|
|
Bio-inspired organic molecules for photodynamic therapy
Švarcová, Nikola ; Cigánek, Martin (referee) ; Krajčovič, Jozef (advisor)
Photodynamic therapy is a treatment method using the clinical application of photosensitisers for alternative treatment of oncological and inflammatory diseases. Using photosensitisers, substances with absorption properties, is a crucial element for the effective therapy process. Flavins can serve as photosensitisers in photodynamic therapy thanks to their conjugated system. The proposed bachelor thesis is focused on preparing of a novel, riboflavin-inspired flavin derivative. The structural isomers of riboflavin, alloxazines, provide simple synthetic modification for material properties enhancement. The theoretical part deals with the principle and mechanism of photodynamic therapy, modern trends in medical applications, limitations, benefits and essential elements for the effective therapy process. Consequently, the possibility of flavin derivatives potential use as infrared-absorbing photosensitisers is considered. The experimental part aims to prepare the intermediates and final precursors, 1,3-dialkylated uracil and acenaphthene-based 1,2-diketone. Verified synthetic paths described in the thesis provided high yields of the prepared intermediates and final precursors. Thus, the approaches will be utilized in the following synthetic studies to prepare the acenaphthene flavins series.
|
|
|
Polymer probes for photodynamic therapy of solid tumors
Kotalík, Kevin ; Etrych, Tomáš (advisor) ; Kovář, Marek (referee)
One of the currently studied promising strategies in advanced oncologic treatment is photodynamic therapy, a method based on the administration of so-called photosensitisers, i.e. photoactive compounds such as porphyrins, and subsequent irradiation of tumor tissue with light of appropriate wavelength. An excitation of the photosensitiser, present in the tumor area, is hence invoked and reactive oxygen species (ROS) are formed. These species afterward cause the apoptosis of the tumor cells, leading to destruction of tumor tissue. In photodynamic therapy, the strategy of administration of a prodrug which is metabolised to the active photosensitiser can be used with advantages. In photodynamic therapy, this prodrug may be 5-aminolevulinic acid (5-ALA) or its esters which are metabolised to protoporphyrin IX (PPIX), the photosensitiser proper. The targeted drug delivery to the tumor tissue can be achieved by using various delivery systems, e.g. water-soluble polymer conjugates carrying the drug. Due to their size, these polymer conjugates are accumulated in solid tumors on the basis of the enhanced permeability and retention (EPR) effect. Macromolecules can penetrate the tumor vasculature, which, unlike that of healthy tissue, is imperfectly developed and contains gaps between endothelial cells....
|
|
|
Selectively substituted cyclodextrins for analytical and pharmaceutical applications
Benkovics, Gábor ; Jindřich, Jindřich (advisor) ; Lhoták, Pavel (referee) ; Šindelář, Vladimír (referee)
3 Selectively substituted cyclodextrins for analytical and pharmaceutical applications Abstract This thesis is focused on the selective modification of cyclodextrins, and its primary aim is the preparation and characterization of mono- and persubstituted derivatives of cyclodextrins in a regioselective and straightforward manner. The work is divided into two main parts describing synthetic strategies and applications of modified cyclodextrins with one or several substituents, respectively. The first section deals with the introduction of a single chromophoric moiety on the cyclodextrin scaffold such as cinnamyl, rhodaminyl, fluoresceinyl and eosinyl groups. The complete set of monocinnamyl-α-cyclodextrin regioisomers has been prepared by direct alkylation, and the self-assembling properties of the corresponding regioisomers were thoroughly investigated by dynamic light scattering and NMR experiments. These investigations revealed that the different isomers (mono-6-O-, mono-2-O- and mono-3-O- cinnamyl-α-cyclodextrin) form distinct supramolecular species through intermolecular association. A fast method for the unambiguous identification of the pure regioisomers has also been developed based on a series of 2D NMR measurements. Xanthene-modified β-cyclodextrins, other representatives of monosubstituted...
