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.

Polímeros termossensíveis apresentam grandes alterações em suas propriedades quando submetidos a pequenas mudanças de temperatura (T) próximas à temperatura de solução crítica inferior (LCST) ou superior (UCST). Um dos polímeros termossensíveis mais estudados é o Poli(N-isopropilacrilamida) (PNIPAm) porque ele apresenta a LCST, aproximadamente, 32 oC ( 305 K), próxima à temperatura do corpo humano. Em temperatura abaixo da LCST o polímero apresenta-se solúvel devido um grande número de interações hidrofílicas (ligações de hidrogênio polímero-água), entretanto quando a temperatura é elevada acima da LCST ocorre a precipitação do polímero devido a um aumento de interações polímero-polímero e uma diminuição brusca nas interações polímero-água. Com essas características o PNIPAm tem despertado o interesse para aplicações em um vasto campo de pesquisas, como por exemplo na liberação controladas de fármacos. Nesse trabalho, utilizando simulações de dinâmica molecular (DM), foi proposta uma imagem microscópica do fenômeno de transição de fases apresentado por esse polímero em solução aquosa influenciado por alterações na estereoquímica do backbone (taticidade), bem como o efeito da copolimerização com Acrilamida (Am). Com base nas análises estruturais e termodinâmicas, os resultados sugerem que as diferentes estereoquímicas (isotático, atático e sindiotático) possibilitam diferentes conformações dificultando ou possibilitado um maior número de interações polímero-polímero e polímero água modificando a LCST. Já o aumento da concentração de Am (xAm) na copolimerização aumenta o número de interações polímero-água dificultando o colapso da cadeia. / Thermosensitive polymers exhibit large changes in their properties when submitted to small changes in temperature T, near the lower (LCST) or upper critical solution temperature( UCST). The most extensively studied thermosensitive polymer is PNIPAm because it has a LCST of approximately 32 oC (305 K), near human body temperature. For temperatures below the LCST the polymer is soluble due to strong hydrophilic interactions (polymer-water hydrogen bonds). However, when the temperature is raised above the LCST, the precipitation of the polymer occurs due to increased polymer-polymer interactions and a sharp decrease in polymer-water interactions. That feature makes the PNIPAm a compound widely studied and with a wide range of applications, such as for drug delivery. In this work, using molecular dynamics simulations, it was proposed a microscopic picture of the phase transition phenomenon presented by this polymer in aqueous solution influenced by changes in stereochemistry of the backbone (tacticity), as well as the effect of copolymerization with acrylamide (Am). Based on the thermodynamic and structural analysis, the results suggest that different stereochemistries (isotactic, atactic and syndiotactic) enable different conformations allowing different scenarios of polymer-polymer and polymer-water interactions, therefore modifying the LCST. The presence of the strongly polar copolymer acrylamide as the effect of maintain the high hydration even at higher temperatures, shifting in this way the LCST to higher values.

In this work, thermosensitive hydrogels having tunable thermo-mechanical properties were synthesized. Generally the thermal transition of thermosensitive hydrogels is based on either a lower critical solution temperature (LCST) or critical micelle concentration/ temperature (CMC/ CMT). The temperature dependent transition from sol to gel with large volume change may be seen in the former type of thermosensitive hydrogels and is negligible in CMC/ CMT dependent systems. The change in volume leads to exclusion of water molecules, resulting in shrinking and stiffening of system above the transition temperature. The volume change can be undesired when cells are to be incorporated in the system. The gelation in the latter case is mainly driven by micelle formation above the transition temperature and further colloidal packing of micelles around the gelation temperature. As the gelation mainly depends on concentration of polymer, such a system could undergo fast dissolution upon addition of solvent. Here, it was envisioned to realize a thermosensitive gel based on two components, one responsible for a change in mechanical properties by formation of reversible netpoints upon