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The need to tailor release-rate profiles from polymeric microspheres remains one of the leading challenges in controlled drug delivery. Microsphere size, which has a significant effect on drug release rate, can potentially be varied to design a controlled drug delivery system with desired release profile. In addition, drug release rate from polymeric microspheres is dependent on material properties such as polymer molecular weight. Mathematical modeling provides insight into the fundamental processes that govern the release, and once validated with experimental results, it can be used to tailor a desired controlled drug delivery system. To these ends, PLG microspheres were fabricated using the oil-in-water emulsion technique. A quantitative study that describes the size distribution of poly(lactide-coglycolide) (PLG) microspheres is presented. A fluid mechanics-based correlation that predicts the mean microsphere diameter is formulated based on the theory of emulsification in turbulent flow. The effects of microspheres’ mean diameter, polydispersity, and polymer molecular weight on therapeutic drug release rate from poly(lactide-co-glycolide) (PLG) microspheres were investigated experimentally. Based on the experimental results, a suitable mathematical theory has been developed that incorporates the effect of microsphere size distribution and polymer degradation on drug release. In addition, a numerical optimization technique, based on the least squares method, was developed to achieve desired therapeutic drug release profiles by combining individual microsphere populations. The fluid mechanics-based mathematical correlation that predicts microsphere mean diameter provided a close fit to the experimental results. We show from in vitro release experiments that microsphere size has a significant effect on drug release rate. The initial release rate decreased with an increase in microsphere size. In addition, the release profile changed from first order to concave-upward (sigmoidal) as the microsphere size was increased. The mathematical model gave a good fit to the experimental release data. Using the numerical optimization technique, it was possible to achieve desired release profiles, in particular zero-order and pulsatile release, by combining individual microsphere populations at the appropriate proportions. Overall, this work shows that engineering polymeric microsphere populations having predetermined characteristics is an effective means to obtain desired therapeutic drug release patterns, relevant for controlled drug delivery.

L’objectif de ce travail était d’élaborer un copolymère biodégradable dans le but de développer une endoprothèse biorésorbable. Ainsi, des copolymères de lactide et de glycolide ont été synthétisés par copolymérisation par ouverture de cycle, dans des conditions permettant le contrôle de leurs paramètres macromoléculaires. Après plastification et mise en forme des copolymères par extrusion, l’étude des propriétés mécaniques, à l’état sec et après immersion en milieu aqueux, a été réalisée. Les essais de traction ont permis de vérifier l’importance de la vitesse de sollicitation et d’accéder à certaines grandeurs caractéristiques du matériau. L’étude de la dégradation des copolymères, sous forme de jonc, a mis en évidence un mécanisme de dégradation hétérogène sur une durée en accord avec l’application visée. La plastification par des molécules acides a permis d’accélérer la vitesse d’hydrolyse des copolymères. En conclusion, les propriétés mécaniques et de dégradation des copolymères PDLGA synthétisés sont donc en adéquation avec le cahier des charges de l’application biomédicale. / This work describes the synthesis of biodegradable copolymer to design a bioabsorbable endoprosthesis. Lactide and glycolide-based copolymers were synthesized by ring opening polymerization. Experimental conditions were chosen to produce controlled structures. The study of mechanical properties was performed in dry and wet states. During the tensile experiments, the effect of strain rate was noticed and some characteristics parameters were determined. Hydrolytic degradation of materials was fast and revealed a heterogeneous mechanism. Addition of acidic molecules for plasticizing increased the degradation rate of the copolymers.Mechanical properties and degradation of the PDLGA copolymers are indeed in good agreement with the specifications of this biomedical application.

