Recently, a particular interest has been devoted to “smart”/stimuli-responsive amphiphilic polymeric materials. Strictly speaking, such structures do not present an amphiphilic character but can be transformed as such by external stimuli within their close environment, e.g., pH, temperature, light, ionic strength, ... and are then able to produce reversible self-assemblies greatly attractive in the biomedical field as drug delivery systems. The originality of this thesis relies upon the synthesis of “intelligent” hydrophilic triblock copolymers containing acrylamide and acrylate-based monomers presenting both thermo- and pH-responsiveness. The applied synthetic strategy aimed at performing the controlled copolymerization reactions entirely in aqueous conditions and in a “one-pot process” via Atom Transfer Radical Polymerization (ATRP). This synthetic approach represents a real challenge knowing that ATRP of (meth)acrylamide comonomers is difficult to control in aqueous medium. However, by the help of kinetic studies and related theoretical modeling, a fine control over the copolymerization process has been made available allowing the synthesis of polyacrylamide-based triblock copolymers with different charge states. Ultimately, all series of triblock copolymers have been investigated for forming polyelectrolyte complexes potentially useful as drug delivery (nano)systems. The first part of the thesis aims at reporting the control and the understanding of the aqueous ATRP of N-isopropylacrylamide (NIPAAm) initiated by a model low molecular weight initiator. The NIPAAm polymerization has been kinetically studied varying different parameters. Correlated with a theoretical modeling, the reactions involved in the ATRP process have been identified highlighting the importance of molecular diffusion limitations. This step was crucial in view to extrapolate to the synthesis of poly(N-isopropylacrylamide)-based copolymers. The second part focuses on the controlled synthesis of poly(ethylene oxide)-b-poly(N- isopropylacrylamide) diblock copolymers using the macroinitiator method. Different conditions such as solvent mixture, nature of the catalyst and of macroinitiator, i.e., poly(ethylene oxide), have been studied ultimately yielding well-tailored polyacrylamide-based triblock copolymers based on NIPAAm, N,N-dimethylaminoethyl acrylate and 2-acrylamido-2-methyl-1-propane sodium sulfonate comonomers The “smart” character of the resulting triblock copolymers has been investigated affording in specific conditions micellar self-assemblies. Last but not least, polyelectrolyte complexes have been prepared by coulombic interactions between the resulting triblock copolymers, e.g., poly(ethylene oxide)-b-poly(N- isopropylacrylamide)-b-poly(N,N-dimethylaminoethyl acrylate) and poly(ethylene oxide)-b- poly(N-isopropylacrylamide)-b-poly(2-acrylamido-2-methyl-1-propane sodium sulfonate) whose the thermo-responsiveness could be highlighted. The so-formed polyelectrolyte complex nanoparticles constitute promising nanovectors of the third generation able to kinetically tune the drug release in function of local temperature variation.

Styrenic block copolymer thermoplastic elastomers are one of the most widely used thermoplastic elastomers (TPEs) today. The focus of this research is to fundamentally understand the structure-processs-property relationships in these materials. Deformation behavior of the block copolymers with cylindrical and lamellar morphologies has been investigated in detail using unique techniques like deformation calorimetry, transmission electron microscopy (TEM), combined in-situ small angle x-ray and wide angle x-ray scattering (SAXS/WAXS). The research involves the study of structural changes that occur at different length scales along with the energetics involved upon deformation. The structural changes in the morphology of these systems on deformation have been investigated using combined SAXS/WAXS setup. Small angle x-ray scattering probed the changes at the nano-scale of polystyrene (PS) cylinders, while wide angle x-ray scattering probed the changes at molecular length scales of the amorphous/crystalline domains of the elastomeric mid-block in these systems. TEM analysis of the crosslinked elastomers (by UV curing) further confirms the interpretation of structural details as obtained from SAXS upon deformation. New structural features at both these length scales have been observed and incorporated into the overall deformation mechanisms of the material. Characteristic structural parameters have been correlated to differences in their mechanical response in the commercially relevant cylindrical block copolymers. Effect of various process conditions and thermal treatments has been investigated. The process conditions affect the structure at both micro-scopic (grain size) and nano-scopic (domain size) length scales. A correlation has been obtained between a mechanical property (elastic modulus) and an easily measurable structural parameter (d-spacing). Effect of various phase transitions such as order-to-order transition has been studied. Selective solvents can preferentially swell one phase of the block copolymer relative to other and thus bring a change in morphology. Such kinetically trapped structures when annealed at higher temperature try to achieve their thermodynamic equilibrium state. Such changes in morphology significantly affect their tensile and hysteretic response. In another work it has been shown that by carefully compounding these styrenic block copolymers having different morphologies, it is possible to completely disrupt the local scale order and remove the grain boundaries present in these materials. Finally, a new test technique has been developed, by modifying an existing Charpy device to test polymeric films at a high strain rate. A custom designed load-cell is used for force measurements which imposes harmonic oscillations on a monotonic loading signal. The data obtained from this device can be used to analyze visco-elastic response of polymeric films at frequencies much higher than the conventional dynamic mechanical analyzer (DMA).

