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Myocardial infarction (MI) is a leading cause of death in the United States, claiming the lives of approximately 500,000 people each year. The infarcted heart undergoes a compensatory process called cardiac remodeling, which adversely changes left ventricular (LV) size and function and eventually may lead to heart failure. To date, the only clinical treatments for this condition include surgical restoration of blood flow to the ischemic region (e.g., angioplasty), or pharmacological treatments (e.g., angiotensin converting enzyme inhibitors) which indirectly manage the symptoms of cardiac remodeling. Reperfusion of ischemic heart tissue significantly limits myocardial damage after an MI; however, many MI patients are not candidates for traditional reperfusion surgery. Recently, there has been much interest in non-surgical myocardial reperfusion via pro-angiogenic compounds, specifically vascular endothelial growth factor (VEGF). Although animal studies using therapeutic VEGF have shown promising results, these results have failed to translate into successful clinical trials. This may be due to the short half-life of VEGF in circulation. Increasing the dose of VEGF may increase its availability to the target tissue, but harmful side-effects remain a concert. Encapsulating VEGF and selectively targeting it to the MI border zone may improve vascularization, cardiac function, reduce adverse remodeling associated with MI, and may avoid harmful side effects associated with systemic delivery. Anti-P-selectin conjugated immunoliposomes containing VEGF were developed to target the P-selectin ligand overexpressed in the infarct border zone in a rat MI model. Serial echocardiography and Doppler imaging were used to characterize evolutionary changes in LV geometry and function over a period of four weeks after MI. At four weeks, hearts were excised and stained to measure vascularization and collagen deposition. Targeted VEGF treatment resulted in significant improvements in fractional shortening at four weeks post-infarction (32.9 ± 2.2% for targeted VEGF treated vs. 16.9 ± 1.4% for untreated MI). Functional improvements in treated MI hearts were accompanied by a 74% increase in perfused vessels in the MI border zone, compared to untreated MI hearts. Left ventricular filling dynamics were significantly improved in the targeted VEGF treated group, which resulted in a decrease in LV end diastolic pressure in VEGF treated hearts (23.4 ± 2.9 mm Hg), compared to untreated MIs (81.8 ± 31.8 mm Hg). At four weeks after infarction, hearts treated with targeted VEGF therapy exhibited a 37% reduction in collagen deposition, compared to untreated MI hearts. Targeted VEGF therapy significantly improves vascularization, cardiac function, and moderates adverse cardiac remodeling after an infarction. / Mechanical Engineering

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Various approaches are currently used to treat and manage psoriasis, and biological treatments are often the latest approaches. All biological treatments have major side effects as they are given systemically via injections. One of the latest biological treatments for psoriasis, one which has shown great efficacy with fewer side effects, is Secukinumab. Secukinumab is an anti-IL17 antibody that works by stopping the action of IL17, a cytokine that is known to have a major role in the pathogenesis of psoriasis. This work is based on the development of a new way to commence drug therapy to reduce the side effects of the treatment. Our work is based on the studies of the genotoxicity of the drug Secukinumab in its bulk and liposome form using comet and micronucleus assays on lymphocytes. The results from both assays have illustrated the safety of the drug and demonstrated the reduction of the DNA damage induced in both healthy individuals and patients with psoriasis. Secukinumab significantly decreases-H2O2 induced damage and efficiently attenuates its adverse effects both in the comet (p<0.0001) and micronucleus assays (p<0.01). The two concentrations of Secukinumab used (2.1 and 2.8μg/ml) efficiently decreased H2O2-induced DNA damage in both groups to nearly the level of the negative control. Overall, Secukinumab reveals protective and anti-genotoxic effects by demonstrating its potential in reducing DNA damage caused by oxidative stress