Ovarian cancer is one of the five most common causes of cancer death in women in the USA and UK. It is usually diagnosed when it is well established beyond the ovary in the peritoneum. Intravenous injection of cisplatin is a common palliative therapy for ovarian cancer patients. Intraperitoneal therapy has been shown to improve survival for patients. Poly(lactide-co-glycolide) (PLGA) is a biodegradable polyester which has been proven safe for medical implantation. PLGA microspheres or fibres have been considered in this work as depots for delivering intraperitoneal cisplatin directly to the tumour site. The aims of this work were (1) to develop microsphere depot formulations with improved drug release profiles compared to previous work; (2) Novel cisplatin containing solid and hollow fibres were to be developed and investigated as alternative structures for depot devices; (3) The drug release profiles were to be examined using mathematical models to allow rational comparison of the devices. It was found that cisplatin containing PLGA 65:35 solid and hollow fibres represent a novel, reproducible formulation for encapsulating higher amounts of cisplatin for an equivalent mass of excipient than other polymer formulations. The fibres developed in this study were able to maintain elevated concentrations of unbound cisplatin in the presence of a biological matrix for approximately 100 hours in vitro.

Câncer é a segunda causa de morte no mundo e foi responsável por 8,8 milhões de mortes em 2015, de acordo com a Organização Mundial da Saúde (OMS). Segundo o Instituto Nacional do Câncer (INCA), essa doença é um problema de utilidade pública. Em valores absolutos, o câncer de próstata, neoplasia maligna mais comum entre os homens, é o sexto tipo mais comum no mundo. Dentre os tratamentos para câncer de próstata estão a cirurgia, quimioterapia e radioterapia. Um dos principais tipos de radioterapia é a braquiterapia, realizada por meio de sementes radioativas de iodo-125, que são inseridas na próstata do paciente e liberam pequenas doses de radiação. Essas sementes podem ser introduzidas soltas ou em cordas poliméricas Quando introduzidas soltas, de acordo com a literatura, essas sementes podem migrar para outros órgãos. Para evitar essa migração, usa-se as sementes em cordas poliméricas. As cordas poliméricas são constituídas pelo poli(ácido lático-co-ácido glicólico), PLGA. O PLGA pode ser obtido por meio de seus dímeros cíclicos: glicolídeo e lactídeo. Esses dímeros, por sua vez, podem ser produzidos a partir de seus respectivos monômeros, os ácidos glicólico e lático. O objetivo desse trabalho foi analisar e discutir as condições favoráveis à síntese dos dímeros glicolídeo e lactídeo, dentre elas, etapas do processo e valores de temperatura e pressão. Foram executados sete experimentos com diferentes temperaturas e pressões nas três etapas da síntese: desidratação do ácido, formação do pré-polímero e despolimerização do pré-polímero. Na etapa intermediária da síntese, foi obtido o PLA quando foram utilizadas temperaturas acima de 150°C. A etapa final mostrou que temperaturas abaixo de 200°C não formam os dímeros. / Cancer is the second leading cause of world death and it was responsible for 8.8 million deaths in 2015, according to the World Health Organization (WHO). According to the National Cancer Institute (INCA), this disease is a public utility problem. In absolute values, prostate cancer, the most common cancer among men, is the sixth most common type in the world. Among prostate cancer treatments are surgery, chemotherapy and radiotherapy. One of the main radiotherapy types is brachytherapy, performed by iodine-125 radioactive seeds, which are inserted into the patient\'s prostate and release small radiation doses. These seeds can be introduced loose or such as stranded seeds. When introduced such as loose seeds, according to literature, these seeds can migrate to other organs. In order to avoid this migration, it is used stranded seeds. The stranded seeds are composed of PLGA, poly(lactic acid-co-glycolic acid). PLGA can be obtained by its cyclic dimers: glycolide and lactide. These dimers can be produced from their respective monomers, glycolic and lactic acids. The purpose of this study was to analyze and discuss the favorable conditions of the glycolide and lactide synthesis, such as process steps and temperature and pressure values. Seven experiments were performed at different temperatures and pressures in three synthesis steps: acid dehydration, prepolymer formation and depolymerization of prepolymer. In intermediary step, the PLA was obtained when temperatures were above 150°C. The final step showed that dimers are not formed at temperatures below 200°C.

