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The Study of Receptor-specific Radiopharmaceuticals Interactions with Biological Systems at the Cellular Level
Bárta, Pavel ; Lázníček, Milan (advisor) ; Nachtigal, Petr (referee) ; Štětina, Rudolf (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Pavel Bárta Supervisor Prof. PharmDr. Ing Milan Lázníček, CSc. Title of Doctoral Thesis The study of receptor-specific radiopharmaceuticals interactions with biological systems at the cellular level The targeting of receptor specific peptides or antibodies is one important diagnostic and therapeutic tool in the fight against cancer diseases. Receptor specific peptides often have their origin from the human natural peptide hormones; hence they are commonly marked as peptide analogues. The peptide analogues contain in their amino acids sequence the binding site identical with the site of natural peptides, which they are originated from. This binding site is responsible for the interaction with the targeted receptor. The peptide analogues are employed instead of the natural peptides because their biological properties can be improved, for example facilitating distribution in the organism to their place of action, or protection from biological degradation. The peptide ligand binding itself on targeted receptors and its internalization into cells typically does not trigger a therapeutic effect. From this reason, peptide analogues carry active substances like cytotoxine or...
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Study on Renal Accumulation of Receptor-specific Radiopeptides
Kubačková, Tereza ; Trejtnar, František (advisor) ; Lázníček, Milan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Tereza Kubačková Consultant: doc. PharmDr. František Trejtnar, CSc. Title of Thesis: Study on renal accumulation of receptor-specific radiopeptides Radiolabeled peptides targeted to cholecystokinin/gastrin receptors are promising compounds for radiodiagnostics and radiotherapy of some malignancies. Shorter chain derivates of gastrin called minigastrins are particularly interesting. The use of these agents is limited by their nephrotoxicity caused by accumulation of the radiopeptides in the kidney. The aim of the study was to investigate accumulation rate and renal uptake mechanisms of new receptor specific peptides from the group of gastrin analogs using in vitro models. The investigation was aimed at a comparison of the renal uptake of DOTA-minigastrin 48 (DOTA-MG48) and DOTA-minigastin 11 (DOTA-MG11), both labeled with indium-111. In addition, a potential influence of the radiolabel on the renal accumulation was also investigated using DOTA- MG11 labeled with indium-111 or with lutecium-177. A comparison of the renal accumulation of the radiolabeled minigastrins with compounds from another group of receptor specific radiopeptides - somatostatin analogs such as 111 In-DOTA-NOC...
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Interspecies Comparison of Plasma Protein Binding of Recently Prepared Radopharmaceuticals
Drymlová, Petra ; Lázníček, Milan (advisor) ; Trejtnar, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Petra Drymlová Consultant: Prof. PharmDr. Ing. Milan Lázníček, CSc Title of thesis: Interspecies comparison of plasma protein binding of recently prepared radiopharmaceuticals. Plasma protein binding is one of the parameters, which significantly influence pharmacokinetics of drug. The aim of this thesis was to determine binding of three potential radiopharmaceuticals to the proteins of human, bovine, rabit and rat plasma by the method of equilibrium dialysis at 37řC. Concretely these compounds were bifunctional chelating agent 111In-DTPA-oxn, the derivative of commonly used chelate DTPA, and two labelled receptor specific peptides- somatostatin analog 177Lu-DOTA-NOC and gastrin derivative 111In-DOTA-MG-1. The results shows that plasma protein binding of 111In-DTPA-oxn is very low and pharmacokinetically unimportant as at the standard compound 111In-DTPA. Plasma protein binding of somatostatin derivative 177In-DOTA-NOC is between 30,0- 41,4 % and increases in order: bovine < rabbit < human < rat plasma. Statistically significant difference to human plasma was found only at bovine plasma. Plasma protein binding of peptide 111In- DOTA-MG-1 was found very low and in spite of...
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Study of Biological Properties of Hyaluronic Acid Derivatives
Svanovský, Evžen ; Lázníček, Milan (advisor) ; Tilšer, Ivan (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxikology Candidate: Mgr. Evžen Svanovský Supervisor: Prof. PharmDr. Ing. Milan Lázníček, CSc. Title of Doctoral Thesis: Study of biological properties of hyaluronic acid derivatives This PhD thesis, is dealing with physiological properties of Hyaluronic Acid labelled with 111 In isotope. HA is naturally occurring Glycosaminoglycan within organisms with many important functions on the cellular and organ level, including physiological and pathological processes. Its character of physiologically occurring substance makes its tracing in the organism very difficult. Thus preparation of suitable derivative and repeatable procedure of labelling of this molecule became the most important point of the whole work. During the experimental part DTPA-HA molecule created by CPN Dolni Dobrouč has been labelled using well-known method used for labelling of DTPA molecules with 111 In. A reproducible procedure has been created where 0,4 M Acetate buffer pH 5,5 is mixed with an equal volume of DTPA-HA purified by gel filtration and required amount of isotope 111 In and the whole mixture is mixed for 0,5 h. This method was used for labelling of DTPA-HA molecules of three different molecular weights 10, 100 and 400kDa,...
