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As part of a currently intense research effort into the development of novel potent macromolecular pharmaceuticals, diagnostic tools and carriers for targeted drug delivery, this project involved the synthesis of glycopolymers. Polymethacrylate derivatives carrying carbohydrate residues were efficiently prepared in a stereo-controlled manner, following two different routes. As revealed by a thorough characterisation of the materials obtained, the synthetic procedure strongly affected the polymers' composition and, in turn, their properties, such as their self-association in aqueous media and the interaction of the compounds bearing D-galactose units with a specific lectin. Polymers containing peracetylated saccharide residues were shown to be surface-active, forming stable spread Langmuir films. These monolayers acted as effective dl-aspartic acid nucleation promoters, whilst the soluble analogues (for which the sugars are deacetylated) seemed to possess a certain activity as dl-aspartic acid growth inhibitors. The behaviour of the deprotected polymers in aqueous solution was thoroughly investigated, prior to testing whether the materials carrying galactosyl units on the side chains could be recognised by a galactose-specific protein. For the first time for polymeric glycoconjugates, thermodynamic binding parameters relative to this protein-carbohydrate interaction were directly evaluated using isothermal titration microcalorimetry.

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Recently, there has been an explosion of interest in developing biopharmaceutical therapeutics for the treatment of life altering conditions. The main issue with the utilization of biopharmaceutical therapeutics is the mode of administration. The Oral Ghost Drug Delivery (OGDD) device could potentially enable the administration of these peptide therapeutics via the oral route and significantly extend the application of these advanced therapeutic compounds.

Student Number : 9903022H MSc Dissertation School of Chemistry Faculty of Science / Cancer is characterised by the unconstrained growth of cancerous cells, which damages the healthy cells and ultimately the tissue of the host. Chemotherapy forms an essential component in the treatment of this disease, however most anti-tumour drugs suffer from various deficiencies, e.g. increased toxicity, reduced serum half life and poor water solubility. The focus of this project was to address some of these deficiencies by conjugating selected drugs to a water-soluble polymeric carrier. Selected water-soluble biodegradable carriers were synthesized. Copolyaspartamides, polyamidoamines and polyamides were obtained by condensation polymerisation, Michéal–type addition polymerisation and ester amine base-catalysed polymerisation. The nascent water soluble polymers were used to conjugate platinum, ferrocene and tetramethylmelamine derivative, respectively. The percentage drug in each polymer drug conjugate was determined by considering the mass of the drug in the conjugate as a percentage of the total mass of the drug-polymer conjugate. Platinum was linked to the carrier via polymer attached amine, carboxyl and hydroxyl ligands. Platinum content of the conjugates ranged from 7 to 11 % by mass. The ferrocenylation agent, 4-ferrocenylbutanoic acid, and the tetramethylmelamine derivative, 3-(4,6-bis(N,N-dimethylamino)-1,3,5-triazacyclohexatrien-2-yl) propanoic acid was polymer-bound by amidation reactions. Iron content of the ferrocence conjugated ranged from 2 to 12 % by mass. While the drug content based on tetramethylmelamine in the 3-(4,6-bis[N,N-dimethylamino]-1,3,5-triazacyclohexatrien-2-yl) propanoic acid polymer conjugate ranged from 8.4 to 8.6 % by mass. There was a preliminary attempt to coconjugate both, 4-ferrocenylbutanoic acid and 3-(4,6-bis[N,N-dimethylamino]-1,3,5- triazacyclohexatrien-2-yl) propanoic acid to the same polymer. This co-conjugate contained 2.9 % iron and 3.4 % tetramethylmelamine by mass.

