Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

The purpose of this study is to investigate an animal model of distress (conditioned suppression) to assess the effects of magnesium (MAG) and nicotinamide (B3) administration on recovery of anxiety-like behavior following traumatic brain injury (TBI). Post-traumatic stress disorder (PTSD) is comorbid with TBI and both affects a victim’s ability to maintain daily activities and have a good quality of life. Administration of MAG decreases swelling of the brain considerably and lessens cell death. B3 is a neuroprotective precursor to NAD+ and enhances energy levels as well has help reduce free radicals after TBI. A conditioned suppression procedure is an established method for generating disruptive fearful anxiety-like responses in animals and these treatments may help to reduce anxiety responses.

Des nanoparticules multifonctionnelles polymères, préparées par auto-assemblage de plusieurs dérivés du poly (L-glutamate de gamma-benzyle) (PBLG), ont été conçues afin d’assurer le ciblage des tissus osseux et la libération contrôlée de molécules actives. Des propriétés d'attachement aux tissus osseux leur ont été conférées par la présentation en surface de différents ligands ostéotropes, l'alendronate et l' acide poly(glutamique), seuls ou en combinaison. Leur affinité pour les tissus osseux a été évaluée in vivo ainsi que leur distribution fine dans ces tissus. Par ailleurs, des propriétés anticancéreux ont été conférées aux nanoparticules grâce à un mécanisme originale d’association du cisplatin par complexation. Le procédé mis en œuvre permet d’obtenir des cinétiques de libération très progressives de dérivés actifs du platine et déclenchée par la présence des ions chlorure. Enfin, leur cytotoxicité a été mesurée. Cette stratégie constitue donc une approche prometteuse en vue d’améliorer le traitement des métastases osseuses. / Multifunctional bone targeted polymeric nanoparticles prepared by self-assembly of several poly(gamma-benzyl-L-glutamate) (PBLG) derivates have been developed. Their bone binding properties were provided by two different osteotropic moieties, alendronate or/and poly(glutamic acid) exposed on the nanoparticle surface. Their affinity for bone tissues has been evaluated in vitro, ex vivo and in vivo, including their detailed distribution in bone tissues structures. Further, in view of bone cancer therapeutics, nanoparticles were provided with anticancer properties thanks to the complexation of cisplatin, which leaded to very well controlled release properties. Finally, cytotoxicity were studied. Therefore, this strategy constitute a promising approach for the improvement of bone cancer therapeutics.

Remediation of heavy metals from industrial effluents and ground water sources poses a significant challenge. Hexavalent chromium is one such heavy metal, prevalent in industrial wastewaters, which has been proven to be toxic to humans and other living organisms. Most of the conventional methods available for dealing with chromium are either cost prohibitive or generate secondary effluents which are difficult to deal with. The idea of bioremediation has gained much momentum over the last few decades because of its potential low cost and minimum impact on the environment. This study explored the potential for hexavalent chromium bioremediation using a synthetic cationic biopolymer alpha-poly-l-lysine (alpha-PLL) as a biosorbent. In the present research work, equilibrium batch studies were performed in a specially designed dialysis apparatus to obtain preliminary information about the adsorption capacity of the polymer. Metal uptake by the polymer was found to be maximum when the pH of chromium solution (pH 4.6) and that of poly-lysine (pH 5.7) was not changed at the beginning of the experiment. Applying the Langmuir adsorption isotherm model showed that alpha-PLL has a maximum uptake capacity of 42.2 microgram Cr/mg alpha-PLL, and a binding constant of 1.2 microgram/mL +/- 10%. The metal uptake performance of the polymer was also evaluated in a Polymer Enhanced Diafiltration (PEDF) system. The polymer-metal complex was retained and concentrated by the PEDF set up using a tangential flow filtration membrane, while the clean filtrate flowed through. When 3.4 L of 10 mg/L chromium solution in the Cr2O72- form was processed using 300 mL of 2 gm/L PLL, the concentration of chromium in the permeate reached a maximum of 0.79 mg/L. When 30 mg/L chromium solution was used, 2 L could be processed using 300 mL of 2gm/L PLL, and 7.8 mg/L chromium could be detected in the permeate in the end.

Activation of the immune system in gestating mothers has been identified as an important environmental risk factor for neuropsychiatric disorders. Maternal immune activation (MIA) animal models have been used to explore how the maternal immune system may cause expression of pathophysiology in offspring. Protein tyrosine phosphatase (PTP1B) is recruited during inflammation and its regulatory proteins are modulated in MIA. Disrupted regulation of PTP1B has been linked to mental disorders such as Rett Syndrome and anxiety. We asked if ablating neuronal PTP1B could protect from the expression of some neuropsychiatric phenotypes that appear in MIA models. In our MIA model induced with poly I:C injection at gestational day 9.5, we observed increased locomotion and sensorimotor gating and reduced anxiety in 3-month-old male offspring while females showed decreased sensorimotor gating. These effects were not replicated in PTP1B KO mice indicating a role of PTP1B in affecting locomotion and anxiety level in MIA. This model promotes a more balanced understanding of MIA and introduces PTP1B as a player in MIA-induced behaviour changes.