heating without volume change, and second component conferring degradability on demand. As first component, an ABA triblockcopolymer (here: Poly(ethylene glycol)-b-poly(propylene glycol)-b-poly(ethylene glycol) (PEPE) with thermosensitive properties, whose sol-gel transition on the molecular level is based on micellization and colloidal jamming of the formed micelles was chosen, while for the additional macromolecular component crosslinking the formed micelles biopolymers were employed. The synthesis of the hydrogels was performed in two ways, either by physical mixing of compounds showing electrostatic interactions, or by covalent coupling of the components. Biopolymers (here: the polysaccharides hyaluronic acid, chondroitin sulphate, or pectin, as well as the protein gelatin) were employed as additional macromolecular crosslinker to simultaneously incorporate an enzyme responsiveness into the systems. In order to have strong ionic/electrostatic interactions between PEPE and polysaccharides, PEPE was aminated to yield predominantly mono- or di-substituted PEPEs. The systems based on aminated PEPE physically mixed with HA showed an enhancement in the mechanical properties such as, elastic modulus (G′) and viscous modulus (G′′) and a decrease of the gelation temperature (Tgel) compared to the PEPE at same concentration. Furthermore, by varying the amount of aminated PEPE in the composition, the Tgel of the system could be tailored to 27-36 °C. The physical mixtures of HA with di-amino PEPE (HA·di-PEPE) showed higher elastic moduli G′ and stability towards dissolution compared to the physical mixtures of HA with mono-amino PEPE (HA·mono-PEPE). This indicates a strong influence of electrostatic interaction between –COOH groups of HA and –NH2 groups of PEPE. The physical properties of HA with di-amino PEPE (HA·di-PEPE) compare beneficially with the physical properties of the human vitreous body, the systems are highly transparent, and have a comparable refractive index and viscosity. Therefore,this material was tested for a potential biological application and was shown to be non-cytotoxic in eluate and direct contact tests. The materials will in the future be investigated in further studies as vitreous body substitutes. In addition, enzymatic degradation of these hydrogels was performed using hyaluronidase to specifically degrade the HA. During the degradation of these hydrogels, increase in the Tgel was observed along with decrease in the mechanical properties. The aminated PEPE were further utilised in the covalent coupling to Pectin and chondroitin sulphate by using EDC as a coupling agent. Here, it was possible to adjust the Tgel (28-33 °C) by varying the grafting density of PEPE to the biopolymer. The grafting of PEPE to Pectin enhanced the thermal stability of the hydrogel. The Pec-g-PEPE hydrogels were degradable by enzymes with slight increase in Tgel and decrease in G′ during the degradation time. The covalent coupling of aminated PEPE to HA was performed by DMTMM as a coupling agent. This method of coupling was observed to be more efficient compared to EDC mediated coupling. Moreover, the purification of the final product was performed by ultrafiltration technique, which efficiently removed the unreacted PEPE from the final product, which was not sufficiently achieved by dialysis. Interestingly, the final products of these reaction were in a gel state and showed enhancement in the mechanical properties at very low concentrations (2.5 wt%) near body temperature. In these hydrogels the resulting increase in mechanical properties was due to the combined effect of micelle packing (physical interactions) by PEPE and covalent netpoints between PEPE and HA. PEPE alone or the physical mixtures of the same components were not able to show thermosensitive behavior at concentrations below 16 wt%. These thermosensitive hydrogels also showed on demand solubilisation by enzymatic degradation. The concept of thermosensitivity was introduced to 3D architectured porous hydrogels, by covalently grafting the PEPE to gelatin and crosslinking with LDI as a crosslinker. Here, the grafted PEPE resulted in a decrease in the helix formation in gelatin chains and after fixing the gelatin chains by crosslinking, the system showed an enhancement in the mechanical properties upon heating (34-42 °C) which was reversible upon cooling. A possible explanation of the reversible changes in mechanical