and by not inducing any further damage in the lymphocytes of either healthy individuals or patients. Liposomes are highly versatile which have been proven efficient for therapy and research applications. The discovery of new therapies in the treatment of psoriasis is a considerable challenge and is now a necessity. Our study was the first one to determine the genotoxicity of various concentrations of the drug in the lymphocytes of psoriasis patients compared to healthy individuals. In the MTT assay, the data showed a decrease in % cell survival rates after exposure to different concentrations of Secukinumab. Also, the results demonstrated no statistically significant differences on confounding factors such as ethnicity, smoking, drinking habits, gender and age among psoriasis patient and healthy controls. The regulation of gene expression levels of IL-17, IL-22 and RORC were assessed after treatment with Secukinumab in the bulk and liposome form via RT-PCR analysis. Secukinumab bulk (2.1μg/ml) treatment significantly down-regulated gene expression of IL-17, IL22 and RORC to 0.46-fold, 0.47-fold and 0.5-fold, respectively. However, Secukinumab liposome (2.1μg/ml) only decreased the expression of IL-17 and IL-22 significantly, by 0.46-fold and 0.53-fold, respectively. On the other hand, studying the expression of P53 and P21 using qPCR revealed that Secukinumab bulk and liposome has no effect on the expression of these genes in lymphocytes from healthy individuals and psoriasis patients. Western blotting was used to investigate the effect of Secukinumab in both forms on protein expression levels IL-17, IL-22 and RORC. Analysis of the results showed that Secukinumab bulk and liposome had no significant effect on expression levels of any of these proteins in lymphocytes derived from healthy individuals. However, there was a statistically significant down-regulation observed in the protein expression levels of IL-17, IL-22 and RORC in lymphocytes obtained from the psoriasis patients, confirming the sensitivity of the compromised lymphocytes from patient group to Secukinumab treatment. With Secukinumab (bulk form) administration, a 0.5-fold decrease was observed in IL-17, 0.59-fold decrease in IL-22, and a 0.6-fold decrease in RORC expression. However, liposome form reduced their levels to 0.47–fold, 0.5-fold and 0.47–fold, respectively, when compared to the control group. While it had no significant effect on expression of P53 and P21 proteins in lymphocytes from healthy individuals and psoriasis patients and there was no difference observed in their regulation. In conclusion, the use of Secukinumab liposome as topical drug delivery system may be suitable replacement for improving the drug bioavailability and its side effects. / Libyan Cultural Attaché and Libyan embassy

No / Incorporating edge activators (surfactants) into liposomes was shown previously to improve estradiol vesicular skin delivery; this phenomenon was concentration dependent with low or high concentrations being less effective. Replacing surfactants with limonene produced similar behaviour, but oleic acid effects were linear with concentration up to 16% (w/w), beyond which it was incompatible with the phospholipid. This present study thus employed high sensitivity differential scanning calorimetry to probe interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes to explain such results. Cholesterol was included as an example of a membrane stabiliser that removed the DPPC pre-transition and produced vesicles with a higher transition temperature (Tm). Surfactants also removed the lipid pre-transition but reduced Tm and co-operativity of the main peak. At higher concentrations, surfactants also formed new species, possibly mixed micelles with a lower Tm. The formation of mixed micelles may explain reduced skin delivery from liposomes containing high concentrations of surfactants. Limonene did not remove the pre-transition but reduced Tm and co-operativity of the main peak, apparently forming new species at high concentrations, again correlating with vesicular delivery of estradiol. Oleic acid obliterated the pre-transition. The Tm and the co-operativity of the main peak were reduced with oleic acid concentrations up to 33.2 mol%, above which there was no further change. At higher concentrations, phase separation was evident, confirming previous skin transport findings.

