The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively.

Made available in DSpace on 2014-06-12T18:06:06Z (GMT). No. of bitstreams: 2 arquivo7710_1.pdf: 1970770 bytes, checksum: 32db2284b5821407a424ede60f9fb4af (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2007 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O termo reptação está associado ao tipo de movimento executado por répteis, especificamente as serpentes, sendo empregado para descrever a difusão de objetos com a topologia da linha. A reptação de um fio injetado numa cavidade é estudada através de medidas do deslocamento quadrático médio <r2> de um ponto do fio, em função do comprimento h injetado. A espessura do fio é z = 0,1 cm e, o ponto escolhido corresponde ao centro de massa em uma dimensão (CM1D), também denominado por ponto central topológico. A cavidade é circular com raio R = 10 cm e de espessura pouco maior que z, de forma a permitir a existência de apenas uma camada de fio na cavidade. O fio é injetado manualmente à velocidade uniforme, por dois canais dispostos em ângulo de 180°. Foram realizados experimentos com fios de cobre, Sn0,6Pb0,4 (solda elétrica), alumínio, latão, náilon e aço duro. As medidas mostram que <r2> (exceto para fios de náilon e aço duro) passa por um regime transiente no terço inicial do experimento, e por regime quase-estável no tempo restante, por conta do confinamento do CM1D. Inspirando-se no modelo de Flory para polímeros, desenvolvemos um modelo de campo médio onde o ponto central é descrito por uma partícula sujeita a dois potenciais que simulam interações de auto-exclusão, a influência da fronteira e as flutuações devido às propriedades mecânicas do fio e ao ruído inerente ao processo de empacotamento. A lei de escala r~h1/5 prevista pelo modelo, é avaliada com base nos resultados experimentais. Por fim, os resultados obtidos para o fio de solda indicam um comportamento intermediário entre as dinâmicas de reptação de Rouse e de de Gennes

So-called, “Dynamic biomaterials” comprised of stimuli-responsive hydrogels are useful in a wide variety of biomedical applications including tissue engineering, drug delivery, and biomedical implants. More than 150,000 peer-reviewed articles (as of 2016) have been published on these materials, and more specifically, over 100,000 of these are on the most widely studied, poly(N-isopropylacrylamide). This thermoresponsive polymer in a crosslinked hydrogel network undergoes a large volume phase transition (𝑉/𝑉0 ~ 10 − 100) within a small temperature range (𝑇 ~ 1 − 3𝐾) making it particularly useful for tissue engineering applications because of the ability to control the topographical configuration of cells into tissue modules which can be applied in multiple layers to form three dimensional constructs. Nevertheless, applications with poly(N-isopropylacrylamide) hydrogels are hindered by two key obstacles: 1. there is presently no quantitative prediction of mechanical properties over the volume phase transition and 2. the mechanisms of cell attachment and detachment remain controversial and unclear. Current polymer-solution theory, first postulated by Paul Flory and Maurice Huggins in 1942, successfully predicts hydrogel swelling for non-stimuli-responsive polymers based on an empirically derived interaction parameter. However, for stimuli-responsive polymer hydrogels, this theoretical framework fails to quantitatively predict swelling and mechanical properties of the polymer. Currently, only qualitative agreement with experiment has been shown. Cell-cell and cell-matrix interactions are mediated through proteins collectively known as cell adhesion molecules. For cell-matrix interactions, these are generally the transmembrane protein, integrin, and the serum protein, fibronectin. It is widely accepted that nearly all molecular mechanisms of cell-matrix interactions are dependent on recognition of the peptide sequence Arg-Gly-Asp. However, much less is known about mechanical mechanisms involved in cell-cell and cell-matrix interactions. Obstacles to the advancement of these applications are 1) unclear mechanisms of cell release and 2) extended exposure of cells to hypothermic conditions. The author, in collaboration with others, has published work demonstrating reduced cell exposure to hypothermic conditions during tissue module release and elucidated a mechanism of tissue module release: mechanical strain. The central hypothesis of work in this proposal is that tissue module release occurs due to a mechanical strain-rate coinciding with critical force needed overcome the dynamic bond strength of cell adhesion molecules. Advances in this area could improve biomaterial design and accelerate the field of regenerative medicine by reducing or eliminating the need for allograft transplants. This dissertation project, then, seeks to address these two obstacles through biophysical characterization methods and analysis including: atomic force microscopy, scanning electron microscopy, laser-scanning confocal micrscopy, phase-contrast microscopy, and mass-balance analysis. It is hypothesized that, (1) mechanical properties of PNIPAAm hydrogels are quantitatively predicted based on crosslinker ratio in the water-rich phase, (2) release of cells from micropatterned PNIPAAm hydrogels occurs when the lateral strain in the surface exceeds ϵ > 0.25, and (3) the molecular mechanism of rapid cell release from micro-patterned PNIPAAm hydrogels is mediated by the transmembrance protein integrin and its extracellular matrix receptor, fibronectin. Results from these studies could be useful for improving the design of biomaterials based on PNIPAAm hydrogels for applications in tissue engineering.

