Polymer surface modification by atomic layer deposition

Current industrial atomic layer deposition (ALD) processes are almost wholly confined to glass or silicon substrates. For many industrial applications, deposition on polymer substrates will be necessary. Current deposition processes are also typically carried out at temperatures which are too high for polymers. If deposition temperatures in ALD can be reduced to the level applicable for polymers, it will open new interesting areas and applications for polymeric materials. The properties of polymers can be improved for example by coatings with functional and protective properties. Although the ALD has shown its capability to operate at low temperatures suitable for polymer substrates, there are other issues related to process efficiency and characteristics of different polymers where new knowledge will assist in developing industrially conceivable ALD processes. Lower deposition temperature in ALD generally means longer process times to facilitate the self limiting film growth mode characteristic to ALD. To improve process efficiency more reactive precursors are introduced into the process. For example in ALD oxide processes these can be more reactive oxidizers, such as ozone and oxygen radicals, to substitute the more conventionally used water. Although replacing water in the low temperature ALD with ozone or plasma generated oxygen radicals will enable the process times to be shortened, they may have unwanted effects both on the film growth and structure, and in some cases can form detrimental process conditions for the polymer substrate. Plasma assistance is a very promising approach to improve the process efficiency. The actual design and placement of the plasma source will have an effect on film growth characteristics and film structure that may retard the process efficiency development. Due to the fact that the lifetime of the radicals is limited, it requires the placement of the plasma source near to the film growth region. Conversely this subjects the substrate to exposure byother plasma species and electromagnetic radiation which sets requirements for plasma conditions optimization. In this thesis ALD has been used to modify, activate and functionalize the polymer surfaces for further improvement of polymer performance subject to application. The issues in ALD on polymers, both in thermal and plasma-assisted ALD will be further discussed.

Seeder-fertilizer machine: energetic demand as a function of vegetal covering handling and manure deposition shank depth in no-tillage system

The purpose of this work was evaluating the energetic demand of a seeder-fertilizer machine as a function of the type and handling of vegetal covering culture and of the fertilizer deposition shank depth. A Valtra BM100 tractor was used implemented to pull a high precision seeder-fertilizer machine with four ranks of seeding, spaced 0.9 m for maize culture. Experiment was conducted with design in randomized blocks in factorial plots, in the Laboratory of Machines and Agricultural Mechanization experimental area (LAMMA) of UNESP-Jaboticabal, using two covering cultures (black-mucuna and crotalaria), three handlings of this covering, two mechanical (straw crusher and roller knife) and one chemical (pulverization of herbicide), performed 120 days after seeding of covering cultures and three depths of fertilizer deposition shank, completing 18 treatments, with four repetitions, totaling 72 observations. Parameters of displacement speed, gliding, force on traction bar, peak force, power on pulling bar and fuel consumption were evaluated. It was possible to conclude that force on traction bar was less for depths of 0.11 and 0.14 m of fertilizer plough shank, the same occurring for peak force, power on traction bar and volumetric consumption. The specific consumption was lower at a depth of 0.17 m of fertilizer plough shank. Covering cultures and their handlings did not interfere in the performance of machines under inquiry.

Synthesis, characterization and chemical sensor application of conducting polymers

