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Les poly(3-hydroxyalcanoate)s ou PHAs sont des biopolyesters linéaires biodégradables et biocompatibles synthétisés par des microorganismes bactériens en tant que réserve de carbone et d'énergie. Ils sont synthétisés par des bactéries à partir de ressources renouvelables et la diversité de leurs structures possibles se traduit par un large éventail de polymères ayant des propriétés mécaniques très différentes. Nous avons tout d'abord testé les capacités de production de PHAs de nouvelles souches bactériennes marines provenant de tapis microbiens de Polynésie française, en utilisant, entre autres, des substrats naturels comme l'huile de coprah, le glucose et l'acide oléique. Nous avons notamment montré que la souche Pseudomonas guezennei est capable de produire des PHAs avec des taux d'insaturation contrôlés et de masse molaire très élevée. Puis, des oligomères de PHAs fonctionnalisés de structures contrôlées portant des fonctions terminales alcynes ou alcènes ont été préparés par transestérification. Ces oligomères ont ensuite été utilisés pour l'élaboration par chimie click de copolymères amphiphiles greffés EPS-g-PHA avec des exopolysaccharides (EPS) bactériens. Enfin la dernière partie de ces travaux a consisté en la réalisation d'un support de croissance pour le développement de cellules souches pour l'ingénierie tissulaire combinant les propriétés mécaniques des PHAs et les propriétés hydrophiles et bioactives des EPS / Poly(3-hydroxyalkanoate)s, or PHAs, are linear biodegradable and biocompatible biopolyesters synthesized by bacterial microorganisms as energy and carbon supply. They are synthesized by bacteria from renewable resources and the diversity of the achievable structures leads to a large range of mechanical properties. First, we studied the PHAs production ability of several new marine bacteria strains, isolated from microbial mats from French Polynesia, using, among others, natural substrates such as coprah oil, glucose and oleic acid. We showed particularly that the strain Pseudomonas guezennei was able to produce PHAs with controlled amounts of insaturations and high molar masses. Then, we prepared functionalized PHAs oligomers with controlled structure and bearing a terminal alkyne or alkene function. Following that, these oligomers were used to elaborate amphiphilic by click chemistry graft copolymers EPS-g-PHA with bacterial exopolysaccharide (EPS). Finally, the last part of this work was the making of a scaffold for stem cell culture for tissue engineering which combined the mechanical properties of PHAs and the hydrophilicity and bioactive properties of EPS

This Thesis presents the synthesis, characterization and mechanistic explorations into a series of diphenylacetylene-containing oligoester ion channels. Eighteen final compounds were synthesized and tested for ion transport activity utilizing both vesicle and planar bilayer assays. The oligomers varied in length, hydrophobicity and the nature of the aromatic moiety. Compounds incorporating a modified diphenylacetylene (‘Dip’), or a novel phenyl-extended fluorophore (‘Trip’) were made using a reliable, modular synthesis. The final compounds were prepared in a total of 5 to 11 steps from commercial materials in yields ranging from 10 to 40%. The compounds’ activity varied considerably; both highly active and completely inactive compounds were discovered. The differences in activity are controlled by structure via the influence of structural variables on the aqueous phase aggregation and the ability of the compound to insert into the bilayer membrane. These structure-activity studies uncovered two highly-active ion transporters, HO2C-Hex-Dip-Hex-Hex-OH and –OPO32- (Hex = 6-hydroxyhexanoyl) which exhibited activity almost 10-fold higher than the fully-saturated oligoesters developed in previous work. In some cases, the transport activity is initially high but declines over a period of 20-30 minutes following compound addition. This suggests that the compound slowly transitions to an environment where it cannot form active channels. In the bilayer clamp, a variety of behaviours including highly-conducting openings were observed. An apparent voltage-gated response was exhibited by one of the Trip compounds (HO2C-Trip-G(E3)-OH), a property rarely seen for synthetic ion channels. The Dip and Trip molecules exhibited environment-sensitive fluorescence. The observed Dip excimer-like emission is the second reported instance of this in solution. The Trip compounds are solvatochromic; this property was used to infer their location in the membrane. Partitioning into the membrane was followed by a blue-shifting and increased intensity of the fluorescence emission for both series of compounds. For the Trip isomers, which are significantly more emissive than the Dip molecules, this enhancement in intensity could be visualized by eye. For the Dip oligomers, the excimer emission is a broad band with variable shape and intensity; it is time-dependent under some conditions. The excimer emission has a sub-nanosecond lifetime in homogenous solution that is significantly prolonged in the presence of vesicle bilayers, in which a number of lifetimes could be detected. Both monomer and excimer emissions can be quenched by aqueous copper, the excimer emission is more efficiently quenched than is the monomer. The photophysical characteristics of these molecules allowed for a variety of experiments designed to probe their membrane partitioning and localization behaviours. The results indicate the formation of a complex mixture of interconverting monomeric and aggregate species as the compounds move from water to the bilayer. The slow evolution of the mixture is consistent with the times noted for loss of membrane activity in transport assays. From these data a new model that describes the transport process is proposed. The key feature of this model is that transport must occur via a species that forms quickly upon the mixing of the components. Possible structures of the intermediates formed are discussed. / Graduate

