Rendre possible l'administration orale du docétaxel (Dtx), un puissant agent anticancéreux administré par voie intraveineuse, représente un défi important en cancérologie. Disposer de formulations administrables par voie orale, moins toxiques et mieux tolérées, représenterait une avancée majeure au plan clinique. Toutefois, plusieurs études ont montré que la très faible biodisponibilité du Dtx par voie orale résulte simultanément de : (i) sa faible solubilité aqueuse, (ii) son faible passage transépithélial au niveau intestinal, (iii) son efflux par les pompes d’efflux (P-gp) et son métabolisme par le cytochrome P450. Nous avons conçu une formulation capable de répondre simultanément à ces différents problèmes. Ainsi, nous avons tout d’abord fait appel aux cyclodextrines (CDs) pour augmenter la solubilité apparente du Dtx. La complexation du Dtx avec la méthyl-β-CD a permis d’augmenter la solubilité apparente du Dtx d’environ 5000 fois. Ce complexe a ensuite été associé à des nanoparticules(NPs) polymères composées d’un coeur de poly(cyanoacrylate d’alkyle) et recouvert en surface de chitosane thiolé afin de leur conférer des propriétés mucoadhésives et de diminuer localement le métabolisme. Ces NPs ont montré in vitro et ex vivo leur capacité à arriver intactes au niveau de l’intestin, d’y adhérer et de libérer le Dtx de manière contrôlée dans le temps, et finalement d’améliorer son absorption intestinale. Une évaluation de la toxicité de cette formulation vis-à-vis de la muqueuse intestinale suggère que l’encapsulation du Dtx dans les NPs assure une certaine protection de la muqueuse. Au final, la formulation orale proposée offre en perspective la possibilité de moduler la dose administrée, donc d’ajuster finement la posologie et finalement d’offrir au corps médical et aux patients les bénéfices d’une thérapie personnalisée. / Docetaxel (Dtx) is an anticancer drug widely used in therapy. However, severe allergic reactions and peripheral neurotoxicity are caused by the intravenous administration of the commercial formulation Taxotere®, requiring thus the oral administration of dexamethasone and antihistamine before infusion. In this context, there is an urgent need to design new orally administered Dtx formulations to reduce these side effects and improve the patient’s qualityof life. Dtx belongs to the Class IV of the Biopharmaceutical Classification System, which comprises substances with both low solubility in aqueous fluids and low apparent intestinal permeability. This represents a major drawback when foreseeing oral delivery. Moreover, Dtx has been shown to be substrate of biological transporters and/or metabolized in the intestinal barrier. We designed a formulation able to overcome these different problems. First of all, we solved the low solubility problem by using cyclodextrin (CDs). The complexation of Dtx with the Methyl-ß-CD allowed increasing the apparent solubility of the Dtx about 5000 times. This complex was then associated to polymeric core-shell nanoparticles (NPs) based on poly(isobutyl cyanoacrylate) coated with thiolated chitosan. Among the characteristics of this system, mucoadhesion properties are the most important for an oral administration. The presence of the positively charged chitosan chains, and the thiol groups at the surface allow NPs to adhere to the mucus layer. In vitro and ex vivo experiments showed that these NPs were able to ensure a time-controlled release of Dtx and to improve its absorption at the intestinal level. An evaluation of the local intestinal toxicity of this formulation suggests that the encapsulation of Dtx into polymeric NPs had a protective effect allowing a preservation of the mucosa integrity. The further step will be to confirm by in vivo studies if this kind of nanoparticles is able to enhance the bioavailability of Dtx allowing to display an anti-tumor activity.

A Cubebina (CB) é uma lignana da classe das dibenzilbutirolactonas presente em uma ampla variedade de espécies vegetais espalhadas pelo mundo. Nos últimos anos, vários estudos têm demonstrado seu potencial para o tratamento de doenças como Leishmaniose e Doença de Chagas, além de possuir ação antiinflamatória e analgésica. Entretanto, apesar da CB apresentar diversas potencialidades terapêuticas, sua utilização ainda é limitada devido à sua baixa solubilidade em água, que compromete sua biodisponibilidade. Os dendrímeros são estruturas quase esféricas, de dimensão nanométrica, com grande número de subgrupos funcionais reativos e espaços interiores protegidos. São capazes de complexar com moléculas e, dessa forma, aumentar a solubilidade do fármaco. De forma semelhante, as ciclodextrinas (CDs) são oligossacarídeos cíclicos que possuem a capacidade de interagir com moléculas hidrofóbicas através de sua cavidade que também é hidrofóbica. Isso as torna capazes de aumentar a solubilidade de fármacos pouco solúveis aumentando sua biodisponibilidade. Nesse trabalho foram obtidos complexos dessas macromoléculas com a CB por diferentes métodos. Metodologias de quantificação da CB, nas formas livre e complexada, foram desenvolvidas utilizando técnicas de espectrofotometria e de cromatografia líquida de alta eficiência. Esses sistemas foram caracterizados utilizando técnicas apropriadas como estudos de solubilidade de fase, espectroscopia no IV, difração de raios X, RMN H1 e simulações de modelagem e dinâmica molecular. Os resultados demonstraram que tanto os dendrímeros quanto as ciclodextrinas são capazes de gerar complexos solúveis com a CB sendo os melhores resultados obtidos com a HP--CD. Os resultados desse trabalho permitiram concluir que tanto dendrímeros quanto CDs são estruturas adequadas e promissoras para a veiculação da CB, aumentando assim o seu potencial para aplicações biológicas, visando o tratamento de diversas patologias. / Cubebin (CB) is a lignan from the class of dibenzylbutyrolactones present in a wide variety of plant species around the world. Its known for its anti-inflammatory and analgesic effects. In recent years, several studies have demonstrated its potential to treat diseases such as leishmaniasis and Chagas. Although the CB shows several potential therapeutics, its use is still limited due to its low water solubility which compromises its bioavailability. The dendrimers are nearly spherical structures, nanometer-sized, with large number of reactive functional groups and protected inner. They are capable of complexing with molecules and thereby increase the solubility of the drug. Similarly, cyclodextrins (CDs) are cyclic oligosaccharides that have the ability to interact with hydrophobic molecules through the cavity which is also hydrophobic. This makes them capable of increasing the solubility of poorly soluble drugs by increasing their bioavailability. In this work, complexes of macromolecules with CB were obtained by different processes. Methodologies for quantification of free and complexed CB were developed by spectrophotometry and high performance liquid chromatography. Moreover, these systems were characterized by techniques such Phase Solubility Studies, IR spectroscopy, X-ray diffraction, NMRH1, modeling and molecular dynamics simulation. The results showed that both dendrimers and cyclodextrins are capable to form soluble complexes with CB. Best results were obtained with HP--CD. The findings of this study indicate that both dendrimers and CDs are appropriated structures to release the CB and also increase its potential for biological applications, focusing on the treatment of various diseases.