Polymeric materials that conduct electricity are highly interesting for fundamental studies and beneficial for modern applications in e.g. solar cells, organic field effect transistors (OFETs) as well as in chemical and bio‐sensing. Therefore, it is important to characterize this class of materials with a wide variety of methods. This work summarizes the use of electrochemistry also in combination with spectroscopic methods in synthesis and characterization of electrically conducting polymers and other π‐conjugated systems. The materials studied in this work are intended for organic electronic devices and chemical sensors. Additionally, an important part of the presented work, concerns rational approaches to the development of water‐based inks containing conducting particles. Electrochemical synthesis and electroactivity of conducting polymers can be greatly enhanced in room temperature ionic liquids (RTILs) in comparison to conventional electrolytes. Therefore, poly(para‐phyenylene) (PPP) was electrochemically synthesized in the two representative RTILs: bmimPF6 and bmiTf2N (imidazolium and pyrrolidinium‐based salts, respectively). It was found that the electrochemical synthesis of PPP was significantly enhanced in bmimPF6. Additionally, the results from doping studies of PPP films indicate improved electroactivity in bmimPF6 during oxidation (p‐doping) and in bmiTf2N in the case of reduction (n‐doping). These findings were supported by in situ infrared spectroscopy studies. Conducting poly(benzimidazobenzophenanthroline) (BBL) is a material which can provide relatively high field‐effect mobility of charge carriers in OFET devices. The main disadvantage of this n‐type semiconductor is its limited processability. Therefore in this work BBL was functionalized with poly(ethylene oxide) PEO, varying the length of side chains enabling water dispersions of the studied polymer. It was found that functionalization did not distract the electrochemical activity of the BBL backbone while the processability was improved significantly in comparison to conventional BBL. Another objective was to study highly processable poly(3,4‐ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) water‐based inks for controlled patterning scaled‐down to nearly a nanodomain with the intention to fabricate various chemical sensors. Developed PEDOT:PSS inks greatly improved printing of nanoarrays and with further modification with quaternary ammonium cations enabled fabrication of PEDOT:PSS‐based chemical sensors for lead (II) ions with enhanced adhesion and stability in aqueous environments. This opens new possibilities for development of PEDOT:PSS films that can be used in bio‐related applications. Polycyclic aromatic hydrocarbons (PAHs) are a broad group of π‐conjugated materials consisting of aromatic rings in the range from naphthalene to even hundred rings in one molecule. The research on this type of materials is intriguing, due to their interesting optical properties and resemblance of graphene. The objective was to use electrochemical synthesis to yield relatively large PAHs and fabricate electroactive films that could be used as template material in chemical sensors. Spectroscopic, electrochemical and electrical investigations evidence formation of highly stable films with fast redox response, consisting of molecules with 40 to 60 carbon atoms. Additionally, this approach in synthesis, starting from relatively small PAH molecules was successfully used in chemical sensor for lead (II).

Influence of wheat straw and rhizosphere on seed germination, early seedling growth and bio-chemical attributes of Trianthema portulacastrum

Decomposing wheat (Triticum aestivum) straw and rhizosphere-infested soil were evaluated for their suppressive activity against horse purslane (Trianthema portulacastrum), a noxious summer weed in Pakistan. Two separate pot studies were carried out. Wheat straw was incorporated at 4, 6 and 8 g kg-1 soil five days before the sowing of horse purslane. Pots without straw incorporation were maintained as control. In a second study, soil was taken from 15 and 30 cm depths from a previously cropped wheat field immediately after its harvest and was used as growing medium. Soil from an intentionally uncropped area of the same field was used as control. Suppressive activity was measured in terms of germination dynamics, seedling growth, and biochemical attributes such as chlorophyll contents, total soluble phenolics, soluble protein and antioxidant enzymes. Germination, seedling growth, chlorophyll contents and soluble protein of horse purslane were all negatively influenced. Higher phenolics and enhanced activities of antioxidant enzymes were noticed in response to wheat residues incorporation and its rhizosphere soil. Both studies established that the phytotoxic influence of wheat straw and wheat-infested rhizosphere soil on horse purslane can further be exploited for horse purslane management as a sustainable approach.