For the first time, triblock copolymers of novel styrenic-based macromolecules were investigated in detail and examined for structure-morphology-performance relationships. We were able to design novel imidazolium- and phosphonium-containing styrenic macromolecules using controlled radical polymerization and conventional free radical polymerization strategies, for a variety of potential applications including electromechanical devices, ionic liquids, adhesives, and lithium-ion batteries. Block copolymers have a unique architecture providing physical crosslinking to behave as thermoplastic elastomers. We preferred ABA triblock copolymers as compared to random and diblock copolymers for improved mechanical performance. ABA triblock copolymers synthesized using nitroxide-mediated polymerization (NMP) of polystyrene external blocks and a charged imidazolium-containing central block, exhibited sufficient modulus and ionic conductivity for electromechanical transducers. We successfully reported the actuation behavior of triblock copolymers in the presence of added ionic liquid for the first time. We proposed that diluting the ion concentration of the ion-rich phase with neutral polymer comonomers that reduces Tg, increases ion dissociation, and potentially maximizes ionic conductivity. Tendency of ethylene-oxide units to coordinate cations, forming stable crown ether-like, multi-nuclear coordination complexes, promotes solvation and dissociation of ionic aggregates. In situ Fourier transform infrared spectroscopy (FTIR) was used to monitor the thermal polymerization in various acrylate and methacrylate monomers. It was found that acrylates have lower activation energy than methacrylates. The copolymerizations of poly(ethylene glycol)methyl ether acrylate (EG9MEA) and imidazole-containing monomer (VBIm) resulted in controlled polymerization kinetics with narrow molecular weight distributions. The control behavior of the copolymerizations is likely attributed to the observed decrease in calculated apparent rate constants for the copolymerizations with addition of VBIm as comonomer. Reversible addition fragmentation transfer (RAFT) successfully synthesized well-defined A-BC-A triblock copolymers containing a synergy of pendant ether and imidazolium sites. We demonstrated that electromechanical transducers derived from these triblock copolymer membranes with added ionic liquid showed superior actuation performance compared to a benchmark Nafion® membrane, suggesting potential for ionic polymer device applications. This was attributed to optimum modulus, improved ionic conductivity, and microphase-separated morphology of triblock copolymers. Conventional free radical polymerization and anion metathesis of 4-(diphenylphosphino)styrene (DPPS) successfully generated high molecular weight triaryl phosphine-containing copolymers. These macromolecules have no -CH2 group at the benzylic position increasing the thermal stability of the DPPS-containing polymers. Counterion exchange to fluorinated, bulkier anions broadened the library of polyelectrolytes, led to improved thermal stabilities, lower glass transition temperatures, and tunable wetting behavior. We also reported the synthesis of salt-responsive copolymers using conventional free radical polymerization. Adhesive performance measurements such as peel tests and probe tack enforced the application of these polymers as pressure sensitive adhesives. We also demonstrated the synthesis and subsequent neutralization of novel, well-defined A-BC-A triblock copolymers containing a soft central 'BC' block consisting of Sty-Tf2N and DEGMEMA with polystyrene external blocks. Sty-Tf2N monomer enables an important delocalization of the negative charge. Li+ has weak interactions with this anionic structure, consequently enabling a high dissociation level. Li+ ions are associated to the polymer chain to produce high transport numbers. Furthermore, incorporating DEGMEMA lowers the Tg of the charged block copolymers, thereby increasing the segmental mobility and thus ionic conductivity. Finally, the structure-property-morphology study of these triblock copolymers will be helpful for their use in potential applications such as ion-containing membranes, lithium-ion batteries. / Ph. D.

