phase transition temperatures from two methods can vary between 0.2~2.02%. As the length of hydrophobic blocks in copolymers increased, the critical gel temperatures (CGC) decreased slightly, but the critical gel concentrations (CGC) decreased significantly. Also the higher copolymer concentrations gave a wider temperature range for gelation. Thermodynamic parameters calculated from CMC indicate that the micellization process was driven by entropy gain. The micellar radius increases with the PLGA length and micellar radius was proportional to the 0.38th power of PLGA block length. Upon increasing the hydrophobic length, the Flory-Huggins interaction parameters between hydrophobic segments and water were increased . Aminoguanidine hydrochloride in mPEG-PLGA gels with various hydrophobic block lengths or copolymer concentrations in solution release through the dialysis bags. Initially, the longer hydrophobic blocks in mPEG-PLGA or the higher concentrations of copolymer solutions gave rise to the longer time lag. In the equilibrium, the longer hydrophobic blocks or the higher concentrations offered the stronger interactions between aminoguanidine hydrochloride and copolymers , hence the lower fractional release of drug . The lower release rate of drug was caused by the longer hydrophobic blocks or the higher copolymer concentrations , owing to the higher viscosity of copolymer solutions.

Grâce à de récentes percées scientifiques, certains médiateurs clés dans divers états pathologiques ont été identifiés et de nouveaux composés thérapeutiques ont été développés pour les inhiber. Bien que très efficaces, ces composés possèdent souvent des propriétés physico-chimiques incompatibles avec celles du corps humain et deviennent, donc, difficiles à formuler. Au cours des dernières décennies, les systèmes de vectorisation de médicaments ont été étudiés comme une solution potentielle promettant une augmentation de la concentration du médicament au site d'action tout en atténuant les problèmes de stabilité et de solubilité. Plus particulièrement, les polymères ont démontré un succès en tant que matière première dans la conception de ces formulations. Cependant, un obstacle majeur à leur développement clinique est le faible niveau d’encapsulation du principe actif. Afin de remédier à cette limitation, les travaux présentés dans cette thèse se sont concentrés sur l'utilisation de copolymères blocs en forme d'étoile et à base d'acide cholique pour faciliter l'encapsulation. Divers principes actifs aux propriétés physico-chimiques variables ont été encapsulés dans nos systèmes polymères, témoignant ainsi de leur grande efficacité et ceci à travers une large gamme de médicaments. Dans un premier temps, les propriétés physico-chimiques de notre système ont été étudiées. Les copolymères bloc sont composés d'un noyau d'acide cholique (CA) sur lequel le poly (allyl glycidyl éther) (PAGE) et le poly (éthylène glycol) (PEG) sont polymérisées séquentiellement pour donner lieu au CA-(PAGE-b-PEG)4 amphiphiles à quatre branches. De plus, le bloc PAGE a été fonctionnalisé pour porter des groupements amines primaires. Les effets de la longueur du bloc PEG et des groupements amines sur le comportement thermosensible des polymères dans l'eau ont été examinés. Cette thermosensibilité a aussi été étudiée en présence de diverses concentrations de sels. Il a été découvert que l'augmentation de la longueur du PEG augmente la température du point de trouble. De même, la fonctionnalisation des blocs PAGE pour porter des groupements amines a augmenté le point de trouble en l'absence de sel, mais a significativement diminué en présence de sel. Cette observation a été attribuée au « salting-out » des polymères. Dans un second temps, employée comme un médicament hydrophobe modèle, la doxorubicine (Dox) a été encapsulée à l’aide de nos copolymères blocs CA-(PAGE-b-PEG)4. Dans ce cas, les interactions polymère-médicament régissant l’encapsulation de la Dox ont été étudiées. Plus précisément, les interactions hydrophobes et électrostatiques ont été comparées pour leur influence sur la charge de médicament à l'intérieur des copolymères blocs. Une charge élevée de Dox a été obtenue à l’aide des interactions électrostatiques par rapport aux interactions hydrophobes avec ou sans la présence d'acide oléique comme co-tensioactif. De plus, les interactions électrostatiques conféraient au système de relargage une réactivité au pH permettant ainsi un relargage de la Dox en présence d’un pH acide. Les copolymères blocs ont présenté une bonne biocompatibilité lors d’essai in vitro. Les nouveaux copolymères blocs en étoile et à base d'acide cholique ont montré un grand potentiel en tant que vecteurs de relargage de médicaments pour l’encapsulation de la Dox. Pour démontrer l’étendue de l’application de notre système, des petits acides ribonucléiques interférant (pARNi) ont été encapsulés à l’aide des copolymères blocs CA-(PAGE-b-PEG)4 où le PAGE a été fonctionnalisé pour porter des groupements amines. Les pARNi sont des composés thérapeutiques hydrophiles chargés négativement et nécessitant une méthodologie d’encapsulation différente de celle utilisée pour la Dox. Les groupements allyles du bloc PAGE ont été fonctionnalisés pour porter des amines primaires ou tertiaires. Également, l'acide folique a été greffé sur l'extrémité de la chaîne PEG pour augmenter l'absorption cellulaire. Les (CA-PAGE-b-PEG)4 fonctionnalisés avec des amines primaires ou tertiaires ont présenté une forte complexation des pARNi. Des agrégats micellaires uniformes ont ainsi été obtenus. De plus, des lipides ont été ajoutés comme co-tensioactifs pour aider à stabiliser les nanoparticules dans les milieux de culture cellulaire. Ces systèmes micellaires mixtes avaient une charge élevée de pARNi et une absorption cellulaire améliorée avec une augmentation concomitante de la transfection des pARNi dans des cellules modèles de HeLa et HeLa-GFP, respectivement. Les résultats présentés dans cette thèse témoignent du grand potentiel de l'utilisation de copolymères blocs en forme d'étoile et à base d'acide cholique dans la conception de systèmes de vectorisation de médicaments. Ces résultats offrent des conclusions pertinentes sur les différents paramètres clés contrôlant l’efficacité des systèmes de vectorisation des médicaments à base de polymères pouvant être traduits dans d'autres systèmes. Les stratégies développées ici aideront grandement au développement des systèmes de vectorisation de médicaments et accéléreront potentiellement leur évolution vers la clinique.
Recent scientific breakthroughs have fostered the identification of key mediators of various diseased states while permitting the development of novel therapeutic compounds to address them. Although very potent, these compounds often possess physico-chemical properties that are incompatible with those of the human body and are becoming increasingly difficult to formulate. In the recent decades, drug delivery systems have been studied as a potential solution in the formulation of these therapeutic compounds promising improved accumulation at the site of action while mitigating issues of stability and solubility. Most notably, polymers have shown tremendous success as starting material in the design of these drug formulations. However, one major hurdle curtailing their clinical translatability is their low drug loading levels. In an effort to address this limitation, the work presented in this thesis focused on the use of cholic acid-based star-shaped block copolymers for the encapsulation of active pharmaceutical ingredients with varying physico-chemical properties thereby demonstrating their successful application to a broad range of compounds. First, the physico-chemical properties of our proposed system were studied. The block copolymers are composed of a cholic acid (CA) core onto which poly(allyl glycidyl ether) (PAGE) and poly(ethylene glycol) (PEG) are polymerized sequentially to afford an amphiphilic CA-(PAGE-b-PEG)4 with four branches. The PAGE block was further functionalized to bear pendant amine groups. The effects of PEG length and of the amine groups on the thermoresponsive behavior of the polymers in water at various salt concentrations were examined. It was discovered that increasing the length of PEG increases the cloud point temperature. Similarly, functionalizing the PAGE blocks to bear pendant amine groups increased the cloud point in the absence of salt, but significantly decreased the cloud point in the presence of salt. This observation was attributed to the salting-out of the polymers. Acting as a model hydrophobic drug, doxorubicin (Dox) was first encapsulated using our proposed CA-(PAGE-b-PEG)4 block copolymers. In this case, the polymer-drug interactions driving the loading of Dox was studied. Specifically, hydrophobic and electrostatic interactions were compared for their influence on the drug loading inside the block copolymers. A high loading of Dox was achieved vis electrostatic interactions compared to hydrophobic interactions with or without the presence of oleic acid as a cosurfactant. Also, the electrostatic interactions conferred a pH responsiveness to the system where the Dox remained encapsulated at physiological pH but was released in acidic pH. The block copolymers displayed good biocompatibility in vitro. The new functionalized star block copolymers based on cholic acid showed great potential as drug delivery carriers for the loading of Dox. To demonstrate the widespread application of our proposed system, small interfering RNA (siRNA) was loading using the CA-(PAGE-b-PEG)4 block copolymers where PAGE was functionalized with amine. siRNA is a hydrophilic, negatively charged therapeutic compound necessitating a different loading methodology than that used for Dox. The allyl groups of PAGE were functionalized to bear primary or tertiary amines and folic acid was grafted onto the PEG chain end to increase cell uptake. (CA-PAGE-b-PEG)4 functionalized with either primary or tertiary amines show high siRNA complexation. Uniform micellar aggregates were obtained. Lipids were added as co-surfactants to help stabilize the nanoparticles in the cell culture media. The mixed micelles had high siRNA loading and improved cell uptake with a concomitant increase in siRNA transfection in HeLa and HeLa-GFP model cells, respectively. The results presented in this thesis, demonstrate the feasibility of using cholic acid-based star-shaped block copolymers in the design of drug delivery systems and offers insights into key parameters controlling their efficacy which can be translated to other polymer-based systems. The strategies developed herein will greatly aid in the development of drug delivery systems and potentially accelerate their progress into the clinic.