Connexin domains relevant to the chemical gating of gap junction channels

Most cells exchange ions and small metabolites via gap junction channels. These channels are made of two hemichannels (connexons), each formed by the radial arrangement of six connexin (Cx) proteins. Connexins span the bilayer four times (M1-M4) and have both amino- and carboxy-termini (NT, CT) at the cytoplasmic side of the membrane, forming two extracellular loops (E1, E2) and one inner (IL) loop. The channels are regulated by gates that close with cytosolic acidification (e.g., CO2 treatment) or increased calcium concentration, possibly via calmodulin activation. Although gap junction regulation is still unclear, connexin domains involved in gating are being defined. We have recently focused on the CO2 gating sensitivity of Cx32, Cx38 and various mutants and chimeras expressed in Xenopus oocytes and studied by double voltage clamp. Cx32 is weakly sensitive to CO2, whereas Cx38 is highly sensitive. A Cx32 chimera containing the second half of the inner loop (IL2) of Cx38 was as sensitive to CO2 as Cx38, indicating that this domain plays an important role. Deletion of CT by 84% did not affect CO2 sensitivity, but replacement of 5 arginines (R) with sparagines (N) at the beginning of CT (C1) greatly enhanced the CO2 sensitivity of Cx32. This suggests that whereas most of CT is irrelevant, positive charges of C1 maintain the CO2 sensitivity of Cx32 low. As a hypothesis we have proposed a model that involves charge interaction between negative residues of the beginning of IL1 and positive residues of either C1 or IL2. Open and closed channels would result from IL1-C1 and IL1-IL2 interactions, respectively

Isolation of bovine plasma albumin by liquid chromatography and its polymerization for use in immunohematology

The aim of the method described here is to remove hemoglobin, the major contaminant in the bovine plasma obtained from slaughterhouses, by adding a mixture of 19% cold ethanol and 0.6% chloroform, followed by fibrinogen and globulin precipitation by the Cohn method and nonspecific hemagglutinin by thermocoagulation. The experimental volume of bovine plasma was 2,000 ml per batch. Final purification was performed by liquid chromatography using the ion-exchange gel DEAE-Sepharose FF. The bovine albumin thus obtained presented > or = 99% purity, a yield of 25.0 ± 1.2 g/l plasma and >71.5% recovery. N-acetyl-DL-tryptophan (0.04 mmol/g protein) and sodium caprylate (0.04 mmol/g protein) were used as stabilizers and the final concentration of albumin was adjusted to 22.0% (w/v), pH 7.2 to 7.3. Viral inactivation was performed by pasteurization for 10 h at 60°C. The bovine albumin for the hemagglutination tests used in immunohematology was submitted to chemical treatment with 0.06% (w/v) glutaraldehyde and 0.1% (w/v) formaldehyde at 37°C for 12 h to obtain polymerization. A change in molecular distribution was observed after this treatment, with average contents of 56.0% monomers, 23.6% dimers, 12.2% trimers and 8.2% polymers. The tests performed demonstrated that this polymerized albumin enhances the agglutination of Rho(D)-positive red cells by anti-Rho(D) serum, permitting and improving visualization of the results.

Enhanced expression of Ang-(1-7) during pregnancy

Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.

The action of red wine and purple grape juice on vascular reactivity is independent of plasma lipids in hypercholesterolemic patients

Although red wine (RW) reduces cardiovascular risk, the mechanisms underlying the effect have not been identified. Correction of endothelial dysfunction by RW flavonoids could be one mechanism. We measured brachial artery reactivity by high-resolution ultrasonography, plasma lipids, glucose, adhesion molecules (ICAM-1 and VCAM), and platelet function in 16 hypercholesterolemic individuals (8 men and 8 women; mean age 51.6 ± 8.1 years) without other risk factors. Twenty-four normal subjects were used as controls for vascular reactivity. Subjects randomly received RW, 250 ml/day, or purple grape juice (GJ), 500 ml/day, for 14 days with an equal wash-out period. At baseline, all 16 subjects were hypercholesterolemic (mean LDL = 181.0 ± 28.7 mg/dl) but HDL, triglycerides, glucose, adhesion molecules, and platelet function were within normal limits. Brachial artery flow-mediated dilation was significantly decreased compared to controls (9.0 ± 7.1 vs 12.1 ± 4.5%; P < 0.05) and increased with both GJ (10.1 ± 7.1 before vs 16.9 ± 6.7% after: P < 0.05) and RW (10.1 ± 6.4 before vs 15.6 ± 4.6% after; P < 0.05). RW, but not GJ, also significantly increased endothelium-independent vasodilation (17.0 ± 8.6 before vs 23.0 ± 12.0% after; P < 0.01). GJ reduced ICAM-1 but not VCAM and RW had no effect on either molecule. No significant alterations were observed in plasma lipids, glucose or platelet aggregability with RW or GJ. Both RW and GJ similarly improved flow-mediated dilation, but RW also enhanced endothelium-independent vasodilation in hypercholesterolemic patients despite the increased plasma cholesterol. Thus, we conclude that GJ may protect against coronary artery disease without the additional negative effects of alcohol despite the gender.