"Síntesis y caracterización de nuevas poliesteramidas: estudio de sus propiedades."El estudio de los polímeros biodegradables ha adquirido un gran interés en los últimos años por ser una alternativa al reciclado de los productos plásticos. En este contexto, los poliésteres alifáticos constituyen el grupo de polímeros más extensamente estudiado ya que la presencia de grupos ésteres les confiere una gran susceptibilidad a la degradación. Sin embargo, los poliésteres alifáticos lineales poseen temperaturas de fusión muy bajas y reducidas propiedades mecánicas. Por otro lado, en contraste a los poliésteres, las poliamidas alifáticas son materiales con excelentes propiedades térmicas y mecánicas pero resistentes a la degradación. Las poliesteramidas son una familia de polímeros de gran interés puesto que pueden combinar las ventajas de los polímeros anteriormente citados.En este trabajo, se han estudiado nuevas poliesteramidas constituidas principalmente por a-aminoácidos naturales, tales como glicina y L-alanina, debido a su potencial degradabilidad en medios enzimáticos. Se ha insistido en los polímeros caracterizados por una secuencia regular aminoácido-diol-aminoácido-diácido, proponiendose y comparandose dos procedimentos alternativos de síntesis basados en una poliamidación interfacial o en una poliesterificación térmica.Entre los polímeros estudiados con más detalle podemos citar:a) Derivados de butanodiol, al conferir un carácter hidrofílico y por tanto favorecer la degradabilidad del material.b) Derivados de unidades rígidas como el ácido tereftálico o el oxálico por mejorar las propiedades térmicas.Las poliesteramidas alifáticas relacionadas con los nylons y poliésteres 6 10 o 12 10 y que no contienen aminoácidos no se degradan en medio enzimático proteolítico y la degradación hidrolítica transcurre muy lentamente.Además de la síntesis y caracterización de las poliesteramidas, se han realizado estudios estructurales de compuestos modelo, segmentos representativos de los polímeros, con la finalidad de obtener datos cristalográficos para una posible extrapolación a la estructura de las poliesteramidas.Por último, se realizó un estudio del empaquetamiento molecular de poliésteres alifáticos relacionados como son el 6 10 y el 12 10 a través del cual se determinó la orientación azimutal de las cadenas y su desplazamiento relativo. / "Synthesis and characterization of new poly(ester amide)s: a study of its properties."During the last years a great effort has been devoted to study biodegradable polymers since they can help minimize some of today¦s severe waste management problems. Among then, aliphatic polyesters are perhaps the most easily biodegradable synthetic polymers known, due its highly hydrolizable backbone. However, their applications have been limited because of their low melting point and poor mechanical behavior. On the other hand, aliphatic polyamides are materials with excellent mechanical properties but with an enhanced resistance to degradation. In this context, poly(ester amide)s are a family of polymers able to combine the properties mentioned before.In this work, we discuss the possibilities of a new series of poly(ester amide)s that involves a-amino acids, since an enhanced biodegradability is expected. We consider two synthesis methods based on the interfacial polyamidation and thermal polyesterification to prepare poly(ester amide)s represented by the regular secuence: amino acids-diol-amino acids-diacid.Polymers with stiff units like oxaloyl or terephthaloyl residues were studied and characterized because these groups improve thermal properties. We have also studied polymers that incorporate 1,4-butanediol according to its major hydrophylicity responsible for the high degradability of the materials.Other subject of this work is to know how the amino acid content and the ratio between amide and ester groups influences thermal behavior and degradability.In addition to the synthesis and characterization of poly(ester amide)s, we investigated the structure of several related model compounds in order to obtain crystallographyc parameters to extrapolate to the structure of the polymers.Finally, a detailed structural refinement of related polyesters 6 10 and 12 10 has been studied using transmission electron microscopy and X-ray diffraction because of its great interest as degradable polymers.