La poly(2-isopropyl-2-oxazoline) (PIPOZ) est un polymère thermosensible qui possède une température de solution critique inférieure (LCST) autour de 40 °C en solution aqueuse. Les travaux présentés s’intéressent aux propriétés en solution aqueuse et aux interfaces, de l’homopolymère PIPOZ, d’une PIPOZ fonctionnalisée avec un groupement lipidique (lipo-PIPOZ) et de copolymères à blocs à base de poly(éthylène glycol) et de PIPOZ. Si elle est régulièrement comparée à son isomère structurel le poly(N-isopropylacrylamide) (PNIPAM), les études sur les propriétés en solution de la PIPOZ sont cependant moins complètes que celles sur le PNIPAM. Le premier objectif des travaux présentés ici est de parfaire la connaissance du comportement en solution de la PIPOZ en présence d’additifs. Les effets de sels et de solvants hydromiscibles sur la solubilité de la PIPOZ ont été investigués par turbidimétrie et microcalorimétrie sur trois homopolymères de masses moléculaires différentes. Contrairement aux solutions de PNIPAM, l’ajout de méthanol à la solution de PIPOZ ne conduit pas au phénomène de cononsolvency où la solubilité du polymère diminue pour une certaine gamme de fractions volumiques de cosolvant. L’effet a néanmoins été observé dans le cas de système PIPOZ/Eau/THF. L’effet de sels sur la solubilité de la PIPOZ suit la série Hofmeister. La présence de sels chaotropes (NaI et NaSCN) en solution ont révélé un effet bien plus important sur la solubilité de la PIPOZ que pour son isomère. Les valeurs de point troubles de la solution de PIPOZ augmentent de plus de 30 °C pour une concentration en sel supérieure à 1 M. L’autre objectif de cette thèse est de synthétiser un système à base de PIPOZ capable de s’auto-assembler à l’interface air-eau afin de former des films interfaciaux par la technique Langmuir-Blodgett. A cette fin, un amorceur contenant un groupement lipidique (2 chaînes alkyles et un groupement phosphate) a été synthétisé et utilisé pour la polymérisation cationique par ouverture de cycle (CROP) du monomère 2-isopropyl-2-oxazoline conduisant à l’obtention d’un lipo-PIPOZ (Mn = 10 kg.mol-1). L’effet de deux sels (NaSCN et NaCl) sur les films interfaciaux a été étudié. Malgré leur effet opposé sur la solubilité de la PIPOZ en solution, ils conduisent tous les deux à l’expansion de la monocouche de lipo-PIPOZ. Transférés sur des substrats de mica, ces films ont été visualisés par microscopie à force atomique (AFM). La iv présence de sels dans la sous-phase lors de la formation de monocouches conduit à la formation d’agrégats d’épaisseur ~ 10 nm dont le diamètre augmente avec la concentration en sel. Enfin, le dernier objectif est de caractériser les propriétés en solutions de copolymères à blocs PIPOZ-b-PEG-b-PIPOZ. La polymérisation par CROP de la 2-isopropyl-2-oxazoline a été amorcée à partir d’un PEG (Mn = 2 kg.mol-1) bifonctionnel, Le polymère synthétisé (TrOH, Mn = 11 kg.mol-1) a ensuite subit une fonctionnalisation des extrémités de chaînes par des groupements octadécyles conduisant à l’obtention d’un copolymère à blocs téléchélique amphiphile et thermosensible (TrC18). Les propriétés des copolymères en solution aqueuse ont été étudiées par turbidimétrie, diffusion dynamique de la lumière (DLS), microcalorimétrie (DSC), microscopie électronique à transmission et spectroscopie à sonde fluorescente, FT-IR et AFM. Les deux copolymères sont thermosensibles et présentent des valeurs de points troubles de ~ 48 °C pour le copolymère TrOH et de ~ 38 °C pour le copolymère amphiphile. Ce dernier s’auto-assemble à température ambiante et forme, en solution aqueuse, des micelles de type fleurs de rayon hydrodynamique RH ~ 8 nm. L’effet prolongé de la température sur la cristallisation des blocs de PIPOZ a aussi été examinée. Les deux polymères cristallisent en solution aqueuse conduisant à la formation de fibres insolubles dans l’eau. Mots-