Abstract ACCURATE METHODOLOGY FOR MONITORING BIOMEMBRANE EVENTS By Christine A. Winschel, Ph.D. A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctorate of Philosophy in Chemistry at Virginia Commonwealth University. Virginia Commonwealth University, 2012 Major Director: Dr. Vladimir A. Sidorov ASSOCIATE PROFESSOR, DEPARTMENT OF CHEMISTRY This study describes the synthesis and characterization of a new receptor (cyclen 1) capable of strong selective binding of pyrene-based anionic dyes under near-physiological conditions. This receptor comprises four naphthylthiourea groups tethered to a cyclen core via an ester linkage. The most important finding was the ability of cyclen 1 to bind efficiently to a pH-sensitive pyranine dye, a dye that is commonly used in various biomembrane assays. The high affinity of cyclen 1 to pyranine, its impermeability to the lipid bilayer membrane, fast kinetics of binding, and ability to quench pyranine’s fluorescence were used as a basis for a new membrane leakage assay. This membrane leakage assay is fully compatible with the commonly applied pH-stat transport assay, and therefore it allows for differentiation of ion transport and nonselective leakage mechanisms within a single set of experiments. In the second part of this study a new methodology for the detection of lipid flip was developed. This methodology relies on the quenching of the fluorescence of a newly synthesized cascade-blue-labeled lipid through complex formation with cyclen 1. This receptor-dye complexation also has high affinity for binding at micromolar concentrations and can be reversed by either competitive displacement of the lipid probe or by enzymatic degradation of the receptor leading to the label release and fluorescence dequenching. This new methodology is suitable for the study of lipid flip in both model spherical bilayer membranes and in-vitro experiments, and is less invasive to the model and cell membranes than the commonly utilized 7-nitro-1,2,3-benzoxadiazol-4-yl (NBD)-dithionite methodology. Lastly, new pH-sensitive lipids were synthesized and utilized in the formulation of liposomes suitable for controlled drug release. These liposomes contain various amounts of internal NaCl and undergo internal acidification upon the exogenous addition of an HCl co-transporter in a physiologically relevant NaCl solution. Therefore, acidification ultimately leads to the hydrolysis of the pH-sensitive lipids and subsequent contents release. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be non-toxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug release model potentially suitable for in vivo applications.

Les peptides et protéines extracteurs de lipides (PEL) se lient aux membranes lipidiques puis en extraient des lipides en formant de plus petits auto-assemblages, un phénomène qui peut aller jusqu'à la fragmentation des membranes. Dans la nature, cette extraction se produit sur une gamme de cellules et entraîne des conséquences variées, comme la modification de la composition de la membrane et la mort de la cellule. Cette thèse se penche sur l’extraction lipidique, ou fragmentation, induite par le peptide mélittine et la protéine Binder-of-SPerm 1 (BSP1) sur des membranes lipidiques modèles. Pour ce faire, des liposomes de différentes compositions sont préparés et incubés avec la mélittine ou la BSP1. L'association aux membranes est déterminée par la fluorescence intrinsèque des PEL, tandis que l'extraction est caractérisée par une plateforme analytique combinant des tests colorimétriques et des analyses en chromatographie en phase liquide et spectrométrie de masse (LCMS). La mélittine fait partie des peptides antimicrobiens cationiques, un groupe de PEL très répandu chez les organismes vivants. Ces peptides sont intéressants du point du vue médical étant donné leur mode d’action qui vise directement les lipides des membranes. Plusieurs de ceux-ci agissent sur les membranes des bactéries selon le mécanisme dit « en tapis », par lequel ils s’adsorbent à leur surface, forment des pores et ultimement causent leur fragmentation. Dans cette thèse, la mélittine est utilisée comme peptide modèle afin d’étudier le mécanisme par lequel les peptides antimicrobiens cationiques fragmentent les membranes. Les résultats montrent que la fragmentation des membranes de phosphatidylcholines (PC) est réduite par une déméthylation graduelle de leur groupement ammonium. L'analyse du matériel fragmenté