The goal of this project was to develop a non-toxic amphiphilic diblock copolymer nanoparticulate drug delivery system that will solubilize paclitaxel (PTX) and retain the drug in plasma. Methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) diblock copolymers loaded with PTX were characterized and their physicochemical properties were correlated with their performance as nanoparticulate drug delivery systems. A series of MePEG-b-PCL was synthesized with PCL blocks ranging from 2-104 repeat units and MePEG blocks of 17, 44 or 114 repeat units. All copolymers were water soluble and formed micelles except MePEG₁₁₄-b-PCL₁₀₄, which was water insoluble and formed nanospheres. Investigation of the effects of block length on the physicochemical properties of the nanoparticles was used to select appropriate copolymers for development as PTX nanoparticles. The critical micelle concentration, pyrene partition coefficient and diameter of nanoparticles were found to be dependent on the PCL block length. Copolymers based on a MePEG molecular weight of 750 g/mol were found to have temperature dependent phase behavior. Relationships between the concentration of micellized drug and the compatibility between the drug and core-forming block, as determined by the Flory-Huggins interaction parameter, and PCL block length were developed. Increases in the compatibility between PCL and the drug, as well as longer PCL block lengths resulted in increased drug solubilization. The physicochemical properties and drug delivery performance characteristics of MePEG₁₁₄-b-PCL₁₉ micelles and MePEG₁₁₄-b-PCL₁₀₄ nanospheres were compared. Nanospheres were larger, had a more viscous core, solubilized more PTX and released it slower, compared to micelles. No difference was seen in the hemocompatibility of the nanoparticles as assessed by plasma coagulation time and erythrocyte hemolysis. Micellar PTX had an in vitro plasma distribution similar to free drug. The majority of micellar PTX associated with the lipoprotein deficient plasma fraction (LPDP). In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction. In conclusion, although both micelles and nanospheres were capable of solubilizing PTX and were hemocompatible, PTX nanospheres may offer the advantage of prolonged blood circulation, based on the in vitro plasma distribution data, which showed that nanospheres retained PTX more effectively. / Pharmaceutical Sciences, Faculty of / Graduate