Poly(2-isopropyl-2-oxazoline) (PIPOZ) is a thermosensitive polymer whose lower critical solution temperature (LCST) in water is ~ 40 °C. This thesis focuses on the properties in aqueous solution and on interfaces of new poly(2-isopropyl-2-oxazoline) systems. PIPOZ is often compared to its structural isomer, the renowned poly(N-isopropylacrylamide) (PNIPAM). If PNIPAM has been the center of thermosensitive polymer research for the last three decades, it is PIPOZ which has recently been gaining interest. The first aim of the thesis is to improve on the knowledge on PIPOZ properties in aqueous solution in the presence of water-soluble additives. Effect of salts and cosolvents were investigated by turbidimetry and microcalorimetry (DSC) on PIPOZ homopolymers of different molecular weights. Effect of salts on PIPOZ solubility follows the Hofmeister series. Chaotropic anions (SCN-, I-) induce a large increase (up to 30 °C) of the cloud point temperature of PIPOZ solution which is 10 times larger than for PNIPAM. Adding methanol into PNIPAM aqueous solution leads to a decrease in solubility of the polymer. This phenomena is called cononsolvency. Unlike PNIPAM solutions, the addition of methanol in PIPOZ solution does not lead to a cononsolvency effect. Nevertheless, cononsolvency has been observed in the case of THF addition into PIPOZ aqueous solutions. The second aim of this work was to design and synthesize an amphiphilic PIPOZ able to anchor itself at the air-water interface and to form stable monolayer via the Langmuir-Blodgett technique. For that purpose, a lipidic initiator containing two alkyl chains and a phosphate group, was synthesized and used to initiate the cationic ring opening polymerization (CROP) of 2-isopropyl-2-oxazoline. The obtained amphiphilic (lipo-PIPOZ, Mn = 10 kg.mol-1) forms stable monolayers at the air-water interface. The presence of salt (NaCl or NaSCN) in the sub-phase during the compression of the films leads to expansion of the monolayer even if the salts have opposite effect on PIPOZ solubility in solution. The interfacial films were then transferred onto mica substrates and captured by atomic force microscopy (AFM). The salts induced the formation of aggregates (height ~ 10 nm) whose diameter depends on the salt and its concentration. At last, a block copolymer, TrOH, containing a central poly(ethylene glycol) (PEG) (Mn = 2 kg.mol-1) and two PIPOZ blocks was obtained by CROP of 2-isopropyl-2-oxazoline initiated vi by a bi-functionnal PEG. The total molecular weight was Mn ~ 11 kg.mol-1. Hydrophobic chain ends modification has been performed onto TrOH to bring amphiphilicity and to get a telechelic octadecyl-end capped block copolymer TrC18. The properties of these two block copolymers in water were characterized by dynamic light scattering (DLS), microcalorimetry (DSC), electronic transmission microscopy (TEM) and fluorescence spectroscopy, FT-IR and AFM. Cloud point temperature of copolymer solutions was found to be around 48 °C for TrOH and around 38°C for the amphiphilic analogue TrC18. The latter self-assembles at room temperature into flower micelles whose hydrodynamic radius is RH ~ 8 nm. Extended heating of both copolymer solutions leads to crystallization of PIPOZ block and insoluble fibers form in solution.