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Study of stability of receptor specific radiopharmaceuticals
Hanzalová, Lenka ; Lázníček, Milan (advisor) ; Trejtnar, František (referee)
Thesis: Determination of radiochemical purity and stability compared to two selected receptor-specific radiolabelled peptides. Charles University, Faculty of Pharmacy in Hradec Kralove Lenka Hanzalová, May 2011 Abstract: Radiopharmaceuticals are among medicinal substances which have very a limited application over time. Not only due to the fact that it gradually decreases their activity, depending on the half-life of the radionuclide applied, but it may also lead to destructive reactions in the molecule. In view of these reactions, there are decreases in the percentage of radiopharmaceutical degradation of products, which reduces the value of medicines. Degradation of products containing non-peptide nature radionuclides from the parent substances differ in their distribution in the body, increasing side effects, and radiopharmaceuticals, due to their nature, can accumulate in different tissues and subsequently damage them. It is therefore important to know and be able to assume representation of the evolution of the degradation of products over time. In the presented thesis, the problem of determining stability, or radiochemical purity at different time intervals in two days, is solved. Substances being compared were a synthetic somatostatin analogue, labelled with radionuclides two mA, pure beta-emitter 90...
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Radiodignostics of breast cancer
Bahenská, Kristýna ; Lázníček, Milan (advisor) ; Melicharová, Ludmila (referee)
Kristýna Bahenská Radiodiagnostics of breast cancer Vedoucí diplomové práce: Prof. PharmDr. Ing. Milan Lázniček, CSc. Mamodiagnostics is today the only way of oncoprotection dealing with breast cancer . It is also the single tool applicable to decrease mortality of this disease. For further development of breast cancer radiodiagnostics very important role have nuclear medicine and also improvement of imaging methods. These are the contemporary ways helping in more precise diagnostics of breast cancer disease.
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Study of plasma protein binding of receptor-specific peptides
Křivková, Šárka ; Lázníček, Milan (advisor) ; Trejtnar, František (referee)
SUMMARY: Drug binding to plasma proteins is one of the primary pharmacological parameters. The binding rate has significant effects on drug distribution and drug elimination. In vitro investigation of plasma protein binding helps us foresee their destiny after its administration to a living organism. This dissertation focused on studying plasma protein binding of DOTA-NOC marking by 90 Y and 111 In in term of interspecies comparison. The binding was determined by methods of equilibrium dialysis at 37řC. Results showed binding of 90 Y-DOTA-NOC increases respectively: human < rabbit < bovine < rat plasm. Binding of 111 In-DOTA-NOC increases respectively: pork < human < rat < rabbit plasm. KEYWORDS: protein binding, DOTA-NOC, 111 In, 90 Y, interspecies comparison
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Study of plasma binding of receptor-specific peptides
Gregor, David ; Lázníček, Milan (advisor) ; Trejtnar, František (referee)
The binding ability of two receptor specific peptides namely 90Y-DOTA-TATE and 111In-DOTA-TATE was studied in therm of interspecies comparison by the method of equilibrium dialysis. This plasma protein binding was different for the chosen animal species (human, rat, rabbit, bovine eventually pork) whereas binding of 90Y-DOTA- TATE was higher than binding of 111In-DOTA-TATE. KEYWORDS: Protein binding, radiofarmaceuticals, equilibrium dialysis, 90Y-DOTA-TATE, 111In- DOTA-TATE
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Determination of radiochemical purity and stability of new radiopharmaceuticals
Vorlová, Nikola ; Trejtnar, František (referee) ; Lázníček, Milan (advisor)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Nikola Vorlová Supervisor: Prof. PharmDr. Ing. Milan Lázniček, CSc. Title of diploma thesis: The determination of radiochemical purity and stability of newly developed radiopharmaceuticals. The theme of this thesis is determination of radiochemical purity and stability of newly developed radiopharmaceuticals from the group of receptor specific peptides and antibodies by using liquid chromatography - HPLC and thin layer chromatography ITLC -SG method. The antibody sample 177Lu-hR3-I has been studied in the theses( 177 Lu enters in to relation with modified antibody Nimotuzumab), which blocs EGF receptors and due to this fact the growth of tumor cells too. It has been detected, that it is necessary for reaching sufficient radiochemical purity to clean this radio-labeled antibody by the gel chromatography after labeling. Radio-chemical purity of this sample circulate from 99,46 % to 88,77 % during period of 6 days. Another samples have been studied, 111In-minigastrin - radioisotope 111 In linked up to three different minigastrins I, II, and III. Minigasrins are gastrin derivates , which have a very good absorptive capacity to receptors for cholecystokinin (CCK-B receptors) occurring in...
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