properties is the strong physical interactions between micelles formed by PEPE being covalently linked to gelatin. Above the transition temperature, the local properties were evaluated by AFM indentation of pore walls in which an increase in elastic modulus (E) at higher temperature (37 °C) was observed. The water uptake of these thermosensitive architectured porous hydrogels was also influenced by PEPE and temperature (25 °C and 37 °C), showing lower water up take at higher temperature and vice versa. In addition, due to the lower water uptake at high temperature, the rate of hydrolytic degradation of these systems was found to be decreased when compared to pure gelatin architectured porous hydrogels. Such temperature sensitive architectured porous hydrogels could be important for e.g. stem cell culturing, cell differentiation and guided cell migration, etc. Altogether, it was possible to demonstrate that the crosslinking of micelles by a macromolecular crosslinker increased the shear moduli, viscosity, and stability towards dissolution of CMC-based gels. This effect could be likewise be realized by covalent or non-covalent mechanisms such as, micelle interactions, physical interactions of gelatin chains and physical interactions between gelatin chains and micelles. Moreover, the covalent grafting of PEPE will create additional net-points which also influence the mechanical properties of thermosensitive architectured porous hydrogels. Overall, the physical and chemical interactions and reversible physical interactions in such thermosensitive architectured porous hydrogels gave a control over the mechanical properties of such complex system. The hydrogels showing change of mechanical properties without a sol-gel transition or volume change are especially interesting for further study with cell proliferation and differentiation. / In der vorliegenden Arbeit wurden thermosensitive Hydrogele mit einstellbaren thermo-mechanischen Eigenschaften synthetisiert. Im Allgemeinen basiert der thermische Übergang thermosensitiver Gele auf einer niedrigsten kritischen Löslichkeitstemperatur (LCST) oder kritischer Mizellkonzentration bzw. –temperatur(CMC/ CMT). Der temperaturabhängige Übergang von Sol zu Gel mit großer Volumenänderung wurde im ersten Fall bei thermosensitiven Hydrogelen beobachtet und ist vernachlässigbar für CMC/ CMT abhängige Systeme. Die Änderung des Volumens führt zum Ausschluss von Wassermolekülen, was zum Schrumpfen und Versteifen des Systems oberhalb der Übergangstemperatur führt. Die Volumenänderung kann unerwünscht sein, wenn Zellen in das Gel eingeschlossen werden sollen. Die Gelierung im zweiten Fall beruht hauptsächlich auf der Mizellbildung oberhalb der Übergangstemperatur und weiterem kolloidalem Packen von Mizellen im Bereich der Gelierungstemperatur. Weil die Gelierung hauptsächlich von der Polymerkonzentration abhängt, kann sich das Gel bei Zugabe von Lösungsmittel leicht wieder lösen. Hier sollten thermosensitive Gele entwickelt werden, die auf zwei Komponenten beruhen. Eine Komponente sollte aus einem ABA-Triblockcopolymer mit thermosensitiven Eigenschaften bestehen, dem Poly(ethylen glycol)-b-Poly(propylenglycol)-b-Poly(ethylen glycol) (PEPE), dessen Sol-Gel-Übergang auf Mizellierung und kolloidalem Jamming der gebildeten Mizellen basiert, und einer weiteren makromolekularen Komponente, einem Biopolymer, dass die Mizellen vernetzt. Auf diese Weise sollten thermosensitive Gele realisiert werden, die keine oder nur eine kleine Volumenänderung während der Änderung der mechanischen Eigenschaften zeigen, die stabiler gegenüber Verdünnung sein sollten als klassische Hydrogele mit einem CMC-basierten Übergang und die jedoch gezielt abgebaut werden können. Die Hydrogele wurden auf zwei Arten vernetzt, entweder durch physikalisches Vermischen, bei dem die Vernetzung durch elektrostatische Wechselwirkungen erfolgte, oder durch kovalente Kopplung der beiden Komponenten. Als makromolekulare Komponente zur Vernetzung der Mizellen wurden Biopolymere (hier: die Polysaccharide Hyaluronsäure (HA), Chondroitinsulfat oder Pektin oder das Protein Gelatin) verwendet, um die Hydrogele enzymatisch abbaubar zu gestalten. Um eine starke ionische/elektrostatische Wechselwirkung zwischen dem PEPE und den Polysachariden zu erzielen, wurde PEPE aminiert, um hauptsächlich monoaminiertes bzw. diaminiertes PEPE einsetzen zu können. Die Gele, die auf der physikalischen Mischung