révèle que les PC sont préférentiellement extraites des membranes, dû à un enrichissement local en PC autour de la mélittine à l'intérieur de la membrane. De plus, un analogue de la mélittine, dont la majorité des résidus cationiques sont neutralisés, est utilisé pour évaluer le rôle du caractère cationique de la mélittine native. La neutralisation augmente l'affinité du peptide pour les membranes neutres et anioniques, réduit la fragmentation des membranes neutres et augmente la fragmentation des membranes anioniques. Malgré les interactions électrostatiques entre le peptide cationique et les lipides anioniques, aucune spécificité lipidique n'est observée dans l'extraction. La BSP1 est la protéine la plus abondante du liquide séminal bovin et constitue un autre exemple de PEL naturel important. Elle se mélange aux spermatozoïdes lors de l’éjaculation et extrait des lipides de leur membrane, notamment le cholestérol et les phosphatidylcholines. Cette étape cruciale modifie la composition lipidique de la membrane du spermatozoïde, ce qui faciliterait par la suite la fécondation de l’ovule. Cependant, le contact prolongé de la protéine avec les spermatozoïdes endommagerait la semence. Cette thèse cherche donc à approfondir notre compréhension de ce délicat phénomène en étudiant le mécanisme moléculaire par lequel la protéine fragmente les membranes lipidiques. Les résultats des présents travaux permettent de proposer un mécanisme d’extraction lipidique en 3 étapes : 1) L'association à l’interface des membranes; 2) La relocalisation de l’interface vers le cœur lipidique; 3) La fragmentation des membranes. La BSP1 se lie directement à deux PC à l'interface; une quantité suffisante de PC dans les membranes est nécessaire pour permettre l'association et la fragmentation. Cette liaison spécifique ne mène généralement pas à une extraction lipidique sélective. L'impact des insaturations des chaînes lipidiques, de la présence de lysophosphatidylcholines, de phosphatidyléthanolamine, de cholestérol et de lipides anioniques est également évalué. Les présentes observations soulignent la complexe relation entre l'affinité d'un PEL pour une membrane et le niveau de fragmentation qu'il induit. L'importance de la relocalisation des PEL de l'interface vers le cœur hydrophobe des membranes pour permettre leur fragmentation est réitérée. Cette fragmentation semble s'accompagner d'une extraction lipidique préférentielle seulement lorsqu'une séparation de phase est induite au niveau de la membrane, nonobstant les interactions spécifiques PEL-lipide. Les prévalences des structures amphiphiles chez certains PEL, ainsi que de la fragmentation en auto-assemblages discoïdaux sont discutées. Finalement, le rôle des interactions électrostatiques entre les peptides antimicrobiens cationiques et les membranes bactériennes anioniques est nuancé : les résidus chargés diminueraient l'association des peptides aux membranes neutres suite à l'augmentation de leur énergie de solvatation. / Lipid-extracting peptides and proteins (LEPs) bind to lipid membranes, extract lipids in the form of smaller auto-assemblies, and ultimately fragment membranes. In nature, this lipid extraction occurs in many different cell systems and causes various consequences, such as a modification of the membrane lipid composition or the cell death. This thesis focuses on the lipid extraction, or fragmentation, induced by the peptide melittin and the protein Binder-of-SPerm 1 (BSP1) on model lipid membranes. To this end, liposomes of different composition are prepared and incubated with melittin or BSP1. The association to membranes is determined by the LEPs intrinsic fluorescence, while the extraction is characterized by a combination of colorimetric phosphorus assays and liquid chromatography-mass spectrometry analyses (LCMS). Melittin is a cationic antimicrobial peptide, a very common category of LEP found in living organisms. Cationic antimicrobial peptides are interesting to medicine because they directly target membrane lipids. The action of many of these peptides is described by the carpet-like mechanism, by which they adsorb to membrane surface, induce the formation of pores and then cause the fragmentation of the membranes. In this thesis, melittin is used as a model peptide in order to study the mechanism by which cationic antimicrobial peptides fragment lipid membranes. Results show that the phosphocholine (PC) membrane fragmentation is reduced by a