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CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical technology Name of the student: Klára Bílková Title of diploma thesis: Influence of plastification on rheological properties of oligoester of lactic acid and glycolic acid branched with dipentaerythritole Consultant: PharmDr. Eva Šnejdrová, Ph.D. The aim of this diploma thesis was the study of rheological properties of the oligoester of DL-lactic and glycolic acids branched with 1% of dipenthaerythritol (1D) and plasticized with 6 various plasticizers in increasing concentrations. Theoretical part was devoted to fundamentals of rheology and measurements of viscosity using rotational viscometers. It describes basic types and constructions of rotational rheometers and summarizes basic facts about bioadhesion and use of rheological method for assessment of bioadhesion. There were prepared matrices from oligoester 1D and plasticizers in concentrations of 20 %, 30 % and 40 % in the experimental part. These plasticizers were tested: ethyl pyruvate, ethyl salicylate, methyl salicylate, triacetin, tributyrin and triethyl citrate. Rheological properties were examinated at 37 řC using spindle viscometer and at 37 řC and 50 řC using rotational rheometer. Rheograms were used to characterize flow properties of tested...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Student: Lenka Šišáková Supervisor of Diploma thesis: PharmDr. Eva Šnejdrová, Ph.D. Title of Diploma thesis: Aciclovir release from mucoadhesive matrices The aim of this diploma thesis was the study of the mucoadhesive parameters of plasticized oligoester of lactic acid and glycolic acid and 3% mannitol as a branching monomer. Knowledge of dissolution testing of drug release from dosage form, principal theories and mechanisms of mucoadhesion and mucoadhesion testing of adhesive formulation is described in theoretical part. Matrices formed from terpolymer of D,L-lactic acid, glycolic acid branched with mannitol and 5 % aciclovir were examined in the experimental part. Triethylcitrate (TEC), ethylpyruvate (EP), methylsalicylate (MS) and ethylsalicylate (ES) were used as plasticizers. Dissolution test has been done. Hydrated mucin from porcine stomach was used as a base. Phosphate-citrate buffer pH 7.4 was used as a dissolution medium. Dissolution was defined as a quantity of released aciclovir in to the dissolution medium after 15, 30, 60 and 90 minutes. The quantity of the released aciclovir was defined by a spectrophotometry. In 90 minutes was released 43 % of aciclovir from the matrice...

Les poly(3-hydroxyalcanoate)s ou PHAs sont des biopolyesters linéaires biodégradables et biocompatibles synthétisés par des microorganismes bactériens en tant que réserve de carbone et d'énergie. Ils sont synthétisés par des bactéries à partir de ressources renouvelables et la diversité de leurs structures possibles se traduit par un large éventail de polymères ayant des propriétés mécaniques très différentes. Nous avons tout d'abord testé les capacités de production de PHAs de nouvelles souches bactériennes marines provenant de tapis microbiens de Polynésie française, en utilisant, entre autres, des substrats naturels comme l'huile de coprah, le glucose et l'acide oléique. Nous avons notamment montré que la souche Pseudomonas guezennei est capable de produire des PHAs avec des taux d'insaturation contrôlés et de masse molaire très élevée. Puis, des oligomères de PHAs fonctionnalisés de structures contrôlées portant des fonctions terminales alcynes ou alcènes ont été préparés par transestérification. Ces oligomères ont ensuite été utilisés pour l'élaboration par chimie click de copolymères amphiphiles greffés EPS-g-PHA avec des exopolysaccharides (EPS) bactériens. Enfin la dernière partie de ces travaux a consisté en la réalisation d'un support de croissance pour le développement de cellules souches pour l'ingénierie tissulaire combinant les propriétés mécaniques des PHAs et les propriétés hydrophiles et bioactives des EPS

Farmaceutická fakulta, Katedra farmaceutické technologie, Hradec Králové, 2014 Vypracovala: Markéta Valentová Školitel: Doc. RNDr. Milan Dittrich, CSc. ABSTRACT STUDY OF POLYESTER DRUG CARRIERS DEGRADATION USING THE DSC METHOD The aim of this work was focused on the study of relations among various parameters of degradation process, such as time-dependent range of glass transition temperature, swelling, erosion, and molar weight decrease. Two model polyesters of two type architectures of polyester molecules were used and monitored during two-week period. In the theoretical part of this diploma thesis are in details described biopolymers with stimulus responsive activity and exploitation of these materials in various biomedical applications in the topic of tissue engineering. The experimental part of this work is directed into the study of molecule degradation parameters, eventually into simulated biodegradation in the in vitro conditions of two different in the type polyesters with the contrast polyester molecule constitution. It was demonstrated that parameter Mn decreases towards the limit values. Between the values of molar weight and glass transition temperature is not Flory-Fox relation in the advanced phase of degradation process. The erosion of the material begins after the lag-time in the dependency...