Câncer é a segunda causa de morte no mundo e foi responsável por 8,8 milhões de mortes em 2015, de acordo com a Organização Mundial da Saúde (OMS). Segundo o Instituto Nacional do Câncer (INCA), essa doença é um problema de utilidade pública. Em valores absolutos, o câncer de próstata, neoplasia maligna mais comum entre os homens, é o sexto tipo mais comum no mundo. Dentre os tratamentos para câncer de próstata estão a cirurgia, quimioterapia e radioterapia. Um dos principais tipos de radioterapia é a braquiterapia, realizada por meio de sementes radioativas de iodo-125, que são inseridas na próstata do paciente e liberam pequenas doses de radiação. Essas sementes podem ser introduzidas soltas ou em cordas poliméricas Quando introduzidas soltas, de acordo com a literatura, essas sementes podem migrar para outros órgãos. Para evitar essa migração, usa-se as sementes em cordas poliméricas. As cordas poliméricas são constituídas pelo poli(ácido lático-co-ácido glicólico), PLGA. O PLGA pode ser obtido por meio de seus dímeros cíclicos: glicolídeo e lactídeo. Esses dímeros, por sua vez, podem ser produzidos a partir de seus respectivos monômeros, os ácidos glicólico e lático. O objetivo desse trabalho foi analisar e discutir as condições favoráveis à síntese dos dímeros glicolídeo e lactídeo, dentre elas, etapas do processo e valores de temperatura e pressão. Foram executados sete experimentos com diferentes temperaturas e pressões nas três etapas da síntese: desidratação do ácido, formação do pré-polímero e despolimerização do pré-polímero. Na etapa intermediária da síntese, foi obtido o PLA quando foram utilizadas temperaturas acima de 150°C. A etapa final mostrou que temperaturas abaixo de 200°C não formam os dímeros. / Cancer is the second leading cause of world death and it was responsible for 8.8 million deaths in 2015, according to the World Health Organization (WHO). According to the National Cancer Institute (INCA), this disease is a public utility problem. In absolute values, prostate cancer, the most common cancer among men, is the sixth most common type in the world. Among prostate cancer treatments are surgery, chemotherapy and radiotherapy. One of the main radiotherapy types is brachytherapy, performed by iodine-125 radioactive seeds, which are inserted into the patient\'s prostate and release small radiation doses. These seeds can be introduced loose or such as stranded seeds. When introduced such as loose seeds, according to literature, these seeds can migrate to other organs. In order to avoid this migration, it is used stranded seeds. The stranded seeds are composed of PLGA, poly(lactic acid-co-glycolic acid). PLGA can be obtained by its cyclic dimers: glycolide and lactide. These dimers can be produced from their respective monomers, glycolic and lactic acids. The purpose of this study was to analyze and discuss the favorable conditions of the glycolide and lactide synthesis, such as process steps and temperature and pressure values. Seven experiments were performed at different temperatures and pressures in three synthesis steps: acid dehydration, prepolymer formation and depolymerization of prepolymer. In intermediary step, the PLA was obtained when temperatures were above 150°C. The final step showed that dimers are not formed at temperatures below 200°C.

