Return Oriented Programming (ROP) is the de-facto technique used to exploit most of today’s native-code vulnerabilities hiding in old and newly developed software alike. By reusing bits and pieces of already existing code (gadgets), ROP can be used to bypass the ever-present Write ⊕ eXecute (W⊕X) security feature, which enforces memory to only be marked as either executable or writable; never both at the same time. Even with its widespread use, crafting more advanced ROP-chains is mostly left as a manual task. This paper attempts to explore the viability of automating ROP-chain generation by leveraging genetic programming (GP), and describes the implementation and design of the ROP-compiler GENROP in this endeavour. We introduce a novel approach to adapt GP to work within the environment of ROP, which attempts to guide the algorithm and preemptively remove pathways which are known ahead of time to be unable to generate a solution. GENROP is tested by attempting to generate a working payload against a number of binaries, and is then evaluated based on success rate and payload size when compared to angrop (another ROP-compiler). The results show that the algorithm is able to generate functioning payloads in most of the tested cases, although it does perform worse than angrop. This can partly be explained by the fact that GENROP uses gadget definitions generated by angrop, which reduces the potential viability of the ROP-compiler, as more unwieldy but potentially usable gadgets are not available. Additionally, it was found that extensively guiding the algorithm has negative consequences in terms of solution diversity. Relying on faster execution times and more iterations might produce better results. Further work is required to assess whether or not generating ROP-chains using genetic programming is a viable approach.

Ring-opening polymerization (ROP) is a promising approach to accessing well-defined polyesters with superior (bio)degradability and recyclability. However, the living/controlled polymerization of glycolide (GL), a well-known sustainable monomer derived from carbon mono/di-oxide, has never been reported due to the extremely low solubility of its polymer in common solvents. Herein, we report the first living/controlled anionic ROP of GL in strong protic fluoroalcohols (FAs), which are conventionally considered incompatible with anionic polymerization. Well-defined polyglycolide (PGA, Ð < 1.15, Mn up to 55.4 kg mol-1) and various PGA-based macromolecules are obtained at room temperature for the first time. NMR titration and computational studies revealed that FAs simultaneously activate the chain-end and monomer without being involved in initiation. Low boiling point FAs and PGA can be recycled through simple distillation and sublimation at 220 oC in vacuo, respectively, providing a promising sustainable alternative for tackling plastic pollution problems. Well-defined multicrystalline multiblock polymers are essential model polymers for advancing crystallization physics, phase separation, self-assembly, and improving the mechanical properties of materials. However, due to the different chain properties and incompatible synthetic methodology, multicrystalline multiblock polymers with more than two crystallites are rarely reported. Herein, by combining polyhomologation, ring-opening polymerization, and “catalyst switch” strategy, we synthesized the first pentacrystalline pentablock quintopolymer, polyethylene-b-poly(ethylene oxide)-b-poly(e-caprolactone)-b-poly(L-lactide)-b-polyglycolide (PE-b-PEO-b-PCL-b-PLLA-b-PGA). The novel “fluoroalcohol-assisted catalyst switch” enables the first successful incorporation of a high melting point polyglycolide into the complex multiblock polymer. Solid-state NMR spectroscopy, X-ray diffraction, and differential scanning calorimetry revealed the existence of five different crystalline phases.

No description available.