gradual demethylation of the ammonium group. Analysis of the fragmented material reveals that PC are preferentially extracted from membranes, due to a local enrichment in PC near melittin in the membrane. Furthermore, a melittin analogue, for which a majority of its cationic residues were neutralized, is used to investigate the role of the cationic character of native melittin. The neutralization increases the peptide affinity for neutral and anionic membranes, reduces fragmentation of neutral membranes and increases fragmentation of anionic membranes. Despite electrostatic interactions between the cationic peptide and the anionic lipids, no lipid specificity is observed in the extraction. BSP1 is the most abundant protein of the bovine seminal plasma and constitutes another example of important LEP found in nature. Upon ejaculation, it mixes with spermatozoa and extracts membrane lipids, such as cholesterol and phosphatidylcholines. This crucial process modulates the lipid composition of sperm membranes, which would then facilitate egg fertilization. However, a prolonged contact between the protein and spermatozoa could damage the semen. This thesis is looking to deepen our understanding of this delicate phenomenon by studying the molecular mechanism by which this protein fragments lipid membranes. Results of the present work suggest a 3-step mechanism for the extraction: 1) Association to membrane interface; 2) Relocation towards the lipid core; 3) Fragmentation of membranes. BSP1 binds directly to two interfacial PC; a sufficient quantity of PC in membranes is necessary for protein association and fragmentation. This specific binding generally does not lead to specificity in the lipid extraction. The impact of unsaturation of the lipid chains, of the presence of lysophosphatidylcholines, of phosphatidylethanolamines, of cholesterol and of anionic lipids is also studied. The present observations underline the complex relationship between a LEP affinity for membranes and the level of fragmentation it induces. The importance of LEP relocation, from the interface to the hydrophobic core of the membranes, for fragmentation is reiterated. This fragmentation seems to be lipid specific only when a phase separation of the lipids occurs in the membrane, notwithstanding specific LEP-lipid interactions. The prevalence of amphipathic structures in certain LEPs, as well as of the auto-assembled discoidal structures resulting from fragmentation is discussed. Finally, the role of electrostatic interactions between cationic antimicrobial peptides and anionic bacterial membranes is detailed: charged residues lower peptide association to neutral membrane due to an increase of their free energy of solvation.

La cucurbitacine E et l'érythrodiol sont des triterpènes naturels oxygénés ayant respectivement un squelette tétra et pentacyclique. Ils sont reconnus pour leurs diverses propriétés biologiques. Dans ce travail de thèse, nous étudions leur interaction avec les membranes des vésicules lipidiques dans le but de mieux comprendre leur pharmacodynamie. Nous avons préparé des liposomes en absence et en présence de la cucurbitacine E et de l'érythrodiol par les techniques d'évaporation en phase inverse suivie d'une extrusion, d'hydratation du film lipidique et d'injection d'éthanol. Les caractéristiques physicochimiques des vésicules lipidiques incorporant ou non la molécule triterpénique ont été étudiées par des techniques adéquates. Les analyses de la cucurbitacine E et de l'érythrodiol par la chromatographie liquide à haute performance ont montré que leurs taux d'incorporation dans les liposomes sont élevés. Les mesures de taille obtenues par la diffusion dynamique de la lumière ont démontré que les liposomes incorporant les triterpènes présentent une taille moyenne inférieure à celle des liposomes témoins. Les images obtenues par la microscopie électronique à transmission ont confirmé la formation de vésicules sphériques. Les mesures des dimensions des vésicules observées par la microscopie à force atomique (AFM), ont révélé que les liposomes incorporant la cucurbitacine E sont plus hauts et résistent mieux à la force exercée par la pointe AFM que les liposomes témoins. Par ailleurs, les liposomes incorporant l'érythrodiol sont plus fragiles que les liposomes témoins et ont tendance à éclater en bicouches lipidiques à la surface du support. Les courbes thermiques obtenues par la calorimétrie différentielle à balayage