The synthetic chemotherapeutic agent, 5-FU, has been used for the treatment of a variety cancers, with colorectal cancer being among the most susceptible. Administration of 5-FU by continuous intravenous infusion has proven to yield greater antitumor efficacy and lower hematotoxicity compared to administration of 5-FU by intravenous bolus injections. Nevertheless, systemic application of 5-FU is often limited by its narrow therapeutic threshold, and therefore in certain situations, such as tumor resection, it may be more appropriate to provide local rather than systemic delivery of 5-FU. It was therefore proposed that 5-FU loaded PLGA millirods may be capable of providing sustained release of 5-FU at a local level which may have equivalent or greater antitumor activity and less cytotoxicity than the systemic or local delivery of soluble 5-FU. PLGA millirods loaded with 5-FU were successfully fabricated by a hot-melt extrusion technique and characterized for in vitro and in vivo release rates. It was demonstrated that percentage loading by weight of 5-FU could be adjusted to modify its release kinetics. It was also shown that millirods could be stably stored under a variety of conditions for at least 2 months. An optimal millirod formulation (PLGA 50:50 loaded with 5-FU (50% w/w)) was tested for antitumor activity and general toxicity in vivo. At the dose of 120 mg/kg 5-FU, millirods (delivered peritumorally) were efficacious (with 100% survival rates) against solid thymomas in tumor-challenged mice (causing complete regression). Whilst the soluble form of 5-FU (delivered intraperitoneally (IP) at 120 mg/kg) was also highly efficacious (90% survival rates) against thymomas it was also more hematotoxic. In addition, the millirod form provided significantly greater antitumor activity against colorectal tumors in mice compared to the soluble form of 5-FU. In terms of in vivo toxicity, surprisingly, the type of formulation did not have a significant effect on mouse weight despite both IP and subcutaneous (SC) delivery causing death of some mice. Importantly, it was found that 5-FU loaded PLGA millirods were significantly less hematotoxic than soluble 5-FU delivered by either IP or SC injection at the equivalent dose. Thus, locally implanted 5-FU loaded PLGA millirods appeared to be less toxic and possessed overall greater antitumor potency than soluble 5-FU delivered by IP or SC injection. This study further investigated whether the combination of 5-FU loaded PLGA millirods with eniluracil (in both thymoma and colorectal tumor models) or immune checkpoint inhibitors (in the colorectal tumor model) could enhance the antitumor efficacy of 5-FU millirods in mice challenged with colorectal tumors. It was found that the combination of 5-FU loaded PLGA millirods and eniluracil (millirod or solution forms) did not significantly enhance the antitumor efficacy of 5-FU millirods in either tumor models. It was also found that immune checkpoint inhibitors did not enhance the antitumor efficacy of 5-FU loaded PLGA millirods in the colorectal tumor model.

Lipotoxic cardiomyopathy increases the risk of heart failure in obese patients by adversely altering heart structure and function via toxic lipid specie mediated cellular stress and cell death. Increased fatty acid uptake and esterification in cardiomyocytes increases toxic lipid intermediates. These cardiotoxic lipid species such as diacylglycerol have recently been shown to deacidify lysosomes in cardiomyocytes by activating protein kinase C βII mediated NADPH oxidase 2 generation of superoxide that inhibits proton pumps on lysosomal membranes by S-nitrosylation. Autophagy, a lysosome dependent cellular survival process, is impaired upon cardiomyocyte lipid-overload due to inhibition of pH-dependent proteolytic autophagosome degradation in the lysosome. Subsequent accumulation of autophagic vesicles heightens cardiomyocyte sensitization to additional stresses of ischemia-reperfusion or ER dysfunction, culminating in impaired cardiac metabolic flexibility leading to cell death. Low cardiomyocyte regenerative capacity calls for strategies to preserve cell number in states of increased stress, such as lipid-induced impairment of autophagy. Lysosome-targeted reacidifying devices can provide an effective means to restore autophagic flux. In this thesis, a therapeutic strategy utilizing poly(DL-lactide-co-glycolide) (PLGA) nanoparticle degradation to reacidify lysosomes and revert cardiotoxic lipid specie induced blockade in autophagic flux in cardiomyocytes is presented. Endocytosed PLGA acidic nanoparticles were designed to rapidly degrade and release acidic monomers in lysosomes to restore pH dependent phosphatase and cathepsin L activity in cardiomyocytes with acute lipotoxicity. Optimized pre-palmitate treatment periods demonstrated that PLGA nanoparticles with polyethylenimine cationic surface coatings provide an effective restoration of autophagic flux in the presence of lipid-overload modeled by acute palmitate treatment in cardiomyocytes.