von aminierten PEPE mit HA bestehen, zeigten im Vergleich zu PEPE bei gleicher Konzentration eine Zunahme der mechanischen Eigenschaften, wie beispielsweise dem elastischem Modulus (G′) und dem Viskositätsmodulus (G′′) bei gleichzeitiger Abnahme der Gelierungstemperatur (Tgel). Durch Variation des Gehalts an aminierten PEPE-, konnte die Tgel in einem Bereich von 27-36 °C eingestellt werden. Interessanterweise zeigten die physikalischen Mischungen mit diaminierten PEPE (HA·di-PEPE) höhere mechanische Eigenschaften (elastischer Modulus G′) und eine höhere Stabilität gegenüber Verdünnungseffekten als Mischungen mit monoaminiertem PEPE (HA·mono-PEPE). Dies zeigt den starken Einfluss der elektrostatischen Wechselwirkungen zwischen der Carboxylgruppe der HA und der Amingruppe von PEPE. Die physikalischen Eigenschaften HA·di-PEPE sind vergleichbar mit den physikalischen Eigenschaften des Glaskörpers im Auge hinsichtlich Transparenz, Brechungsindex und Viskosität. Deswegen wurde das Material hinsichtlich seiner biologischen Anwendung getestet und zeigte sich sowohl im Überstand als auch im direkten Kontakt als nichtzytotoxisch. Zukünftig wird dieses Material in weiteren Untersuchungen bezüglich seiner Eignung als Glaskörperersatz geprüft werden. Zusätzlich konnte der enzymatische Abbau der Hydrogele mit Hyaluronidase gezeigt werden, die spezifisch HA abbaut. Beim Abbau der Hydrogele stieg Tgel bei gleichzeitiger Abnahme der mechanischen Eigenschaften. Aminiertes PEPE wurde zusätzlich zur kovalenten Bindung unter Verwendung von EDC als Aktivator an Pektin und Chondroitinsulfat eingesetzt. Tgel konnte auf 28 – 33 °C eingestellt werden durch Variation der Pfropfungsdichte am Biopolymer bei gleichzeitiger Zunahme der thermischen Stabilität. Die Pec-g-PEPE Hydrogele waren enzymatisch abbaubar, was zu einer leichten Erhöhung von Tgel und zu einer Abnahme von G′ führte. Die kovalente Bindung der aminierten PEPE an HA erfolgte unter Verwendung von DMTMM als Aktivator, der sich in diesem Fall als effektiver als EDC herausstellte. Die Reinigung mittels Ultrafiltration führte zu einer deutlich besseren Aufreinigung des Produkts als mittels Dialyse. Die gegrafteten Systeme waren in Nähe der Körpertemperatur bereits im Gelstadium und zeigten eine Erhöhung der mechanischen Eigenschaften bereits bei sehr geringen Konzentrationen von 2.5Gew.%. Die höheren mechanischen Eigenschaften dieser Hydrogele erklären sich durch die Kombination der Mizellbildung (physikalische Wechselwirkung) des PEPE und der Bildung kovalenter Netzpunkte zwischen PEPE und HA. PEPE bzw. entsprechende physikalische Mischungen derselben Komponenten zeigten kein thermosensitives Verhalten bei einer Konzentration unterhalb von 16 Gew%. Diese thermosensitiven Hydrogele zeigten auch eine Löslichkeit auf Abruf durch enzymatischen Abbau. Das Konzept der Thermosensitivität wurde in 3D strukturierte, poröse Hydrogele (TArcGel)eingeführt, bei dem PEPE kovalent an Gelatin gebunden wurde und mit LDI vernetzt wurde. Das gepfropfte PEPE führte zu einer Erniedrigung der Helixbildung der Gelatinketten. Nach Fixierung der Gelatinketten durch Vernetzung zeigte das System eine Erhöhung der mechanischen Eigenschaften bei Erwärmung (34-42 °C). Dieses Phänomen war reversibel beim Abkühlen. Eine mögliche Erklärung der reversiblen Änderungen bezüglich der mechanischen Eigenschaften sind die starken physikalischen Wechselwirkungen zwischen den Mizellen des PEPE, die kovalent an Gelatin gebunden wurden. Ferner wurde durch AFM Untersuchungen festgestellt, dass bei Temperaturerhöhung (37 °C) die örtlichen elastischen Moduli (E) der Zellwände zugenommen haben. Zusätzlich wurde die Wasseraufnahme der TArcGele durch PEPE und die Temperatur (25 °C und 37 °C) beeinflusst und zeigte eine niedrigere Wasseraufnahme bei höherer Temperatur und umgekehrt. Durch die niedrigere Wasseraufnahme bei hohen Temperaturen erniedrigte sich die Geschwindigkeit des hydrolytischen Abbaus im Vergleich zu dem strukturierten Hydrogel aus reiner Gelatin. Diese temperatursensitiven ArcGele könnten bedeutsam sein für Anwendungen im Bereich Stammzellkultivierung, Zelldifferenzierung und gerichteter Zellmigration. Zusammenfassend konnte bei den thermosensitiven Hydrogelen gezeigt werden, dass die Vernetzung von Mizellen mit einem makromolekularen Vernetzer die Schermoduli, Viskosität und Löslichkeitsstabilität im Vergleich zu reinen ABATriblockcopolymeren mit CMC-Übergang