We are using the yeast two-hybrid (Y2H) system to identify novel protein-protein interactions (PPI) relevant to wood formation. Bait proteins for Y2H binary assays and screening against a xylem cDNA prey library were selected from approximately 400 Populus trichocarpa genes that are at least 8-fold more highly expressed in differentiating secondary xylem versus phloem-cambium, and designated here as poplar biomass (PB) genes. Here we report some of the interactions involving selected PB proteins and efforts to characterize their functions in Populus and Arabidopsis. Members of the ROP GTPase family, PB15 in poplar and ROP11 in Arabidopsis, interact with the domain of unknown function (DUF) 620 (DUF620) proteins (e.g., PB129 in poplar). Ectopic co-expression of PB15 and PB129 in Arabidopsis caused outgrowths at the base of flower pedicels and altered leaf morphology. Interestingly, the co-expression phenotype could not be observed in transgenic plants that are only expressing either one of the interacting partners separately. Transgenics altered in expression of PB15 and/or PB129 were prepared in Populus and characterization of transgenic trees will be performed in greenhouse and field. In addition to DUF620 family proteins, ROP11 also interacts with the COP9 subunit CSN5A in Arabidopsis. We confirmed the interaction of ROP11 and CSN5A in Y2H and employed available mutants for ROP11 and CSN5A in Arabidopsis to genetically characterize this interaction. Surprisingly, loss of ROP11 was found to rescue the csn5a-2 pleiotropic phenotype. Ectopic expression of a ROP11 dominant negative mutant in the csn5a-2 background also complemented the stunted growth phenotype. Transcript analysis and gel blot assays showed that CSN5A transcript levels remained unchanged in all rescue lines, whereas CSN5A protein levels increased relative to WT. Taken together, we concluded that ROP11 negatively regulate CSN5A protein level in plant by some as yet unknown mechanism. / Ph. D.

Ce travail de thèse avait pour objectif d’élaborer un système vecteur ciblantl’endothélium pathologiquement activé dans les tissus enflammés, infectés ou tumoraux.Ce vecteur est sous forme de nanoparticules décorées de ligands glycosides capablesd’interagir avec l’E-sélectine, un récepteur exprimé sur les cellules endothélialesactivées.Nous avons mis au point une synthèse de copolymère amphiphile avec une architectureà bloc muni sur sa partie hydrophile d’un ligand glucidique. Ce copolymère a été par lasuite utilisé pour la préparation de nanoparticules de type coeur/couronne. La partiehydrophobe centrale est entourée d’une couronne hydrophile dont l'encombrementstérique et la mobilité limitent l'opsonisation de la particule. Le ciblage actif a été assurépar la présence d’un ligand du récepteur de l’E-sélectine aux extrémités des chaînes depolymères hydrophiles à la surface du vecteur.Avec ces nanoparticules dont les propriétés de surface sont prédéfinies, nous avonsmontré in vitro l’association efficace avec les cellules endothéliales activées, ce qui apermis de valider ce concept de ciblage moléculaire actif par l’intermédiaire du couplerécepteur/ ligand. Un tel système permettra d’améliorer l’indice thérapeutique et labiodistribution des principes actifs anti-inflammatoire et/ou anticancéreux. / The objective of this work was to develop a delivery system targeting pathologically activated endothelium within inflamed, infectious, and some tumoral tissues. This system is composed of nanoparticles bearing sugar residues that are able to recognize and interact with E-selectin, a receptor expressed on the activated endothelial cells.We synthesized an amphiphilic block copolymer with the hydrophilic part terminated by a carbohydrate ligand. The construction was achieved by a combination of click chemisty, ring-opening polymerization and atom transfer radical polymerization. This copolymer was used to prepare nanoparticles of the core/shell type where the central hydrophobic body is surrounded with the hydrophilic shell that can stabilize the particles in aqueous media and limit their opsonisation. Active targeting was achieved by coupling an analogue of sialyl Lewis X, the physiological ligand of E-selectin to the end of the hydrophilic polymer chains on the surface of the particles.We were able to demonstrate in vitro the efficient association of these nanoparticles with defined surface properties with activated endothelial cells. This allowed us to validate our concept of active molecular targeting using this couple receptor/ligand couple. Such a system could be used to improve the therapeutically index and the biodistribution of anti-inflammatory and anti-tumor drugs.