Thesis (MTech (Food Technology))--Cape Peninsula University of Technology, 2018. / The aim of this study was to produce Bambara groundnut (BGN) starch-catechin complex using chemical initiators (ascorbic acid and hydrogen peroxide) and cyclodextrin (alpha and beta) with the view to obtain a functional ingredient for the food industry. BGN starch was successfully extracted from BGN flour through dry milling method, yielding 32% of BGN starch. Native BGN starch was chemically modified using ascorbic acid (1% w/w) and hydrogen peroxide (165% w/w) as redox, biocompatible initiator for grafting catechin to the BGN starch. In addition, cyclodextrin (alpha and beta) were also used as initiators for modifying BGN starch through complexation methods. Complexation methods used included the microwave, co-evaporation and kneading. The characterization of native and modified BGN starches was carried out by performing scanning electron microscopy, powder X-ray diffraction, Fourier Transform Infrared (FTIR) and fluorescence spectroscopy analysis. Functional, thermal and rheological properties of native and modified BGN starches were evaluated. The pasting properties of BGN starches were determined using the Rapid Visco Analyser (RVA). According to the SEM profile, native BGN starch had round, oval and elliptical shapes typical for legume starches. Native BGN starch displayed a typical type-C crystallinity which is common among legumes with strong peaks at 2θ of 15o, 17o and 23o. BGN starches modified through complexation methods had sharper peaks indicating an increase in starch crystallinity; however, following chemical modification there was loss in starch crystallinity which was evidenced by the amorphous region in the chemically modified BGN starches. Structure of native and modified BGN starches was confirmed by FTIR. The FTIR spectra of native BGN starch showed variable peaks at 3285.34 cm-1, 2931.69 cm-1, 1634.36 cm-1, 1336.77 cm-1 which are attributed to OH stretching, C-H stretching, water bending vibrations and C-O stretching, respectively. Furthermore, the FTIR results confirmed that native BGN starch is made up of glucose molecules just like all other starches. All modified BGN starches displayed a new absorption peak at 1020 cm-1 wavelength, thus indicating that starch modification was successful. On the other hand, all BGN starch-catechin complexes displayed a new absorption peak in the range of 1520 -1560 cm-1, attributed to the C-C stretching within the aromatic ring of the catechin. The successful grafting of catechin to BGN starch was also confirmed by the fluorescence spectroscopy results, where all the BGN starch-catechin complexes had an emission peak at 320 nm while native BGN starch had an emission peak at 270 nm. Antioxidant capacity of BGN starch was determined through DPPH and ORAC antioxidant assays. Within the DPPH assay, the antioxidant activity ranged from 2.26 to 38.31 μmol TE/g. The antioxidant activity of modified BGN starch-catechin complexes was significantly (p ≤ 0.05) higher than the ones modified without catechin. On the other hand, within the ORAC assay, the antioxidant activity ranged from 0.07 to 126.71 μmol TE/g. As opposed to the results obtained in DPPH assay, the antioxidant activity of chemically modified BGN starch-catechin complexes was significantly (p ≤ 0.05) higher than that of complexed BGN starch-catechin complexes. Chemical modification significantly increased the swelling capacity of native BGN starch while complexation methods significantly reduced it.

Includes errata attached to first leaf. Includes bibliographical references. The complexation of a range of monovalent and divalent metal ions by the bibracchial lariat ethers has been investigated. Also investigates the complexation of metal ions and the anionic azo dye Brilliant Yellow by the diazacrown linked cyclodextrin dimers.

Offprints of two author's journal articles inserted at end of the v. / Bibliography: leaves 10-12 / 216 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1985

Includes errata attached to first leaf. / Includes bibliographical references. / vi, 158 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The complexation of a range of monovalent and divalent metal ions by the bibracchial lariat ethers has been investigated. Also investigates the complexation of metal ions and the anionic azo dye Brilliant Yellow by the diazacrown linked cyclodextrin dimers. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 2000

Bibliography: leaf 179 / 179 leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--Dept. of Physical and Inorganic Chemistry, University of Adelaide, 1986

Includes bibliographies / x, 149 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

Thesis (M.Sc.) (Honours) -- University of Western Sydney, Hawkesbury, 2001. / A thesis submitted in fulfilment of the rquirements for the award of the degree of MSc(Hons), University of Western Sydney, Hawkesbury Campus, 2001. Bibliography : leaves 263-294.

Thesis (M.S.)--Youngstown State University, 2008. / Includes bibliographical references (leaves 57-64). Also available via the World Wide Web in PDF format.