erhöht. Dieser Effekt konnte durch kovalente und nichtkovalente Mechanismen, wie beispielsweise Mizell- Wechselwirkungen, physikalische Interaktionen von Gelatinketten und physikalische Interaktionen von Gelatinketten und Mizellen, realisiert werden. Das Pfropfen von PEPE führte zu zusätzlichen Netzpunkten, die die mechanischen Eigenschaften der thermosensitiven architekturisierten, porösen Hydrogele beeinflussten. Insgesamt ermöglichten die physikalischen und chemischen Bindungen und die reversiblen physikalischen Wechselwirkungen in den strukturierten, porösen Hydrogelen eine Kontrolle der mechanischen Eigenschaften in diesem sehr komplexen System. Die Hydrogele, die eine Veränderung ihrer mechanischen Eigenschaften ohne Volumenänderung oder Sol-Gel-Übergang zeigen sind besonders interessant für Untersuchungen bezüglich Zellproliferation und –differenzierung.

Cancer mortality is progression-dependent thus its treatment relies on effective therapy and monitoring of responses. Nanoparticles have long been used to improve the therapeutic index of drugs by facilitating their transit to the target site at higher concentrations than free drugs, whilst protecting healthy tissues from an often potent and cytotoxic payload. Through the EPR (enhanced permeability and retention) effect, injected, PEGylated nanoparticles preferentially accumulate in tumour tissue deeming them eminently suitable for cancer intervention for delivery of both therapeutic and contrast agents The development of theranostic liposomal systems comprising both imaging and therapeutic capabilities exploits the facets of liposomes, and forms an elegant strategy to address major problems which hinder effective cancer therapy. Liposomes can be tailored to be thermosensitive in a low hyperthermic range of ~42°C, above physiological temperature but below that which can induce tissue damage. This allows the use of heating as an external triggering modality to induce targeted drug release. Throughout the course of this work, the photoacoustic contrast agent ICG was successfully incorporated into PEGylated doxorubicin-encapsulating liposomes, marrying two FDA approved entities. The project commenced with the development of the basic liposomal-DOX. Differing lipid compositions of varying fluidities were tested against those which have been previously established. These compositions carried a range of phase transition temperatures, above which the liposomes release the encapsulated DOX. This study concluded with the generation of a library of liposomes with differing release kinetics at 42°C in simulated physiological conditions. The second section of the project investigated the methodology behind the incorporation of ICG into the liposomal bilayers. The lipid composition used for the study was based on the DOXIL® formulation, due to its robust structure and establishment in the field of cancer therapy. The protocols used varied on the basis of chronology in regards to the liposome preparation protocol. The film insertion method incorporated the ICG in initial lipid film generation. The freeze fracture protocol introduced the ICG during lipid film hydration. The post insertion protocol introduced ICG in the final stages of DOX loading. The downsizing protocol was also varied between extrusion and sonication. Through varying of the protocols and downsizing methodology, it was possible to incorporate differing ICG concentrations and attain differing levels of structural stability. The most successful liposome was then tested for its imaging potential in vivo through a photoacoustic imaging modality namely multispectral optoacoustic tomography. This validated accumulation of the liposomes at the tumour site along with co-localisation of both drug and dye. The project culminated in the combination of the two studies, producing a thermosensitive theranostic ICG labelled liposomal doxorubicin system. The system showed improved blood stability than the current clinical systems, and demonstrated imaging potential through IVIS based fluorescence imaging. Through exploitation of the photothermal effects of ICG within a thermosensitive lipid vesicle, it was also possible to induce drug release through irradiation with a non-thermal near-infrared laser. This shows promise for future therapy, allowing simultaneous imaging, optimum release induction and monitoring response to therapy, in a cheap, effective and time-efficient manner.