Estrous cycle and stress: influence of progesterone on the female brain

The female brain operates in a constantly changing chemical milieu caused by cyclical changes in gonadal hormones during the estrous cycle (menstrual cycle in women). Such hormones are highly lipophilic and pass readily from the plasma to the brain where they can influence neuronal function. It is becoming clear that the rapid reduction in peripheral circulating progesterone, which occurs during the late diestrous phase of the cycle, can trigger a withdrawal-like response, in which changes in GABA A receptor expression render hyper-responsive certain brain areas involved in processing responses to stressful stimuli. The periaqueductal gray matter (PAG) is recognised as an important region for integrating anxiety/defence responses. Withdrawal from progesterone, via actions of its neuroactive metabolite allopregnanolone, triggers up-regulation of extrasynaptic GABA A receptors on GABAergic neurons in the PAG. As a consequence, ongoing GABAergic tone on the output cells decreases, leading to an increase in functional excitability of the circuitry and enhanced responsiveness to stressful stimuli during the late diestrous phase. These changes during late diestrus could be prevented by short-term neurosteroid administration, timed to produce a more gradual fall in the peripheral concentration of allopregnanolone than the rapid decrease that occurs naturally, thus removing the trigger for the central withdrawal response.

Chemical and biochemical characterization of soybean produced under drought stress

Brazil is the second soybean (Glycine max L. Merrill) producer and exporter in the world. In 2005, soybean cultivated in the southeastern region of the country suffered drought stress imposed by adverse high temperatures and low humidity during its reproductive stage. Little information is available regarding the effect of drought stress on the quality of grains. In this study chemical and biochemical characteristics of five soybean samples belonging to three different cultivars grown under drought stress were evaluated. The samples did not meet standards for marketing and contained high amounts of green seeds. Grains were analyzed for appearance, 100 seed weight, humidity, water activity, proteins, lipids, lipoxygenase 1 activity, peroxides, and pigment contents after harvest and after 20 months of storage at room temperature. Acidity was measured also after 30 months of storage. The values of water activity and humidity were 0.6-0.7 and 8.7-11.9%, respectively, and they did not change during storage time, but there was an increase in acidity, which alludes to lipase activity. The activity of lipoxygenase 1 was greatly affected. Immediately after harvest, the green pigments were represented mainly by pheophytin a, followed by pheophytin b, small quantities of chlorophyll b and chlorophyll a, and traces of other chlorophyll derivatives. After 20 months of storage almost all green pigments had disappeared. Drought stress probably enhanced membrane permeability, which led to a lower pH and promoted transformation of chlorophylls to pheophytins.

Chemical composition and radical scavenging activity of melanin from Auricularia auricula fruiting bodies

Melanin extracted from Auricularia auricula fruiting bodies (AAFB) was examined by element analyzer, amino acid analyzer, inductively coupled plasma-optical emission spectrometry. Elemental composition analysis revealed that main component of AAFB melanin was pheomelanin. Amino acid analysis showed that 16 amino acids were found in AAFB melanin and total amino acid content was 321. 63 mg/g. There were 13 detectable metal elements in AAFB melanin, which was rich in Ca, Fe, Cu and Zn. In addition, AAFB melanin exhibited stronger scavenging activities on 2,2-diphenyl-l-picrylhydrazyl (DPPH) radical, superoxide radical and hydroxyl radical with IC50 values of 0.18, 0.59 and 0.34 mg/mL, respectively. These results indicated that AAFB melanin might be potentially used as a natural antioxidant.