The aim of this project was to create a novel biodegradable, synthetic scaffold that will provide the correct topographical cues for myoblast alignment and efficient differentiation into myotubes. Skeletal muscle repair after major surgery or serious burns is often overlooked leading to poor healing and consequent loss of power in movements of affected limbs. In order to overcome this problem a tissue engineered construct could be utilised as a grafting patch to encourage further regeneration and enhance possible power to the limb. Using a biodegradable polymer can provide structural support until the tissue is established, and will be excreted by the body's natural processes as it degrades. A synthetic polymer is desirable as it can reduce the risk of immunogenic responses thus reduce risk of graft rejection. For successful in vitro growth of skeletal muscle, the cells must be encouraged to arrange themselves into parallel arrays in order for efficient fusion and consequent contraction. By incorporating the correct topographical cues into the scaffold to promote contact guidance for cellular alignment this can be achieved. Electrospinning is a reliable technique which yields highly reproducible aligned fibres from the micro- to the nanoscale. This project focuses upon creating and characterising the electrospun scaffold, checking biocompatibility with myoblasts by monitoring the topography, residual solvent within the scaffold, the mechanical properties of the scaffold, and a brief investigation into the degradation profile of the electrospun fibres. The immunogenicity of the scaffold was investigated by monitoring cytokine release from macrophages. Myoblast morphology was monitored, as was the efficiency of the cells to differentiate and their potential to become contractile myofibres. Cellular adhesion to the scaffold was also looked into by measuring the expression of integrins during early and late adhesion and on substrates with different topographies. It was found that the electrospun scaffold did not contain a significant amount of residual solvent, and macrophages were not activated any more than on tissue culture plastic. Myoblasts responded to the topography of the aligned fibres by aligning along the length of the fibres, showing elongation and bi-axial cytoskeletal arrangement after just 30 minutes culture on the aligned fibres. This elongation prompted fusion and differentiation of the myoblasts to occur faster than cells which were not exposed to the aligned topography, and this global alignment was maintained in long term culture.

New methods for the preparation of porous biomedical scaffolds have been explored for applications in tissue engineering and drug delivery. Scaffolds with controlled pore morphologies have been generated which incorporate cyclodextrin-drug inclusion complexes as the drug delivery component. Supercritical CO2 was explored as the main processing fluid in the complex formation and in the foaming of the polymer scaffold. The co-solvents, ethanol, ethyl acetate and acetone, were explored in each stage, as needed, to improve the solvent power of CO2. The first goal was to promote cyclodextrin-drug complex formation. Complex formation by traditional methods was compared with complex formation driven by processing in supercritical CO2. Complex formation was promoted by melting the drug in supercritical CO2 or in CO2 + co-solvent mixtures while in the presence of cyclodextrin. Some drugs, such as piroxicam, are prone to degradation near the drug's ambient melting temperature. However, this approach using CO2 was found to circumvent drug thermal degradation, since drug melting temperatures were depressed in the presence of CO2. The second goal was to produce porous polymeric matrices to serve as tissue engineering scaffolds. Poly(lactide-<i>co</i>-glycolide) and poly(ε-caprolactone) were investigated for foaming, since these biomedical polymers are already commonly used and FDA approved. Polymer foaming with CO2 is an alternative approach to conventional solvent-intensive methods for porosity generation. However, two major limitations of polymer foaming using CO2 as the only processing fluid have been reported, including the formation of a non-porous outer skin upon depressurization and limited pore interconnectivity. Approaches to circumvent these limitations include the use of a co-solvent and controlling depressurization rates. The effect of processing parameters, including foaming temperatures and depressurization rate, as well as co-solvent addition, were examined in polymer foaming using CO2. Drug release dynamics were compared for foams incorporated with either pure drug, cyclodextrin-drug physical mixture or cyclodextrin-drug complex. Pore morphology, polymer choice and drug release compound choice were found to alter drug release profiles. / Ph. D.