A stimuli-responsive microgel is a three-dimensional polymer network that is able to absorb and expel a solvent (commonly water). These materials are unique in the fact that their sponge-like behavior can be actuated by environmental cues, like temperature, ion concentration, pH, and light. Because of the dynamic properties of these materials they have found applications in drug-delivery systems, micro-assays, selective filtration, artificial muscle, and non-fouling surfaces. The most well-known stimuli-responsive polymer is Poly(N-isopropylacrylamide) or PNIPAAm and it experiences a switchable swelling or deswelling over a critical temperature ( Tc=~32°C). Below the critical temperature, the gel begins mixing with the surrounding solvent and swells; above this temperature, the opposite is true. The unconstrained hydrogel will continue to swell in all directions until equilibrium is established between its propensity for mixing with the surrounding solvent and the elastic restoring forces of the gel matrix. The strength of the elastic restoring forces is dependent on the interconnectedness of the polymer network and is therefore a function of crosslink density. An increase in crosslink density results in a decreased swelling and vice versa. If the hydrogel is mechanically constrained to a surface, it can experience various wrinkling and buckling conformations upon swelling, as the stresses associated with its confinement are relieved. These conformation characteristics are a strong function of geometry (aspect ratio) and extent of swelling (i.e. crosslink density). In order to capitalize on the utility of this material, it is imperative that its volume transition is well characterized and understood. Toward this end, pNIPAAm gels have been created with 1x10-7 to 2x10-³ mol/cm³ crosslink density and characterized. This was done by first examining its bulk, unattached swelling ability and then by evaluating its microscale properties as a surfaceconfined monolithe. The latter was achieved through the use of confocal microscopy and copolymerization with a fluorescent monomer. This method allows for a detail analysis of the deformations experienced (bulk-structural bending and surface undulating) and will ultimately lend itself to the correlation between crosslink density and the onset of mechanical phenomena.

The aim of this study is to evaluate the specific interactions, solid-state, and solution-state interactions between drug and polymers in amorphous spray dried dispersions and evaluate the subsequent impact on drug dissolution in non-sink media. This is intended to be used as a screening tool for dosage-form development. Formulations with specific theoretical and observed interactions between drug and polymer may exhibit improved dissolution rate, increased absorption rate, increased capacity for drug loading and improved physical stability. Four BCS II class drugs were evaluated: ibuprofen, ketoprofen, nifedipine, and itraconazole. Binary and ternary spray dried dispersions were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between each drug and polymer were determined using theoretical group contribution calculations and DSC data. Solid-state interactions were evaluated using modulated DSC and FTIR, and solution-state interactions were evaluated using 1H-NMR. The maximum amorphous content for each formulation was calculated from the enthalpy of melting point peaks using DSC. Flory-Huggins Specific Interaction Parameters were calculated and show that a negative specific parameter was associated with increased solid-state interactions and improved capacity to contain drug in the amorphous state. Correlations between Flory-Huggins specific interaction parameter, amorphous drug loading, and equilibrium solubility were established. Ternary spray-dried dispersions containing drug, conventional polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary spray-dried dispersions. Solid and solution-state interactions observed in binary systems may be incorporated into ternary systems with arabinogalactan to both maintain amorphous drug capacity and improve dissolution rate compared to the binary. Supersaturation of amorphous binary and ternary dispersions was attained as compared to the crystalline drug. Mechanical properties of polymers as related to dissolution rate were investigated, and ternary systems containing to rapidly swelling and dissolving arabinogalactan had more pronounced erosion properties as compared to binary drug : HPMC dispersions. The resultant ternary systems are an improvement over binary drug polymer systems. / Pharmaceutical Sciences

Yes / In this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility. / The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.).