Targeting oncogenic signaling proteins : new insights using a FRET-based chemical biology approach

Cancer affects more than 20 million people each year and this rate is increasing globally. The Ras/MAPK-pathway is one of the best-studied cancer signaling pathways. Ras proteins are mutated in almost 20% of all human cancers and despite numerous efforts, no effective therapy that specifically targets Ras is available to date. It is now well established that Ras proteins laterally segregate on the plasma membrane into transient nanoscale signaling complexes called nanoclusters. These Ras nanoclusters are essential for the high-fidelity signal transmission. Disruption of nanoclustering leads to reduction in Ras activity and signaling, therefore targeting nanoclusters opens up important new therapeutic possibilities in cancer. This work describes three different studies exploring the idea of membrane protein nanoclusters as novel anti-cancer drug targets. It is focused on the design and implementation of a simple, cell-based Förster Resonance Energy Transfer (FRET)-biosensor screening platform to identify compounds that affect Ras membrane organization and nanoclustering. Chemical libraries from different sources were tested and a number of potential hit molecules were validated on full-length oncogenic proteins using a combination of imaging, biochemical and transformation assays. In the first study, a small chemical library was screened using H-ras derived FRET-biosensors. Surprisingly from this screen, commonly used protein synthesis inhibitors (PSIs) were found to specifically increase H-ras nanoclustering and downstream signalling in a H-ras dependent manner. Using a representative PSI, increase in H-ras activity was shown to induce cancer stem cell (CSC)-enriched mammosphere formation and tumor growth of breast cancer cells. Moreover, PSIs do not increase K-ras nanoclustering, making this screening approach suitable for identifying Ras isoform-specific inhibitors. In the second study, a nanoncluster-directed screen using both H- and K-ras derived FRET biosensors identified CSC inhibitor salinomycin to specifically inhibit K-ras nanocluster organization and downstream signaling. A K-ras nanoclusteringassociated gene signature was established that predicts the drug sensitivity of cancer cells to CSC inhibitors. Interestingly, almost 8% of patient tumor samples in the The Cancer Genome Atlas (TCGA) database had the above gene signature and were associated with a significantly higher mortality. From this mechanistic insight, an additional microbial metabolite screen on H- and K-ras biosensors identified ophiobolin A and conglobatin A to specifically affect K-ras nanoclustering and to act as potential breast CSC inhibitors. In the third study, the Ras FRET-biosensor principle was used to investigate membrane anchorage and nanoclustering of myristoylated proteins such as heterotrimeric G-proteins, Yes- and Src-kinases. Furthermore, Yes-biosensor was validated to be a suitable platform for performing chemical and genetic screens to identify myristoylation inhibitors. The results of this thesis demonstrate the potential of the Ras-derived FRETbiosensor platform to differentiate and identify Ras-isoform specfic inhibitors. The results also highlight that most of the inhibitors identified predominantly perturb Ras subcellular distribution and membrane organization through some novel and yet unknown mechanisms. The results give new insights into the role of Ras nanoclusters as promising new molecular targets in cancer and in stem cells.

Droplet Deposition in the Last Stage of Steam Turbine

During the expansion of steam in turbine, the steam crosses the saturation line and hence subsequent turbine stages run under wet condition. The stages under wet condition run with low efficiency as compared to stages running with supersaturated steam and the life of the last stage cascade is reduced due to erosion. After the steam crosses the saturation line it does not condense immediately but instead it becomes supersaturated which is a meta-stable state and reversion of equilibrium results in the formation of large number of small droplets in the range of 0.05 - 1 μm. Although these droplets are small enough to follow the stream lines of vapor however some of the fog droplets are deposited on the blade surface. After deposition they coagulate into films and rivulets which are then drawn towards the trailing edge of the blade due to viscous drag of the steam. These large droplets in the range of radius 100 μm are accelerated by steam until they impact on the next blade row causing erosion. The two phenomenon responsible for deposition are inertial impaction and turbulent-diffusion. This work shall discuss the deposition mechanism in steam turbine in detail and numerically model and validate with practical data.