La thérapie génique est une approche thérapeutique proposant d’utiliser des acides nucléiques (ADN,ARN, oligonucléotides) comme médicament. Les poly(éthylènimine)s linéaire (lPEI) et branchée (bPEI) sont des vecteurs de références pour le transfert de gènes, dans le domaines des polymères cationiques. L’objectif de ces travaux est de modifier la lPEI par des dérivés de la L-histidine-N-acryloyle, la L-arginine-Nacryloyleou le 1-adamantane méthylamine-N-acryloyle, en utilisant la réaction de Michaël. Les études physico-chimiques de ces polymères mettent en évidence le comportement de ces vecteurs en solution aqueuse et tamponnée, dont les effets peuvent avoir une influence non négligeable sur la complexation de l’ADN et le transfert de gène. La poly(éthylènimine-co-éthylènimine-N-éthylamide-N-2(3(3H-imidazol-4-yl) propionate de sodium) (lPEI-N-his) comportant 10 à 20% de greffons histidine a permis d’obtenir d’excellents résultats en transfection in vitro. Ces polymères ont montrés une très faible cytotoxicité sur les différentes lignées cellulaires utilisées pour cette étude. / Gene therapy is a therapeutic approach aiming at introducing corrective genetic materials into a cellin order to alleviate the symptoms of a disease. The linear (lPEI) and branched (bPEI) poly(ethylenimine) arethe gold standard among the polymeric vectors. The aim of this work is to modify the lPEI by N-acryloyl-Lhistidine,N-acryloyl-L-arginine and N-acryloyl-1 adamantane methylamine residue using the Michaelreaction to improve the transfection efficiency of cationic polymers. The physicochemical studies of thesepolymers are undertaken in aqueous and buffer solutions, and a higher buffering property of these polymersis emphasized. The polyplexes formation is found to be influenced by the behaviour of the macromolecules in the buffer solution. Transfection experiments are conducted in vitro, His-lPEI bearing 10 to 20% histidine residues allowed remarkable transfection efficiency (up to 95%) compared to unmodified lPEI. Moreremarkably, this new kind of cationic polymers showed very low cytotoxicity on cell lines.

Scorpionates are versatile and flexible ligands with a wide range of applications including catalysis, C-H bond activation, formation of new class of materials, and mimicking enzymatic reactions. This is as a result of its steric and electronic properties, and due to the relative ease with which the 3, and 5-positions of the pyrazole ring can be functionalized. In this work, we report the synthesis of a new class of scorpionate ligands known as cyanoscorpionates which can crosslink various metal centers. Thus, bis (4-cyano-3,5-diphenylpyrazolyl)borate BpPh2,4CN was synthesized and fully characterized by 1H NMR and FT-IR. Coordination of bis (4-cyano-3,5-diphenylpyrazolyl)borate BpPh2,4CN to thallium (I) metal was performed and characterized and we are looking to elucidating its molecular structure by X-ray crystallography in future.