Made available in DSpace on 2014-12-17T15:01:56Z (GMT). No. of bitstreams: 1 AlessandroALA_TESE.pdf: 2166690 bytes, checksum: 87b921d322f56a3c11d668a0ad8d9341 (MD5) Previous issue date: 2013-11-11 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The nonionic surfactants when in aqueous solution, have the property of separating into two phases, one called diluted phase, with low concentration of surfactant, and the other one rich in surfactants called coacervate. The application of this kind of surfactant in extraction processes from aqueous solutions has been increasing over time, which implies the need for knowledge of the thermodynamic properties of these surfactants. In this study were determined the cloud point of polyethoxylated surfactants from nonilphenolpolietoxylated family (9,5 , 10 , 11, 12 and 13), the family from octilphenolpolietoxylated (10 e 11) and polyethoxylated lauryl alcohol (6 , 7, 8 and 9) varying the degree of ethoxylation. The method used to determine the cloud point was the observation of the turbidity of the solution heating to a ramp of 0.1 ? C / minute and for the pressure studies was used a cell high-pressure maximum ( 300 bar). Through the experimental data of the studied surfactants were used to the Flory - Huggins models, UNIQUAC and NRTL to describe the curves of cloud point, and it was studied the influence of NaCl concentration and pressure of the systems in the cloud point. This last parameter is important for the processes of oil recovery in which surfactant in solution are used in high pressures. While the effect of NaCl allows obtaining cloud points for temperatures closer to the room temperature, it is possible to use in processes without temperature control. The numerical method used to adjust the parameters was the Levenberg - Marquardt. For the model Flory- Huggins parameter settings were determined as enthalpy of the mixing, mixing entropy and the number of aggregations. For the UNIQUAC and NRTL models were adjusted interaction parameters aij using a quadratic dependence with temperature. The parameters obtained had good adjust to the experimental data RSMD < 0.3 %. The results showed that both, ethoxylation degree and pressure increase the cloudy points, whereas the NaCl decrease / Os tensoativos n?o i?nicos, quando em solu??o aquosa, apresentam a propriedade de separa??o em duas fases, sendo uma denominada de fase dilu?da, baixa concentra??o em tensoativo, e a outra rica em tensoativo denominada de coacervato. A aplica??o deste tipo de tensoativo nos processos de extra??o de solutos de meios aquosos vem aumentando o que implica na necessidade do conhecimento das propriedades termodin?micas desses tensoativos. Neste trabalho foram determinados os pontos de n?voa dos tensoativos polietoxilados, da fam?lia do nonilfenolpolietoxilado variando o grau de etoxila??o (9,5;10;11;12 e 13), da fam?lia do octilfenolpolietoxilado variando o grau de etoxila??o (10 e 11) e do ?lcool laur?lico polietoxilado nos graus de etoxila??o (6;7;8 e 9). O m?todo utilizado para determina??o do ponto de n?voa foi a observa??o do turvamento da solu??o ao aquecer o sistema a uma rampa de 0,1oC/minuto, e no estudo da press?o foi utilizada uma c?lula de alta press?o, m?ximo (300 bar). Atrav?s dos dados experimentais obtidos dos respectivos tensoativos, foram utilizados os modelos de Flory-Huggins, UNIQUAC e NRTL para descrever as curvas do ponto de n?voa dos referidos tensoativos. Foram tamb?m estudados a influ?ncia da concentra??o do NaCl e da press?o no ponto de n?voa. Este ?ltimo par?metro ? importante para os processos de recupera??o avan?ada de petr?leo nos quais os tensoativos em solu??o s?o submetidos a press?es elevadas. Enquanto que o efeito do NaCl permite obter pontos de n?voa a temperaturas mais pr?xima da temperatura ambiente viabilizando sua utiliza??o em processos sem controle de temperatura. O m?todo num?rico utilizado para ajustar os par?metros foi o Levenberg-Marquardt. Para o modelo de Flory-Huggins foram determinados par?metros de ajuste como a entalpia da mistura, entropia da mistura e o n?mero de agrega??o. Para os modelos UNIQUAC e NRTL foram ajustados par?metros de intera??o aij utilizando uma depend?ncia quadr?tica com a temperatura. Os par?metros obtidos tiveram bons ajustes aos dados experimentais com RMSD < 0,3%. Os resultados mostraram que tanto a etoxila??o quanto a press?o aumentam o ponto de n?voa do tensoativo, enquanto que o NaCl diminui