Élaboration d’un simulateur de gravure par plasma de haute densité basé sur une approche cellulaire pour l’étude de profils dans divers matériaux

La réalisation de dispositifs à des dimensions sous-micrométriques et nanométriques demande une maîtrise parfaite des procédés de fabrication, notamment ceux de gravure. La réalisation des ces dispositifs est complexe et les exigences en termes de qualité et de géométrie des profils de gravure imposent de choisir les conditions opératoires les mieux adaptées. Les simulations de l'évolution spatio-temporelle des profils de gravure que nous proposons dans cette thèse s'inscrivent parfaitement dans ce contexte. Le simulateur que nous avons réalisé offre la possibilité de mieux comprendre les processus qui entrent en jeu lors de la gravure par plasma de profils dans divers matériaux. Il permet de tester l'influence des paramètres du plasma sur la forme du profil et donc de déterminer les conditions opératoires optimales. La mise au point de ce simulateur s'appuie sur les concepts fondamentaux qui gouvernent la gravure par plasma. À partir de l'état des lieux des différentes approches numériques pouvant être utilisées, nous avons élaboré un algorithme stable et adaptable permettant de mettre en évidence l'importance de certains paramètres clés pour la réalisation de profils de gravure par un plasma à haute densité et à basse pression. Les capacités de cet algorithme ont été testées en étudiant d'une part la pulvérisation de Si dans un plasma d'argon et d'autre part, la gravure chimique assistée par les ions de SiO2/Si dans un plasma de chlore. Grâce aux comparaisons entre profils simulés et expérimentaux, nous avons montré l'importance du choix de certains paramètres, comme la nature du gaz utilisé et la pression du plasma, la forme initiale du masque, la sélectivité masque/matériau, le rapport de flux neutre/ion, etc. Nous avons aussi lié ces paramètres à la formation de défauts dans les profils, par exemple celle de facettes sur le masque, de parois concaves, et de micro-tranchées. Enfin, nous avons montré que le phénomène de redépôt des atomes pulvérisés entre en compétition avec la charge électrique de surface pour expliquer la formation de profils en V dans le Pt pulvérisé par un plasma d'argon.

Mise au point de nanoparticules polymères pour l'administration parentérale d'agents anticancéreux hydrophobes