Les travaux de thèse retranscrits dans ce mémoire ont pour sujet l’élaboration de nouveaux ligands pour la coordination de métaux et l’application des complexes correspondants pour la catalyse et la thérapie.La première partie du manuscrit traite de l’élaboration de ligands phosphine-diène, de leurs analogues saturés et des complexes arène-ruthénium correspondants. Le départ d’arène permet au ligand phosphine-cycloheptadiène de former avec le ruthénium un complexe bimétallique cationique où le ligand est chélate κ-P/diène-η4. Ces complexes ont été appliqués en catalyse pour l’addition radicalaire par transfert d’atome (ATRA) de CCl4 au styrène. Lors de l’utilisation de conditions dures, la supériorité des complexes « diène » a pu être mise en évidence par rapport aux analogues saturés.La seconde partie rapporte le développement de nouveaux analogues de base de Schiff : les « salicylamidines ». L’utilisation de différentes voies de synthèse a permis d’obtenir plusieurs générations de ligands. Ils ont été utilisés pour la coordination de métaux et sont particulièrement adaptés à la formation de complexes avec le zinc et l’aluminium. Certains de ces composés ont été utilisés pour la polymérisation par ouverture de cycle (ROP) de lactides et ont démontré une bonne activité.La dernière partie concerne la synthèse et l’évaluation de complexes métalliques comme agents anticancéreux. Des complexes phosphine-or et phosphine-ruthénium ont été synthétisés et évalués pour leur activité antiproliférative. Les complexes phosphine-or présentent une activité remarquable, meilleure que le cisplatine. La nature de l’arène des complexes phosphine-ruthénium influe fortement sur leur activité, les dérivés « benzoate d’éthyle » donnent des cytotoxicités significativement meilleures que les analogues « p-cymène ». Des complexes de titane et de zirconium avec un ligand de type aza-dipyrrométhène ont été synthétisés. Une étude préliminaire de leurs propriétés photophysiques a été réalisée et a indiqué que les composés étaient fluorescents. L’étude de leur propriété anticancéreuse a démontré une faible cytotoxicité. / The subject of this thesis concerns the development of new ligands, their coordination chemistry, and the synthesis of the corresponding metal complexes for catalysis and therapy.The first part of this work relates to the synthesis of diene-phosphine ligands, their saturated analogs, and the corresponding arene-ruthenium complexes. Arene decoordination allows the formation of a cationic bimetallic complex where the ligand is diène-η4/κ-P coordinated to the ruthenium. These complexes have been applied to atom transfer radical addition (ATRA) of CCl4 to styrene. When harsh reaction conditions are used, the superiority of the “diene” complexes is highlighted comparing to saturated analogs.The second part concerns the development of new Schiff base analogs: the “salicylamidines”. Several ligand generations have been obtained following different synthetic paths. They have been used for metal coordination, and are especially well-suited for the formation of zinc and aluminium complexes. Some of the compounds have been applied to ring opening polymerization (ROP) of lactides, and demonstrated good activity.The last part reports on the synthesis and assessment of metal-based anticancer agents. Some phosphine-gold and phosphine-ruthenium complexes have been synthesized and tested for their antiproliferative activity on several cancer cell lines. The phosphine-gold complexes showed impressive activities, better than cisplatine. Activity of phosphine-ruthenium is strongly influenced by the nature of the arene, ethyl benzoate derivatives are significantly more cytotoxic than p-cymene ones. Titanium and zirconium complexes with aza-dipyrromethene ligand were synthesized. Preliminary photophysical study was performed and indicated fluorescence. Their anticancer properties were assessed, and they are only poorly cytotoxic.