Crosslinkable and pH-sensitive amphiphilic block copolymers are promising candidates to establish pH-stable and permeable vesicles for synthetic biology. Here, we report the fabrication of crosslinked and pH-stable polymersomes as swellable vesicles for the pH-dependent loading and release of small dye molecules. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

This work presents the synthesis and the self-assembly of symmetrical amphiphilic ABA and BAB triblock copolymers in dilute, semi-concentrated and highly concentrated aqueous solution. A series of new bifunctional bistrithiocarbonates as RAFT agents was used to synthesise these triblock copolymers, which are characterised by a long hydrophilic middle block and relatively small, but strongly hydrophobic end blocks. As hydrophilic A blocks, poly(N-isopropylacrylamide) (PNIPAM) and poly(methoxy diethylene glycol acrylate) (PMDEGA) were employed, while as hydrophobic B blocks, poly(4-tert-butyl styrene), polystyrene, poly(3,5-dibromo benzyl acrylate), poly(2-ethylhexyl acrylate), and poly(octadecyl acrylate) were explored as building blocks with different hydrophobicities and glass transition temperatures. The five bifunctional trithiocarbonates synthesised belong to two classes: the first are RAFT agents, which position the active group of the growing polymer chain at the outer ends of the polymer (Z-C(=S)-S-R-S-C(=S)-Z, type I). The second class places the active groups in the middle of the growing polymer chain (R-S-C(=S)-Z-C(=S)-S-R, type II). These RAFT agents enable the straightforward synthesis of amphiphilic triblock copolymers in only two steps, allowing to vary the nature of the hydrophobic blocks as well as the length of the hydrophobic and hydrophilic blocks broadly with good molar mass control and narrow polydispersities. Specific side reactions were observed among some RAFT agents including the elimination of ethylenetrithiocarbonate in the early stage of the polymerisation of styrene mediated by certain agents of the type II, while the use of the RAFT agents of type I resulted in retardation of the chain extension of PNIPAM with styrene. These results underline the need of a careful choice of RAFT agents for a given task. The various copolymers self-assemble in dilute and semi-concentrated aqueous solution into small flower-like micelles. No indication for the formation of micellar clusters was found, while only at high concentration, physical hydrogels are formed. The reversible thermoresponsive behaviour of the ABA and BAB type copolymer solutions in water with A made of PNIPAM was examined by turbidimetry and dynamic light scattering (DLS). The cloud point of the copolymers was nearly identical to the cloud point of the homopolymer and varied between 28-32 °C with concentrations from 0.01 to 50 wt%. This is attributed to the formation of micelles where the hydrophobic blocks are shielded from a direct contact with water, so that the hydrophobic interactions of the copolymers are nearly the same as for pure PNIPAM. Dynamic light scattering measurements showed the presence of small micelles at ambient temperature. The aggregate size dramatically increased above the cloud point, indicating a change of aggregate morphology into clusters due to the thermosensitivity of the PNIPAM block. The rheological behaviour of the amphiphilic BAB triblock copolymers demonstrated the formation of hydrogels at high concentrations, typically above 30-35 wt%. The minimum concentration to induce hydrogels decreased with the increasing glass transition temperatures and increasing length of the end blocks. The weak tendency to form hydrogels was attributed to a small share of bridged micelles only, due to the strong segregation regime occurring. In order to learn about the role of the nature of the thermoresponsive block for the aggregation, a new BAB triblock copolymer consisting of short polystyrene end blocks and PMDEGA as stimuli-responsive middle block was prepared and investigated. Contrary to PNIPAM, dilute aqueous solutions of PMDEGA and of its block copolymers showed reversible phase transition temperatures characterised by a strong dependence on the polymer composition. Moreover, the PMDEGA block copolymer allowed the formation of physical hydrogels at lower concentration, i.e. from 20 wt%. This result suggests that PMDEGA has a higher degree of water-swellability than PNIPAM. / Die Arbeit behandelt die Synthese und das Selbstorganisationsverhalten von neuen funktionellen symmetrischen "stimuli-responsiven" Triblockcopolymeren ABA und BAB in wässrigen verdünnten und höher konzentrierten Lösungen. Neue symmetrische, bifunktionelle Bistrithiocarbonate wurden als RAFT-Agentien benutzt, um Triblockcopolymere mit langen hydrophilen (A) Innen- und kurzen hydrophoben (B) Außenblöcken zu synthetisieren. Als hydrophile A Blöcke wurden Poly(N-isopropylacrylamid) PNIPAM und Poly(methoxy diethylene glykol acrylat) PMDEGA benutzt, während als hydrophobe Blöcke B Poly(4-tert-butyl styrol), Polystyrol, Poly(3,5-dibromo benzyl acrylat), Poly(2-ethylhexyl acrylat), und Poly(octadecyl acrylat) als Bausteine mit unterschiedlicher Glasübergangstemperatur untersucht wurden. Die Selbstorganisation von ABA und BAB Copolymeren in Wasser mit A Blöcken aus PNIPAM wurde anhand von Trübungsphotometrie, dynamischer Lichtstreuung (DLS) und Rheologie untersucht. Die amphiphilen Blockcopolymere sind direkt wasserlöslich. Bei Konzentrationen von 0.01 bis 50 wt% zeigen Trübungsmessungen bei den Blockcopolymeren wie bei den Homopolymeren eine Übergangstemperatur bei 28-32 °C. Zurückzuführen ist dies auf die Bildung von Mizellen, bei der die hydrophoben Blöcke von einem direkten Kontakt mit Wasser abgeschirmt werden. DLS zeigt kleine Mizellen bei niedrigen Temperaturen und Aggregate mit großem hydrodynamischem Durchmesser bei Temperaturen oberhalb der Übergangstemperatur. Die rheologische Untersuchung von BAB Polymeren zeigt die Bildung von Hydrogelen bei höheren Konzentrationen (über 30-35 wt%). Die minimal benötigte Konzentration, bei der die von Hydrogelen auftreten, nimmt mit wachsender Glasübergangstemperatur ab, und nimmt mit der Länge der hydrophoben Blöcke B zu. Im Unterschied zu PNIPAM zeigen wässrige Lösungen von PMDEGA und seinen Blockcopolymeren reversible Übergangstemperaturen abhängig von der chemischen Struktur. Außerdem bilden PMDEGA Blockcopolymere Hydrogele bei niedriger Konzentration (ab 20 wt%). Dieses Ergebnis deutet darauf hin, dass PMDEGA stärker Wasser bindet als PNIPAM.