Polímeros termossensíveis apresentam grandes alterações em suas propriedades quando submetidos a pequenas mudanças de temperatura (T) próximas à temperatura de solução crítica inferior (LCST) ou superior (UCST). Um dos polímeros termossensíveis mais estudados é o Poli(N-isopropilacrilamida) (PNIPAm) porque ele apresenta a LCST, aproximadamente, 32 oC ( 305 K), próxima à temperatura do corpo humano. Em temperatura abaixo da LCST o polímero apresenta-se solúvel devido um grande número de interações hidrofílicas (ligações de hidrogênio polímero-água), entretanto quando a temperatura é elevada acima da LCST ocorre a precipitação do polímero devido a um aumento de interações polímero-polímero e uma diminuição brusca nas interações polímero-água. Com essas características o PNIPAm tem despertado o interesse para aplicações em um vasto campo de pesquisas, como por exemplo na liberação controladas de fármacos. Nesse trabalho, utilizando simulações de dinâmica molecular (DM), foi proposta uma imagem microscópica do fenômeno de transição de fases apresentado por esse polímero em solução aquosa influenciado por alterações na estereoquímica do backbone (taticidade), bem como o efeito da copolimerização com Acrilamida (Am). Com base nas análises estruturais e termodinâmicas, os resultados sugerem que as diferentes estereoquímicas (isotático, atático e sindiotático) possibilitam diferentes conformações dificultando ou possibilitado um maior número de interações polímero-polímero e polímero água modificando a LCST. Já o aumento da concentração de Am (xAm) na copolimerização aumenta o número de interações polímero-água dificultando o colapso da cadeia. / Thermosensitive polymers exhibit large changes in their properties when submitted to small changes in temperature T, near the lower (LCST) or upper critical solution temperature( UCST). The most extensively studied thermosensitive polymer is PNIPAm because it has a LCST of approximately 32 oC (305 K), near human body temperature. For temperatures below the LCST the polymer is soluble due to strong hydrophilic interactions (polymer-water hydrogen bonds). However, when the temperature is raised above the LCST, the precipitation of the polymer occurs due to increased polymer-polymer interactions and a sharp decrease in polymer-water interactions. That feature makes the PNIPAm a compound widely studied and with a wide range of applications, such as for drug delivery. In this work, using molecular dynamics simulations, it was proposed a microscopic picture of the phase transition phenomenon presented by this polymer in aqueous solution influenced by changes in stereochemistry of the backbone (tacticity), as well as the effect of copolymerization with acrylamide (Am). Based on the thermodynamic and structural analysis, the results suggest that different stereochemistries (isotactic, atactic and syndiotactic) enable different conformations allowing different scenarios of polymer-polymer and polymer-water interactions, therefore modifying the LCST. The presence of the strongly polar copolymer acrylamide as the effect of maintain the high hydration even at higher temperatures, shifting in this way the LCST to higher values.

Polímeros termossensíveis apresentam grandes alterações em suas propriedades quando submetidos a pequenas mudanças de temperatura (T) próximas à temperatura de solução crítica inferior (LCST) ou superior (UCST). Um dos polímeros termossensíveis mais estudados é o Poli(N-isopropilacrilamida) (PNIPAm) porque ele apresenta a LCST, aproximadamente, 32 oC ( 305 K), próxima à temperatura do corpo humano. Em temperatura abaixo da LCST o polímero apresenta-se solúvel devido um grande número de interações hidrofílicas (ligações de hidrogênio polímero-água), entretanto quando a temperatura é elevada acima da LCST ocorre a precipitação do polímero devido a um aumento de interações polímero-polímero e uma diminuição brusca nas interações polímero-água. Com essas características o PNIPAm tem despertado o interesse para aplicações em um vasto campo de pesquisas, como por exemplo na liberação controladas de fármacos. Nesse trabalho, utilizando simulações de dinâmica molecular (DM), foi proposta uma imagem microscópica do fenômeno de transição de fases apresentado por esse polímero em solução aquosa influenciado por alterações na estereoquímica do backbone (taticidade), bem como o efeito da copolimerização com Acrilamida (Am). Com base nas análises estruturais e termodinâmicas, os resultados sugerem que as diferentes estereoquímicas (isotático, atático e sindiotático) possibilitam diferentes conformações dificultando ou possibilitado um maior número de interações polímero-polímero e polímero água modificando a LCST. Já o aumento da concentração de Am (xAm) na copolimerização aumenta o número de interações polímero-água dificultando o colapso da cadeia. / Thermosensitive polymers exhibit large changes in their properties when submitted to small changes in temperature T, near the lower (LCST) or upper critical solution temperature( UCST). The most extensively studied thermosensitive polymer is PNIPAm because it has a LCST of approximately 32 oC (305 K), near human body temperature. For temperatures below the LCST the polymer is soluble due to strong hydrophilic interactions (polymer-water hydrogen bonds). However, when the temperature is raised above the LCST, the precipitation of the polymer occurs due to increased polymer-polymer interactions and a sharp decrease in polymer-water interactions. That feature makes the PNIPAm a compound widely studied and with a wide range of applications, such as for drug delivery. In this work, using molecular dynamics simulations, it was proposed a microscopic picture of the phase transition phenomenon presented by this polymer in aqueous solution influenced by changes in stereochemistry of the backbone (tacticity), as well as the effect of copolymerization with acrylamide (Am). Based on the thermodynamic and structural analysis, the results suggest that different stereochemistries (isotactic, atactic and syndiotactic) enable different conformations allowing different scenarios of polymer-polymer and polymer-water interactions, therefore modifying the LCST. The presence of the strongly polar copolymer acrylamide as the effect of maintain the high hydration even at higher temperatures, shifting in this way the LCST to higher values.