|
|
|
Fluorescence Detection of Skin Tumours
Stíbal, Adam ; Dědic, Roman (advisor) ; Hála, Jan (referee)
This thesis discusses the photodynamic therapy (PDT) and it's application for dia- gnostics of tumours. The PDT is based on production of reactive oxygen species (ROS) from the molecules of photosensitizers (PS). PS are preferentially accumulated in disea- sed tissues, where ROS are produced and cause selective destruction of the target tissue, while surrounding healthy tissue remains intact. The photodynamic diagnostics uses the fluorescence of PS for digital and spectral imaging. This thesis is focused on detection of tumours from spectral characteristics of protoporphyrin IX fluorescence induced in tis- sue by methyl-aminolevulinate. The main part of the research was realised on rats' scars in vivo, the solutions of homogenized mouse fibroblasts were also studied. The way to distinguish between diseased and healthy tissue was found using measurements of fluo- rescence bleaching kinetics.
|
|
|
Preparation and photophysical evaluation of tetra-3,4-pyridoporphyrazines suitable for the photodynamic therapy
Čermák, Pavel ; Nováková, Veronika (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Biophysics and Physical Chemistry Candidate: Pavel Cermak Supervisor: Assoc. Prof. Veronika Novakova, PhD. Title of Thesis: Preparation and photophysical evaluation of tetra-3,4- pyridoporphyrazines suitable for the photodynamic therapy Tetra-3,4-pyridoporphyrazines (TPyPz) are aza-analogues of phthalocyanines. Their large system of conjugated bonds enables them to absorb light in the red part of the absorption spectrum. Due to their ability to produce singlet oxygen, they can be potentially used as photosensitizers in photodynamic therapy (PDT). Its mechanism is based on co-functioning of three elements - photosensitizer, light and oxygen. Photosensitizer excited by light absorption transfers its energy into tissue oxygen, thus, creating cytotoxic singlet oxygen. This method is beneficial for its high selectivity, low toxicity, minimal invasion and fast effect. The aim of this work was to synthetize and study water-soluble TPyPz suitable for PDT. Water solubility was achieved by quarternized amines, forming of salts or using suitable delivery systems (hydrophilic emulsion). Hydrophilicity was also increased by introduction of hydrophilic non-charged substituents (OH). At first, appropriate precursors for...
|
|
|
Molecular mechanisms of apoptosis induced by photodynamic activation in cancer cells
Moserová, Irena ; Králová, Jarmila (advisor) ; Kuželová, Kateřina (referee) ; Kovář, Jan (referee)
Photodynamic therapy (PDT) is a treatment modality for cancer. It combines selective accumulation of chemical compounds, called photosensitizers (PS), with light to irreversibly damage cancer cells via oxidative stress. The main goal of this thesis was to study photosensitizers represented by a unique group of newly synthesized porphyrin derivatives with glycol chain substitution. Glycol-functionalized porphyrins containing one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin (mTPP(EG)1-4) were compared with fluorinated (pTPPF(EG)4) and nonfluorinated (TPP(EG)4) derivatives having glycol chains in para-phenyl positions. The cellular uptake and photodynamic activity was significantly dependent on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, exhibited efficient intracellular transport and high induction of apoptosis in tumor cell lines in vitro. After initial testing effective prototype hydroxy ethylene glycol derivatives were selected and analyzed in detail. Para derivatives pTPP(EG)4 and pTPPF(EG)4 accumulated mainly in lysosomes whereas meta derivatives mTPP(EG)1-4 in the endoplasmic reticulum (ER). Position of ethylene glycol chain on the...
|
|
|
Selectively substituted cyclodextrins for analytical and pharmaceutical applications
Benkovics, Gábor ; Jindřich, Jindřich (advisor) ; Lhoták, Pavel (referee) ; Šindelář, Vladimír (referee)
3 Selectively substituted cyclodextrins for analytical and pharmaceutical applications Abstract This thesis is focused on the selective modification of cyclodextrins, and its primary aim is the preparation and characterization of mono- and persubstituted derivatives of cyclodextrins in a regioselective and straightforward manner. The work is divided into two main parts describing synthetic strategies and applications of modified cyclodextrins with one or several substituents, respectively. The first section deals with the introduction of a single chromophoric moiety on the cyclodextrin scaffold such as cinnamyl, rhodaminyl, fluoresceinyl and eosinyl groups. The complete set of monocinnamyl-α-cyclodextrin regioisomers has been prepared by direct alkylation, and the self-assembling properties of the corresponding regioisomers were thoroughly investigated by dynamic light scattering and NMR experiments. These investigations revealed that the different isomers (mono-6-O-, mono-2-O- and mono-3-O- cinnamyl-α-cyclodextrin) form distinct supramolecular species through intermolecular association. A fast method for the unambiguous identification of the pure regioisomers has also been developed based on a series of 2D NMR measurements. Xanthene-modified β-cyclodextrins, other representatives of monosubstituted...