Les copolymères à blocs amphiphiles s’auto-assemblent en solution aqueuse grâce à l’association de leurs segments hydrophobes. Les nanoparticules formées à partir de copolymères biocompatibles et biodégradables tels que les poly(hydroxyalkanoates) (PHAs) sont particulièrement attractives pour la conception de systèmes à libération prolongée de principes actifs. La relation entre la composition/structure chimique du copolymère, ses propriétés d’auto-assemblage et ses effets sur les cellules in-vitro doit être étudiée. Des copolymères à blocs poly(acide malique)-b-poly(3-hydroxybutyrate) (PMLA-b-PHB), PMLA-b-PHB-b-PMLA et poly(triméthylène carbonate)-b-poly(acide-malique) (PTMC-b-PMLA) ont été synthétisés par polymérisation par ouverture cycle (ROP) des monomères correspondants, suivie d’une hydrogénolyse. Une gamme de copolymères bien définis, caractérisés par spectroscopie RMN 1H, 13C{1H}, HSQC, HMBC, et DOSY, par analyses SEC, DSC, TGA, et mesure des angles de contact, présentant des balances hydrophile/hydrophobe modulables, a été obtenue grâce au control précis de la fraction hydrophile f (11-82%). Des auto-assemblages modulables ont été formés par nanoprécipitation des copolymères en l’absence d’agent tensio-actif. De larges agrégats ainsi que des micelles cœur-couronne (Rh = 16-335 nm) ont été obtenus en fonction du copolymère utilisé (dibloc vs. tribloc). Des micelles stables pendant 10 jours à 37 °C en solution aqueuse ont été obtenues pour les copolymères avec f allant jusqu’à 50%. Les copolymères PMLA-b-PHB et PTMC-b-PMLA n’ont pas révélé de toxicité aigüe in-vitro. De plus, l’utilisation du PHB a avantageusement permis de diminuer la captation des nano-objets par les macrophages et d’augmenter la captation par les cellules hépatiques. / Amphiphilic block copolymers are able to form self-assembled systems in aqueous solution by association of their hydrophobic segments. Nanoparticles formed from biodegradable and biocompatible polymers such as poly(hydroxyalkanoate) copolymers are particularly attractive for drug delivery applications. The relationship between the chemical structure/composition of the macromolecule, its self-assembly properties and its effect on cells in-vitro has to be studied.The synthesis of poly(-malic acid)-b-poly(3-hydroxybutyrate) (PMLA-b-PHB), PMLA-b-PHB-b-PMLA, and poly(trimethylene carbonate)-b-poly(-malic acid) (PTMC-b-PMLA) was established through the ring-opening polymerization (ROP) of the corresponding monomers followed by hydrogenolysis. A range of well-defined copolymers characterized by 1H, 13C{1H}, HSQC, HMBC, DOSY NMR spectroscopy, SEC, DSC, TGA, contact angle analyses, with tunable hydrophilic/hydrophobic balance were thus obtained through the precise control of the hydrophilic weight fraction f (11-82%). Tunable self-assembled systems were obtained by nanoprecipitation of the amphiphilic PHA-based copolymers without the use of a surfactant. Large aggregates and core-shell micelles (Rh = 16-335nm) were obtained depending on the polymer topology. PHB-based copolymers with f up to 50% formed highly stable micelles at 37 °C over a period of 10 days in aqueous solution. PMLA-b-PHB as well as PTMC-b-PMLA copolymers revealed no acute in-vitro cytotoxicity. The use of PHB as hydrophobic segment enabled to minimize the non-specific scavenging by macrophages cells while the cellular uptake by hepatocytes was favored.

Ce travail de thèse concerne la synthèse et la caractérisation d'homo et de copolymères stimulables à base de N,N-diéthylacrylamide (DEAm). Des homopolymères ont été préparés par polymérisation radicalaire contrôlée par transfert réversible par addition-fragmentation (RAFT). Cette polymérisation a été conduite en présence de trois agents de transfert différents et s'est avérée contrôlée quelles que soient les conditions expérimentales. Deux types de copolymères ont ensuite été préparés, de type PEG-b-PDEAm et PDEAm-b-polypeptides par polymérisation RAFT et combinaison RAFT/ polymérisation par ouverture de cycle (ROP), respectivement. Ces copolymères double hydrophiles ont été caractérisés et leur comportement en solution aqueuse a été évalué. Nous avons montré la formation de micelles c?ur-couronne au dessus de la LCST. Nous avons également développé une stratégie de synthèse originale dans le cas des PDEAm-b-polypeptides puisque la ROP a été réalisée en utilisant un macroamorceur de type thiol. Après déprotection des copolymères sensibles au pH et à la température ont été obtenus et montre des propriétés de structuration différentes en fonction de ces deux stimuli. / This manuscript deals with the synthesis and characterization of responsive copolymers containing N,N-diethylacrylamide (DEAm). Homopolymers were prepared by controlled radical polymerization, especially Reversible Addition-Fragmentation Transfer (RAFT). Polymerization was achieved using three different chain transfer agents and was controlled whatever the experimental conditions. PEG-b-PDEAm and PDEAm-b-polypeptides were synthesized by RAFT polymerization and RAFT/Ring Opening Polymerization (ROP) respectively. These double hydrophilic block copolymers were characterized and their behavior in aqueous solution was evaluated. We showed that core/corona micelles were obtained above the lower critical solution temperature. We also developed a new strategy for the synthesis of PDEAm-b-polypeptides as ROP was achieved using a thiol macroinitiator. After deprotection pH- and thermo-sensitive copolymers were afforded which proved different structuration as a function of both stimuli.