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Com o crescimento populacional e aumento das atividades humanas, grandes quantidades de poluentes são despejadas diariamente no meio ambiente. Nos ecosssistemas aquáticos, organismos são expostos por longos períodos à baixas concentrações de contaminantes. Assim estudos que focam em novas metodologias que sejam rápidas e não invasivas, são necessários para a avaliação de efeitos subletais. Um exemplo é a espectroscopia no infravermelho com transformada de Fourier (FTIR). Esta técnica é capaz de detectar alterações macromoleculares em amostras biológicas de forma rápida e não destrutiva, sendo uma ferramenta atrativa para análises ecotoxicológicas. Assim, o objetivo deste estudo foi verificar a aplicabilidade do FTIR como metodologia alternativa, utilizando perfis de composição macromoleculares como indicadores de efeitos subletais, em organismos expostos a elementos-traço. Para tal, ostrácodes (Chlamydoteca sp.) foram expostos aos elementos Cu, Cd, Hg e Mn. As alterações em perfis biomoleculares foram avaliadas em ostrácodes expostos por 48h ao Mn. Os resultados revelaram uma correlação negativa entre concentração de exposição e proporção de ácidos graxos saturados e insaturados com relação à proteína em organismos expostos ao Mn e a mesma correlação foi observada para o conteúdo de ácidos nucléicos. Isto sugere que os organismos tiveram seu metabolismo lipídico e sua capacidade de produção de proteína celular alterados devido à exposição ao Mn. Ademais, foram realizados testes crônicos (9 dias) com ostrácodes expostos ao Cu, Cd, Hg e Mn. Foi observada a diminuição de lipídios saturados e insaturados em relação à proteína em organismos expostos ao Cd, sugerindo o uso de reservas lipídicas devido ao estresse fisiológico. Ostrácodes expostos ao Cu, tiveram o aumento dos ácidos nucléicos, no qual o DNA pode ter sido o componente dominante. Alterações significativas relacionadas ao conteúdo de carbonato de cálcio foram reveladas nos organismos expostos ao Cd e ao Cu, o que sugere mudanças na composição da carapaça e possível alteração na capacidade de muda e crescimento dos organismos. Portanto, este estudo permite concluir que a espectroscopia de FTIR é capaz de detectar indícios de efeitos subletais em organismos expostos a contaminantes e que as alterações de composição macromolecular são uma ferramenta complementar promissora para futuras avaliações ecotoxicológicas. / With population growth and increases in human activities, large amounts of pollutants are released daily into the environment. In aquatic ecosystems organisms are exposed for long periods at low concentrations of contaminants. Therefore, studies that focus on fast and non-invasive new methodologies are necessary for the assessment of sublethal effects in organisms. An example is the Fourier Transform Infrared Spectroscopy (FTIR). This technique can detect macromolecular changes of biological samples in a fast, inexpensive and non-destructive way, all of which lend to the attractiveness of this methodology for ecotoxicological analyzes. Thus, the aim of this study was to verify the applicability of FTIR as an alternative methodology, using the composition of macromolecular profiles as an indicator of sublethal effects in organisms exposed to trace elements. For this, ostracods (Chlamydoteca sp.) were exposed to the elements Cu, Cd, Hg and Mn. Changes in biomolecular profiles were evaluated in ostracods exposed for 48h to Mn. The results showed a negative correlation between the concentration of exposure and the proportion of saturated and unsaturated fatty acids for protein in organisms exposed to Mn and the same correlation was observed for the content of nucleic acids. This suggests that the organisms had their lipid metabolism and their cellular protein production capacity altered due to Mn exposure. In addition, four chronic tests (9 days) were performed on ostracods exposed to the trace elements Cu, Cd, Hg and Mn. A decrease in saturated and unsaturated lipids in relation to the protein was observed in organisms exposed to Cd, suggesting that the use of lipid reserves was due to the physiological stress. Ostracods exposed to Cu had an increase in nucleic acids, in which DNA may have been the dominant component. Significant changes related to the calcium carbonate content were revealed in the organisms exposed to Cd and Cu, which suggests changes in carapace composition and the possible alteration in the organism capacity of molting and growth. Therefore, this study concludes that FTIR spectroscopy can detect indications of sublethal effects in organisms exposed to contaminants and that changes in macromolecular composition are a promising complementary tool for future ecotoxicological assessments.