|
|
|
Preparation and photophysical evaluation of tetra-3,4-pyridoporphyrazines suitable for the photodynamic therapy
Čermák, Pavel ; Nováková, Veronika (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Biophysics and Physical Chemistry Candidate: Pavel Cermak Supervisor: Assoc. Prof. Veronika Novakova, PhD. Title of Thesis: Preparation and photophysical evaluation of tetra-3,4- pyridoporphyrazines suitable for the photodynamic therapy Tetra-3,4-pyridoporphyrazines (TPyPz) are aza-analogues of phthalocyanines. Their large system of conjugated bonds enables them to absorb light in the red part of the absorption spectrum. Due to their ability to produce singlet oxygen, they can be potentially used as photosensitizers in photodynamic therapy (PDT). Its mechanism is based on co-functioning of three elements - photosensitizer, light and oxygen. Photosensitizer excited by light absorption transfers its energy into tissue oxygen, thus, creating cytotoxic singlet oxygen. This method is beneficial for its high selectivity, low toxicity, minimal invasion and fast effect. The aim of this work was to synthetize and study water-soluble TPyPz suitable for PDT. Water solubility was achieved by quarternized amines, forming of salts or using suitable delivery systems (hydrophilic emulsion). Hydrophilicity was also increased by introduction of hydrophilic non-charged substituents (OH). At first, appropriate precursors for...
|
|
|
Fluorescence Detection of Skin Tumours
Stíbal, Adam ; Dědic, Roman (advisor) ; Hála, Jan (referee)
This thesis discusses the photodynamic therapy (PDT) and it's application for dia- gnostics of tumours. The PDT is based on production of reactive oxygen species (ROS) from the molecules of photosensitizers (PS). PS are preferentially accumulated in disea- sed tissues, where ROS are produced and cause selective destruction of the target tissue, while surrounding healthy tissue remains intact. The photodynamic diagnostics uses the fluorescence of PS for digital and spectral imaging. This thesis is focused on detection of tumours from spectral characteristics of protoporphyrin IX fluorescence induced in tis- sue by methyl-aminolevulinate. The main part of the research was realised on rats' scars in vivo, the solutions of homogenized mouse fibroblasts were also studied. The way to distinguish between diseased and healthy tissue was found using measurements of fluo- rescence bleaching kinetics.
|
|
|
Molecular mechanisms of apoptosis induced by photodynamic activation in cancer cells
Moserová, Irena ; Králová, Jarmila (advisor) ; Kuželová, Kateřina (referee) ; Kovář, Jan (referee)
Photodynamic therapy (PDT) is a treatment modality for cancer. It combines selective accumulation of chemical compounds, called photosensitizers (PS), with light to irreversibly damage cancer cells via oxidative stress. The main goal of this thesis was to study photosensitizers represented by a unique group of newly synthesized porphyrin derivatives with glycol chain substitution. Glycol-functionalized porphyrins containing one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin (mTPP(EG)1-4) were compared with fluorinated (pTPPF(EG)4) and nonfluorinated (TPP(EG)4) derivatives having glycol chains in para-phenyl positions. The cellular uptake and photodynamic activity was significantly dependent on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, exhibited efficient intracellular transport and high induction of apoptosis in tumor cell lines in vitro. After initial testing effective prototype hydroxy ethylene glycol derivatives were selected and analyzed in detail. Para derivatives pTPP(EG)4 and pTPPF(EG)4 accumulated mainly in lysosomes whereas meta derivatives mTPP(EG)1-4 in the endoplasmic reticulum (ER). Position of ethylene glycol chain on the...
|
guest ::