ont permis de conclure que la cucurbitacine E est localisée à l'interface polaire-apolaire de la membrane liposomiale alors que l'érythrodiol s'insère entre les chaînes acyles des phospholipides et aboutit à la formation des domaines hétérogènes au niveau de la membrane. La cinétique de libération de la sulforhodamine B, mesurée par la spectroscopie de fluorescence, a révélé que la membrane liposomiale devient, en présence de la cucurbitacine E, plus perméable à la sulforhodamine B incorporée dans la phase aqueuse interne. L'ensemble des résultats suggère que la cucurbitacine E et l'érythrodiol interagissent avec la membrane lipidique et affectent ses propriétés physico-chimiques. Leur effet sur la membrane ne semble pas être similaire. Des études ultérieures impliquant d'autres triterpènes sont envisagées pour identifier le (s) motif (s) structural (aux) et les paramètres physico-chimiques régissant leur interaction et localisation membranaire / Cucurbitacin E and erythrodiol are natural oxygenated triterpenes having respectively, a tetra and pentacyclic skeleton. They are known for their numerous biological properties. In this thesis, we studied their interaction with the membranes of lipid vesicles to better understand their pharmacodynamics. We have prepared liposomes in the absence and presence of cucurbitacin E and erythrodiol using the reverse phase evaporation technique followed by extrusion, the hydration of lipid film and the ethanol injection techniques. The physicochemical characteristics of lipid vesicles incorporating or not the triterpenic molecules were investigated by appropriate techniques. The determination of cucurbitacin E and erythrodiol in the vesicles by high performance liquid chromatography showed high incorporation efficiencies of both triterpenes. Size measurements obtained by dynamic light scattering showed that liposomes incorporating triterpenes were smaller than empty liposomes. The images obtained by transmission electron microscopy confirmed the formation of spherical vesicles. Measurements of vesicles dimensions by atomic force microscopy (AFM) demonstrated that liposomes incorporating cucurbitacin E were higher and more resistant to the force exerted by the AFM tip than the blank liposomes. Liposomes incorporating erythrodiol were more fragile and tend to break up into lipid bilayers on the mica surface. Results obtained by differential scanning calorimetry suggested that cucurbitacin E is localized at the polar-apolar interface of the liposomal membrane while erythrodiol is inserted between the acyl chains of the phospholipids leading to the formation of heterogeneous lipid domains. The release kinetics of the sulforhodamin B encapsulated into the aqueous phase and measured by fluorescence spectroscopy revealed that the liposomal membrane becomes in the presence of cucurbitacin E, more permeable to this probe. The overall results suggest that cucurbitacin E and erythrodiol affect differently

La thérapie photodynamique (PDT) est une modalité de traitement des petites tumeurs accessibles à la lumière. Elle repose sur l'action combinée d'un photosensibilisateur qui, en présence d'oxygène et sous l'effet d'une irradiation lumineuse, induit la synthèse d'espèces réactives de l'oxygène cytotoxiques. L'effet tumoricide de la PDT se traduit par des dommages directs sur les cellules ainsi que des dommages indirects de la néovascularisation tumorale et une activation du système immunitaire. Dans cette étude, nous avons démontré dans une première partie l'intérêt de se baser sur la distribution intratumorale de la mTHPC et non pas sur les études de biodistribution pour l'optimisation des conditions de traitement par PDT et en particulier de l'intervalle drogue-lumière (IDL). Un co-ciblage des vaisseaux et du parenchyme tumoral via un fractionnement de l'administration de la mTHPC a permis d'obtenir un taux de guérisons de 100%. Cette efficacité a été corrélée à la potentialisation de la mort des cellules par apoptose et valorisée par son association à des dommages secondaires cutanés restreints. La stratégie de fractionnement de l'administration s'avère donc être très prometteuse dans un contexte clinique. Dans la seconde partie de cette étude, nous avons établi la redistribution de la mTHPC in vivo dans le modèle de la membrane chorioallantoïdienne de poulet (CAM) à partir de formulations liposomales (Foslip®, Fospeg®) et son impact sur les dommages vasculaires photoinduits