Le sujet de cette thèse concerne l’élaboration de copolymères greffés possédant un squelette poly(1,4-butadiène) et une haute densité de greffons polaires. La synthèse de copolymères à squelette strictement poly(1,4-butadiène) et possédant une haute densité de greffons selon un enchaînement strictement tête-à-tête a été réalisée par polymérisation par ouverture de cycle par métathèse (ROMP) de monomères cyclobutène 3,4-disubstitués. Le choix des greffons polaires s’est porté sur des poly(Ɛ-caprolactone)s (PCL) et des poly(L-lactide)s (PLLA) obtenus par polymérisation par ouverture de cycle (ROP). Ces polyesters aliphatiques qui présentent une biocompatibilité élevée et une (bio)dégradation rapide, sont utilisés dans de nombreuses applications biomédicales. De plus, les copolymères greffés à greffons polyester peuvent donner accès à des nanomatériaux poreux suite à leur organisation en solution ou à l’état solide, suivie de l’hydrolyse des chaînes polyester.Les copolymères greffés poly(1,4-butadiène)-g-polyester ont été synthétisés selon les stratégies grafting through et grafting from, à partir d’inimers (initiator-monomer) cyclobutène portant une ou deux fonctionalités alcool, capable d’amorcer la ROP du L-lactide ou de l’ Ɛ-caprolactone. La stratégie grafting through a, dans un premier temps, été étudiée. Des macromonomères polyester de type PCL ou PLLA ont été synthétisés. La ROMP de ces macromonomères a conduit à des copolymères greffés poly(1,4-butadiène)-g-polyesters en forme d’étoile de structure définie et dont la densité des greffons est parfaitement contrôlée. La stratégie grafting from a, quant-à-elle, permis d’accéder à des copolymères greffés en forme de peigne. L’organisation des architectures macromoléculaires obtenues a été visualisée par microscopie à force atomique (AFM) et microscopie électronique à transmission (TEM). / The objective of this work was the preparation of graft copolymers with a poly(1,4-butadiene) backbone and a high density of polar grafts. We used a consecutive Ring-Opening Metathesis Polymerization (ROMP)/Ring-Opening Polymerization (ROP) route to prepare poly(1,4-butadiene)-g-polyesters from cyclobutenyl macromonomers bearing one or two polyester segment(s) derived from L-lactide (L-LA) or Ɛ-caprolactone (Ɛ-CL). Poly(L-lactide)s (PLLA) or poly(Ɛ-caprolactone)s (PCL) are important polymers as they are easily (bio)degradable and have tremendous applications as engineering plastics and within the biomedical field. An attractive feature of polyester-grafted copolymers is their potential to act as building blocks for nanomaterials synthesis thanks to the hydrolytically degradable polyester grafts. Cyclobutenyl polyester macromonomers bearing one and two PCL or PLLA arms have been successfully prepared by organocatalyzed ROP of Ɛ-CL or L-LA from a cyclobutenyl alcohol acting as an initiator. Subsequent "grafting through" by ROMP using Grubbs’ second generation catalyst afforded poybutadiene brushes featuring pendant polyester (PLLA or PCL) side-chains. This efficient ROP/ROMP two-step approach has thus allowed the synthesis of well-defined poly(1,4-butadiene)-g-polyester copolymers. The synthesis of graft copolymers via the grafting from approach by ROMP and ROP was also studied. ROMP of 3,4-disubstituted cyclobutenes containing one and two initiating hydroxyl sites for ROP was first investigated with ruthenium initiators. The resulting well-defined poly(1,4-butadiene)s were then used as macroinitiators for the ROP of L-LA or Ɛ-CL. After the ROP, brush copolymers with high molecular weight have been obtained and characterized by microscopy.