Táto práca si dáva za cieľ chemicky zasieťovať biodegradovateľný makromonomér ,-itaconyl-PLGA–PEG–PLGA vo vodnom roztoku pri teplote okolia a pri teplote tela (37 °C). ,-itaconyl-PLGA–PEG–PLGA makromonomér môže vo vode vytvárať fyzikálnu sieť vďaka hydrofóbnym interakciám medzi hydrofóbnym PLGA a hydrofilným PEG. Vďaka dvojitej väzbe kyseliny itakonovej, ktorá je k makromonoméru pripojená na jeho koncoch, sa naskytuje možnosť dodatočného chemického zasieťovania fotopolymerizáciou. Výsledkom je hybridná sieť, ktorá zvyšuje mechanickú stabilitu a životnosť hydrogélu. Na priame sledovanie formovania siete prostredníctvom zmeny mechanických vlastností bola v práci použitá fotoreológia.

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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

abstract: Current treatment methods for cerebral aneurysms are providing life-saving measures for patients suffering from these blood vessel wall protrusions; however, the drawbacks present unfortunate circumstances in the invasive procedure or with efficient occlusion of the aneurysms. With the advancement of medical devices, liquid-to-solid gelling materials that could be delivered endovascularly have gained interest. The development of these systems stems from the need to circumvent surgical methods and the requirement for improved occlusion of aneurysms to prevent recanalization and potential complications. The work presented herein reports on a liquid-to-solid gelling material, which undergoes gelation via dual mechanisms. Using a temperature-responsive polymer, poly(N-isopropylacrylamide) (poly(NIPAAm), the gelling system can transition from a solution at low temperatures to a gel at body temperature (physical gelation). Additionally, by conjugating reactive functional groups onto the polymers, covalent cross-links can be formed via chemical reaction between the two moieties (chemical gelation). The advantage of this gelling system comprises of its water-based properties as well as the ability of the physical and chemical gelation to occur within physiological conditions. By developing the polymer gelling system in a ground-up approach via synthesis, its added benefit is the capability of modifying the properties of the system as needed for particular applications, in this case for embolization of cerebral aneurysms. The studies provided in this doctoral work highlight the synthesis, characterization and testing of these polymer gelling systems for occlusion of aneurysms. Conducted experiments include thermal, mechanical, structural and chemical characterization, as well as analysis of swelling, degradation, kinetics, cytotoxicity, in vitro glass models and in vivo swine study. Data on thermoresponsive poly(NIPAAm) indicated that the phase transition it undertakes comes as a result of the polymer chains associating as temperature is increased. Poly(NIPAAm) was functionalized with thiols and vinyls to provide for added chemical cross-linking. By combining both modes of gelation, physical and chemical, a gel with reduced creep flow and increased strength was developed. Being waterborne, the gels demonstrated excellent biocompatibility and were easily delivered via catheters and injected within aneurysms, without undergoing degradation. The dual gelling polymer systems demonstrated potential in use as embolic agents for cerebral aneurysm embolization. / Dissertation/Thesis / Ph.D. Bioengineering 2012