par la PDT / Photodynamic therapy (PDT) is a therapeutic strategy for the treatment of small localized tumors accessible to the visible light irradiation. It is based on the combined action of photosensitizer (PS), light and molecular oxygen. Tumoricidal effect of PDT is triggered by direct damage of malignant cells and indirect vascular damage followed by an activation of the immune system. The present study investigates the relationship between photoinduced apoptosis in each compartment of interest (vascular versus neoplastic) and mTHPC-PDT treatment efficiency in function of the intratumoral distribution of mTHPC. The latter was defined by the drug-light intervals. In the first part, we demonstrated the importance of the intratumoral distribution of mTHPC to optimize photodynamic parameters. The fractionation of the PS administration permitted to obtain a tumor cure rate of 100% correlated to a massive apoptosis of pathological tissues. Moreover, this treatment strategy induced only limited skin damages and few inflammation which could be an advantage in clinical context. In the second part, we evidenced the mTHPC redistribution from liposomal formulations (Foslip®, Fospeg®) in vivo in the chick chorioallantoic membrane model (CAM) and its influence on photoinduced vascular damage

Les triterpènes sont un groupe important et structurellement diversifié de produits naturels issus du squalène. Les progestatifs et les glucocorticoïdes sont des triterpènes oxygénés ayant un squelette tétracyclique et reconnus pour leurs diverses propriétés thérapeutiques. Par ailleurs, l'érythrodiol et l'uvaol sont des triterpènes pentacycliques reconnus pour leurs effets bénéfiques dans l'alimentation humaine. Dans ce travail, l'interaction avec les membranes des vésicules lipidiques et la liaison à la sérum albumine humaine de ces molécules sont étudiées dans le but de mieux comprendre leurs propriétés pharmacologiques. Les vésicules lipidiques ont été caractérisées par DSC, spectroscopie Raman, FTIR et polarisation de fluorescence du DPH pour comprendre l'effet des molécules sélectionnées sur la fluidité membranaire.Également, nous avons étudié la liaison du cholestérol, d'une série de progestatifs et de glucocorticoïdes à l'albumine humaine par la spectroscopie de fluorescence.Les résultats ont démontré que les progestatifs, les glucocorticoïdes, l'érythrodiol et l'uvaol altèrent les propriétés physiques de la bicouche lipidique.Les progestatifs et les glucocorticoïdes démontrent un attachement modéré à l'albumine. Par ailleurs, la dydrogestérone présente la constante de liaison la plus importante. Enfin, notre étude a démontré que la constante de liaison du cholestérol à l'albumine est faible en comparaison avec les autres molécules étudiées. Notre étude a conduit à une connaissance approfondie des mécanismes moléculaires et des caractéristiques structurales impliqués dans l'interaction des triterpènes avec les protéines et les membranes synthétiques / The triterpenoids are a large and structurally diverse group of natural products derived from squalene. Progesterone derivatives and glucocorticoids are a group of oxygenated triterpenes having a tetracyclic skeleton and identified for their therapeutic properties. Whereas, erythrodiol and uvaol are pentacyclic triterpenes, known for their beneficial effects on human diet. In this thesis, we studied their interaction with the membranes of lipid vesicles and with human serum albumin to better understand their pharmacological properties. DSC, Raman spectroscopy, FTIR and fluorescence polarization of DPH were used to investigate the effect of triterpenes on the membrane fluidity. Besides, we used fluorescence spectroscopy to study the binding of cholesterol, a series of progesterone derivatives and another series of glucocorticoids to albumin. The results revealed that progesterone derivatives, glucocorticoids, erythrodiol and uvaol changed the physical properties of the bilayers. Progesterone derivatives and glucocorticoids have been proven to bind moderately to albumin. Dydrogesterone showed the highest binding constant. Finally, our study demonstrated that cholesterol exhibited a much weaker interaction with albumin compared to progesterone derivatives and glucocorticoids.Our work has led to a better understanding of triterpenes molecular mechanisms of their interaction with proteins and biological membranes and structural features controlling these interactions