La perception des emballages alimentaires est passée d’utile à source majeure de contaminants dans les aliments et menace pour l’environnement. La substitution du verre par des con-tenants en plastiques recyclés ou biosourcés réduit l’impact environnemental des boissons embouteillées. La thèse a développé de nouveaux outils de simulation 3D et d’optimisation pour accélérer le prototypage des emballages éco-efficaces pour les boissons alcoolisées. La durée de conservation des boissons, la sécurité sanitaire des matériaux plastiques recyclés, les contraintes mécaniques, et la quantité de déchets sont considérées comme un seul problème d'optimisation multicritères. Les nouvelles bouteilles sont générées virtuellement et itérativement en trois étapes comprenant : i) une [E]valuation multiéchelle des transferts de masse couplés ; ii) une étape de [D]écision validant les contraintes techniques (forme, capacité, poids) et réglementaires (durée de conservation, migrations); iii) une étape globale de ré[S]olution recherchant des solutions de Pareto acceptables. La capacité de prédire la durée de vie des liqueurs dans des conditions réelles a été testée avec succès sur environ 500 miniatures en PET (polyéthylène téréphtalate) sur plusieurs mois. L’ensemble de l’approche a été conçu pour gérer tout transfert de matière couplé (perméation, sorption, migration). La sorption mutuelle est prise en compte via une formulation polynaire de Flory-Huggins. Une formulation gros grain de la théorie des volumes libres de Vrentas et Duda a été développée pour prédire les propriétés de diffusion dans les polymères vitreux de l’eau et des solutés organiques dans des polymères arbitraires (polyesters, polyamides, polyvinyles, polyoléfines). 409 diffusivités issues de la littérature ou mesurées ont été utilisée pour validation. La contribution de la relaxation du PET vitreux a été analysée par sorption différentielle (binaire et ternaire) de 25 à 50 °C. Une partie du code source sera partagé afin d'encourager l'intégration de davantage de paramètres affectant la durée de conservation des boissons et des produits alimentaires (cinétique d'oxydation, piégeage d'arômes). / The view of plastic food packaging turned from useful to a major source of contaminants in food and an environmental threat. Substituting glass by recycled or biosourced plastic containers reduces environmental impacts for bottled beverages. The thesis developed a 3D computational and optimization framework to accelerate the prototyping of eco-efficient packaging for alcoholic beverages. Shelf-life, food safety, mechanical constraints, and packaging wastes are considered into a single multicriteria optimization problem. New bottles are virtually generated within an iterative three steps process involving: i) a multiresolution [E]valuation of coupled mass transfer; ii) a [D]ecision step validating technical (shape, capacity, weight) and regulatory (shelf-life, migrations) constraints; iii) a global [Solving] step seeking acceptable Pareto solutions. The capacity to predict shelf-life of liquors in real conditions was tested successfully on ca. 500 hundred bottle min iatures in PET (polyethylene terephthalate) over several months. The entire approach has been designed to manage any coupled mass transfer (permeation, sorption, migration). Mutual sorption is considered via polynary Flory-Huggins formulation. A blob formulation of the free-volume theory of Vrentas and Duda was developed to predict the diffusion properties in glassy polymers of water and organic solutes in arbitrary polymers (polyesters, polyamides, polyvinyls, polyolefins). The validation set included 433 experimental diffusivities from literature and measured in this work. The contribution of polymer relaxation in glassy PET was analyzed in binary and ternary differential sorption using a cosorption microbalance from 25 to 50°C. Part of the framework will be released as an open-source project to encourage the integration of more factors affecting the shelf-life of beverages and food products (oxidation kinetics, aroma scalping).

Computational methodologies were employed to study a supramolecular micellar structure and its application, nanoreactor. This task was done through rigorous scale-up procedure using both atomistic and mesoscopic simulations. Primarily, density functional theory (DFT) calculation was used to characterize the smallest unit of complex molecules in the multicomponent mixture system. The following step involved transferring the information achieved by DFT calculation to larger scale simulation, such as molecular dynamics (MD) simulation. Lastly, based on the atomistic simulation results, we performed a series of dissipative particle dynamics (DPD) simulations to study a full body of polymeric multicompartment micelle. In the course of research, we built a systematic procedure to minimize the complexity of computation and efficiently characterize macromolecular structures and its application.