Il a été démontré que l’acidité de l’environnement tumoral jouait un rôle dans la résistance aux chimiothérapies. L’utilisation de nanovecteurs, tels que les nanocapsules lipidiques (LNC), permet non seulement d’améliorer le temps de biodistribution de substances actives, mais aussi de cibler l’environnement tumoral tout en protégeant les actifs de cet environnement acide. L’objectif de cette thèse porte ainsi sur l’optimisation et l’évaluation de LNC furtives et pH-sensibles dans le contexte du mélanome.Dans un premier temps, ces travaux ont consisté à caractériser la vascularisation de mélanomes humain et murin. Ces études ont permis de comparer différentes tumeurs (densité, taille et structure) et de déterminer si l’usage de nanomédecines est approprié dans ce contexte.La seconde partie s’est orientée sur l’élaboration de polymères combinant furtivité et pH-sensibilité. Ces copolymères composés de N-vinylpyrrolidone (NVP)et de vinylimidazole ont été synthétisés par polymérisation RAFT et post-insérés à la surface des LNC. Ces modifications ont donné lieu à des LNC présentant des charges de surface pH-dépendantes,entrainant une augmentation de leur internalisation à pH acide dans des cellules de mélanome. Finalement, des études de biodistribution ont mis en évidence l’intérêt de la NVP dans le développement de nanovecteurs furtifs. En conclusion, les copolymères développés ont permis de prolonger le temps de circulation, mais aussi d’apporter des propriétés pH-sensibles qui pourraient améliorer l’internalisation tumorale des LNC in vivo et donc de potentialiser l’effet d’une thérapie anticancéreuse. / Tumor acidity has been shown to play a major role in resistance to chemotherapy. The use of nanomedicines, as lipid nanocapsules (LNC), allows to protect drugs from this acidic environment. They can also improve the biodistribution of therapeutics and to target the tumor environment. The aim of this thesis concerns the evaluation and characterization of stealth and pH-sensitive LNC in the context of melanoma. Firstly, these works consisted in characterizing the vascularization of human and mice melanoma. These studies allowed to compare different tumors (density, size and structure), and determine if the used of nanocarrier is suitable in the context of melanoma.The second part of this thesis described the development and the characterization of new copolymers, combining stealth and pH-sensitive properties. These copolymers, composed of Nvinylpyrrolidone(NVP) and vinylimidazole, were synthesized by RAFT polymerization and were post in sertedonto LNC surface. These modifications allowed to obtain charge reversal nanocarriers, leading to increase their melanoma cell uptake underacid pH. Finally, biodistribution of these modified nanoparticles was studied in vivo and highlighted the interest of NVP in the development of stealth nanocarriers. To conclude, the developed copolymers able to extend nanocarrier circulation time and to provide pH-responsive properties which should increase the tumor internalization of LNC invivo and potentiate the effect of anticancer drugs.

Since decades, nucleation, or the ability of certain organic or inorganic substances to trigger the crystal growth, has been empirically used in the plastics industry. Talc, for instance, is a well-known nucleating agent of poly(ethylene terephthalate) (PET) and other polymers, that allows one to enhance the crystallisation rate of the polymer material and to control its spherulites size. The exact mechanism involved in this nucleation had however remained unknown at the onset of this thesis. Through electron diffraction, performed on thin PET films nucleated by macroscopic talc particles as model samples, this work demonstrates an epitaxial relationship between polymer and substrate and thus confirms the seemingly ubiquitous role of epitaxy in the nucleation of polymers. However, in order to compare the talc-nucleated morphology of PET with the virgin one, new methods of sample preparation for transmission electron microscopy (TEM) have also been developed. Coupled with theoretically justified image analysis techniques, they allow the direct observation of PET crystalline lamellae, both in the bulk and in thin films. Analyses of the semicrystalline structure in the reciprocal and direct spaces were performed from small-angle X-ray scattering (SAXS) data and from observations by TEM on melt-crystallised samples. These independent results were shown to be in good agreement and bring strong evidence in favour of a semicrystalline space-filling model, where the average crystalline thickness is slightly smaller than the average width of the amorphous regions. Discrepancies between characteristic distances derived by several methods from the same experimental results were attributed to the broad distribution of thicknesses, in contrast with the ideal linear stack model commonly used to analyse the data.

Polycyclic aromatic hydrocarbons (PAHs) are environmentally significant compounds due to the toxicity of some members. They are ubiquitous and are persistent bioaccumulative toxins(PBTs). The toxicity of PAHs represents a risk to human health, and there are varied risk assessment approaches to quantifying the risk posed by PAHs based on exposure routes and scenarios. PAHs are not carcinogenic until they are metabolically activated as the body attempts to break them down and forms reactive metabolites that bind to the DNA causing subsequent replication in the cells. Fundamental to assessing the risk posed by PAHs is understanding the metabolism of PAHs. Since exposure to PAHs is never to single PAHs, understanding what differences may occur in mixtures of PAHs gives accurate assessment of the dangers of PAHs. Understanding the dynamics of complex metabolism vis-a-vis single metabolism of PAHs and possible effects on the toxicity expression of PAHs is a necessary advancement to accurately impact and guide remediation strategies. Studies were carried out comparing the metabolism of the PAHs Phenanthrene (PHE), Flouranthene (FLA) and Benzo[a]pyrene (BAP) in single, binary and ternary mixtures by monitoring the disappearance of the parent compound. It was observed that PAH metabolism in the single PAH experiment differed from metabolism in both binary and ternary mixtures. Enzyme competition was evident in the metabolism of mixtures, changing significantly the metabolism patterns of individual PAHs. PAH structure was also seen to affect metabolism in mixtures and the possible creation of toxicity effects during mixture metabolism. PAH concentration changed over time with faster change during single PAH metabolism followed by ternary mixture metabolism and finally binary metabolism. These results affirm that substrate interactions must be considered in the risk assessment approaches to the dangers posed by exposure to PAHs.