Plusieurs agents anticancéreux très puissants sont caractérisés par une solubilité aqueuse limitée et une toxicité systémique importante. Cette dernière serait liée d’une part à la solubilisation des agents anticancéreux à l’aide de surfactifs de bas poids moléculaire, connus pour leur toxicité intrinsèque, et d’autre part, par le manque de spécificité tissulaire des anticancéreux. Les vecteurs colloïdaux à base de polymères permettraient de résoudre certains défis liés à la formulation d’agents anticancéreux hydrophobes. D’abord, les polymères peuvent être sélectionnés afin de répondre à des critères précis de compatibilité, de dégradation et d’affinité pour le médicament à formuler. Ensuite, le fait d’encapsuler l’agent anticancéreux dans un vecteur peut améliorer son efficacité thérapeutique en favorisant son accumulation au niveau du tissu cible, i.e. la tumeur, et ainsi limiter sa distribution au niveau des tissus sains. Des travaux antérieurs menés au sein de notre laboratoire ont mené à la mise au point de micelles à base de poly(N-vinyl-pyrrolidone)-bloc-poly(D,L-lactide) (PVP-b-PDLLA) capables de solubiliser des agents anticancéreux faiblement hydrosolubles dont le PTX. Ce dernier est commercialisé sous le nom de Taxol® et formulé à l’aide du Crémophor EL (CrEL), un surfactif de bas poids moléculaire pouvant provoquer, entre autres, des réactions d’hypersensibilité sévères. Bien que les micelles de PVP-b-PDLLA chargées de PTX aient démontré une meilleure tolérance comparée au Taxol®, leur potentiel de ciblage tumoral et leur efficacité thérapeutique étaient similaires à la forme commerciale à doses égales. Ceci était possiblement dû au fait que les micelles étaient rapidement déstabilisées et ne pouvaient retenir leur cargo suite à leur administration intraveineuse. Nous avons donc décidé de poursuivre les travaux avec un autre type de vecteur, soit des nanoparticules, qui possèdent une stabilité intrinsèque supérieure aux micelles. L’objectif principal de cette thèse de doctorat était donc de mettre au point des nanoparticules polymères pour l’administration parentérale d’agents anticancéreux faiblement solubles dans l’eau. Les nanoparticules devaient permettre d’encapsuler des agents anticancéreux hydrophobes et de les libérer de manière contrôlée sur plusieurs jours. De plus, elles devaient démontrer un temps de circulation plasmatique prolongée afin de favoriser l’accumulation passive du médicament encapsulé au niveau de la tumeur. La première partie du travail visait à employer pour la première fois le copolymère amphiphile PVP-b-PDLLA comme émulsifiant dans la préparation de nanoparticules polymères. Ainsi, une méthode de fabrication des nanoparticules par émulsion huile-dans-eau a été appliquée afin de produire des nanoparticules à base de PDLLA de taille inférieure à 250 nm. Grâce aux propriétés lyoprotectrices de la couronne de PVP présente à la surface des nanoparticules, celles-ci pouvaient retrouver leur distribution de taille initiale après lyophilisation et redispersion en milieu aqueux. Deux anticancéreux hydrophobes, soit le PTX et l’étoposide (ETO), ont été encapsulés dans les nanoparticules et libérés de ces dernières de façon contrôlée sur plusieurs jours in vitro. Une procédure de « salting-out » a été appliquée afin d’améliorer le taux d’incorporation de l’ETO initialement faible étant donnée sa solubilité aqueuse légèrement supérieure à celle du PTX. Le second volet des travaux visait à comparer le PVP comme polymère de surface des nanoparticules au PEG, le polymère le plus fréquemment employé à cette fin en vectorisation. Par le biais d’études d’adsorption de protéines, de capture par les macrophages et de biodistribution chez le rat, nous avons établi une corrélation in vitro/in vivo démontrant que le PVP n’était pas un agent de surface aussi efficace que le PEG. Ainsi, malgré la présence du PVP à la surface des nanoparticules de PDLLA, ces dernières étaient rapidement éliminées de la circulation sanguine suite à leur capture par le système des phagocytes mononucléés. Par conséquent, dans le troisième volet de cette thèse, le PEG a été retenu comme agent de surface, tandis que différents polymères biodégradables de la famille des polyesters, certains synthétiques (PDLLA et copolymères d’acide lactique/acide glycolique), d’autres de source naturelle (poly(hydroxyalkanoates)(PHAs)), ont été investiguées comme matériaux formant le cœur des nanoparticules. Il en est ressorti que les propriétés physicochimiques des polyesters avaient un impact majeur sur l’efficacité d’encapsulation du PTX et son profil de libération des nanoparticules in vitro. Contrairement aux PHAs, les polymères synthétiques ont démontré des taux d’incorporation élevés ainsi qu’une libération contrôlée de leur cargo. Des études de pharmacocinétique et de biodistribution ont démontré que les nanoparticules de PDLLA dotées d’une couronne de PEG conféraient un temps de circulation plasmatique prolongé au PTX et favorisaient son accumulation tumorale. Les nanoparticules polymères représentent donc une alternative intéressante au Taxol®.