Nanopartiklar (NP) erbjuder unika möjligheter för medicinska tillämpningar, inklusive kontrollerad frisättning av cancerläkemedel, användning som bildkontrast vid avbildningsprocedurer eller hypertermisk behandling av cancerceller. Flash nanoprecipitation (FNP) producerar NPs för att kombinera dessa tillämpningar i en snabb, billig och skalbar beläggningsprocess. Användning av FNP med en Multi-Inlet Vortex Mixer (MIVM) är en lovande metod för att enkelt belägga hydrofoba oljesyra järnoxid NP (IONP) med olika biokompatibla block-copolymerer. Amfifila block-copolymerer baserade på hydrofil polyetylenglykol (PEG) och hydrofob poly(laktid) (PLA), poly(laktid-co-glykolid) (PLGA) eller poly(kaprolakton) (PCL) syntetiserades framgångsrikt. Den organiska katalysatorn 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) användes för att öka biokompatibiliteten hos de resulterande polymererna PEG-PLA, PEG-PL7,5KG2,5KA och PEG2K-PCL2K. Syntes av hydroxylterminerad poly(akrylsyra) (PAA-OH) följt av polymerisation med PLGA prövades. De amfifila blockpolymererna användes i kombination med stabilisatorn polysorbat 80 (Tween80®) i FNP för att bilda nakna polymera NP med en MIVM som reaktor. DLS och STEM bekräftade partikelstorlekar mellan 50 - 100 nm. Tillsatsen av 13 ± 2 nm hydrofoba oljesyra-IONPs gav en ökning av partikelstorleken samt en ökning av partikelstabiliteten över tid. STEM-bilder visade att enstaka IONPs fästs på utsidan av de polymera NPs. Hydrofoba interaktioner mellan polymeren och oleinsyra-IONPs är möjliga. För att uppnå inkapsling av oljesyra-IONPs bör justeringar av processparametrarna för FNP övervägas i framtida forskning. Ytterligare experiment krävs för att utforska möjliga läkemedelstillsatser, frisättningsmekanismer och hypertermi hos de polymerbelagda IONP-partiklarna. / Nanoparticles (NPs) offer unique possibilities for medical applications, including the controlled release of cancer drugs, the use as imaging contrast during imaging procedures or the hyperthermic treatment of cancer cells. Flash nanoprecipitation (FNP) produces NPs to combine these applications in a fast, cheap, and scalable coating process. The use of FNP with a Multi-Inlet Vortex Mixer (MIVM) is a promising method to easily coat hydrophobic oleic acid iron oxide NPs (IONPs) with various biocompatible block-copolymers. Amphiphilic block-copolymers based on hydrophilic polyethylene glycol (PEG) and hydrophobic poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) or poly(caprolactone) (PCL) were successfully synthesized. The organic catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used to increase biocompatibility of the resulting polymers PEG-PLA, PEG-PL7.5KG2.5KA and PEG2K-PCL2K. The synthesis of hydroxyl terminated poly(acrylic acid) (PAA-OH) followed by the polymerization with PLGA was attempted. The amphiphilic block-copolymers were used in combination with the stabilizer polysorbate 80 (Tween80®) in FNP to form bare polymeric NPs using a MIVM as the reactor. DLS and STEM confirmed particle sizes between 50 - 100 nm. The addition of 13 ± 2 nm hydrophobic oleic acid IONPs yielded an increase in particle size as well as increase in particle stability over time. STEM images showed attachment of single IONPs to the outside of the polymeric NPs. Hydrophobic interactions between the polymer and oleic acid IONPs are possible. To achieve encapsulation of the oleic acid IONPs, adjustments to the process parameters of FNP should be considered in future research. Additional experiments are required to explore possible drug addition, release mechanisms and hyperthermia behavior of the polymer coated IONPs particles.