The presented thesis on thermosensitive polymer gel is focused especially on a thermosensitive triblock copolymer, which is composed of hydrophobic polylactide, polyglycolid and hydrophilic polyethylene glycol (PLGA-PEG-PLGA). Thermosensitive copolymers are very attractive for their phase sol-gel transitions and gel-suspension transitions. The aqueous solution of this copolymer behaves like a sol at laboratory temperature and like a gel at body temperature. These systems are used as injectable carriers for targeted drug delivery with controlled release. However, the influence of the resulting polymer concentration and temperature on the thermosensitive hydrogel nanostructure was not yet fully studied. In the experimental part, the viscoelastic behavior of hydrogels was observed by dynamic rheological analysis at different polymer concentrations and temperature conditions. The average size and distribution of micelles of triblock copolymer in aqueous solution were measured using dynamic light scattering technique. Characterization of fibrous micelles was complemented by imaging technique, cryogenic transmission electron microscopy.

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Yes / This mini-review highlights the latest advances in the chemistry and biology of Pluronic® triblock copolymers. We focus on their applications in medicine, as drug delivery carriers, biological response modifiers, and pharmaceutical ingredients. Examples of drug delivery systems and formulations currently in clinical use, clinical trials or preclinical development are highlighted. We also discuss the role that Pluronic® copolymers may play in the innovative design of new nanomedicines in the near future. / We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB) and EPSRC (EP/G004897/1 to APB) for support.

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.

Crosslinkable and pH-sensitive amphiphilic block copolymers are promising candidates to establish pH-stable and permeable vesicles for synthetic biology. Here, we report the fabrication of crosslinked and pH-stable polymersomes as swellable vesicles for the pH-dependent loading and release of small dye molecules. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.