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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 Transport Mechanisms of Receptor-Specific Radiopharmaceuticals in the Kidney Cells.
Cihlo, Jan ; Lázníček, Milan (advisor) ; Šimůnek, Tomáš (referee) ; Komárek, Pavel (referee)
Renal accumulation of radiolabelled receptor specific substances can represent clinical problems for diagnosis and therapy of some typical malignancies due to radionephrotoxicity of these substances. The aim of this work was to design a suitable in vitro model for evaluating cumulative disposals of studied radiopharmaceuticals in the kidney and for finding possible mechanisms reducing the reabsorption of these substances by renal tubular cells. The suggested model designed for this purpose provides another opportunity for evaluation of their radionephrotoxical potential. The aforementioned in vitro method was standardised and used for the study of transport mechanism of some representatives of radiolabelled somatostatin analogues (111In/125I/90Y/177Lu-DOTA-Tyr3-octreotate, 111In/90Y/177Lu-DOTA-1-Nal3-octreotide), antibodies (111In/90Y/99mTc-AntiCD66) and albumin (FITC-albumin, 99mTc-albumin). All studied radioactive substances were radiolabelled with good practice and analyzed using HPLC and/or ITLC-SG methods. The radiolabelling technique of all studied specifically acting substances (radiolabelled peptides and antibodies) and also any concrete radionuclide showed no significant influence over the internalization into the renal OK cells. The difference of the internalized amount of FITC-albumin and...
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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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Modification of antibody fragments and their radiolabeling by unconventional positron emitters and biological testing for PET diagnostics
Čepa, Adam ; Lázníček, Milan (advisor) ; Komárek, Pavel (referee) ; Melichar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmacology and Toxycology Candidate Adam Cepa, MSc. Supervisor Prof. PharmDr. Ing. Milan Laznicek, CSc. Title of Doctoral Thesis Modification of antibody fragments and their radiolabeling by unconventional positron emitters and biological testing for PET diagnostics Special oncology diagnostics require new types of selective radiopharmaceuticals, especially those that are suitable for molecular PET imaging and therapy, respectively, teranostics. The aim of this work is to present a new target radiopharmaceutical for immunoPET diagnosis and therapy based on the monoclonal antibody IgG M75 directed to human carbonic anhydrase IX, nimotuzumab (hR3) target epidermal growth factor receptor (EGFR) and one of the bombesin derivatives (BBN) repeats. These molecules were labeled with radionuclides 64Cu (t1/2 12.70 hours), 61Cu (t1/2 3.33 hours), 68Ga (t1/2 68 min), 177Lu (t1/2 6.71 days). These potential radiopharmaceuticals were evaluated in vitro and in vivo. The IgG M75 antibody and its scFv-Fc M75 fragment were prepared by the genetic modification were conjugated to a specific chelator specific phosphinate (PHS) and radiolabeled by the radionuclides 61,64Cu. The stability of the labeled conjugate was tested in human...
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Modification of antibody fragments and their radiolabeling by unconventional positron emitters and biological testing for PET diagnostics
Čepa, Adam ; Lázníček, Milan (advisor) ; Komárek, Pavel (referee) ; Melichar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmacology and Toxycology Candidate Adam Cepa, MSc. Supervisor Prof. PharmDr. Ing. Milan Laznicek, CSc. Title of Doctoral Thesis Modification of antibody fragments and their radiolabeling by unconventional positron emitters and biological testing for PET diagnostics Special oncology diagnostics require new types of selective radiopharmaceuticals, especially those that are suitable for molecular PET imaging and therapy, respectively, teranostics. The aim of this work is to present a new target radiopharmaceutical for immunoPET diagnosis and therapy based on the monoclonal antibody IgG M75 directed to human carbonic anhydrase IX, nimotuzumab (hR3) target epidermal growth factor receptor (EGFR) and one of the bombesin derivatives (BBN) repeats. These molecules were labeled with radionuclides 64Cu (t1/2 12.70 hours), 61Cu (t1/2 3.33 hours), 68Ga (t1/2 68 min), 177Lu (t1/2 6.71 days). These potential radiopharmaceuticals were evaluated in vitro and in vivo. The IgG M75 antibody and its scFv-Fc M75 fragment were prepared by the genetic modification were conjugated to a specific chelator specific phosphinate (PHS) and radiolabeled by the radionuclides 61,64Cu. The stability of the labeled conjugate was tested in human...
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Analysis of the Biological Behavior of Receptor-Specific Radiopharmaceuticals in Vitro
Melicharová, Ludmila ; Lázníček, Milan (advisor) ; Pávek, Petr (referee) ; Komárek, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Department of: Pharmacology and Toxicology Candidate: PharmDr. Ludmila Melicharová Supervisor: Prof. PharmDr. Ing. Milan Lázníček, PhD. Title of Doctoral Thesis: Analysis of the biological behavior of receptor-specific radiopharmaceuticals in vitro In the present work were studied receptor-specific radiopharmaceuticals and their biological behavior. Studies were performed with radiolabelled somatostatin and gastrin analogues. All of these substances are potentially useful in the diagnosis and therapy of neuroendocrine tumors. Somatostatin analogues under study: DOTA-TATE and DOTA-NOC labelled with 111 indium, 177 lutetium, 90 yttrium and 125 iodine. The studies were performed on AR42J cell line (rat pancreatic tumour cells). Internalization rate of these analogues and their specific binding to the cells with high density of appropriate receptors were determined. The data were compared with values obtained after intravenous administration of the same peptides to rats. The uptake of radioactive peptides in tissues with high density of somatostatin receptors in vivo were correlated with the results obtained in vitro conditions. We have compared four 111 In labelled gastrin analogues (so called minigastrins /MG/, namely MG11, MG45,...
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Study of plasma protein binding of radiopharmaceuticals
Hafinec, Václav Matyáš ; Lázníček, Milan (advisor) ; Ramos Mandíková, Jana (referee)
Study of Plasma Protein Binding of Radiopharmaceuticals Summary The purpose of this work is the study of binding of substances (177 Lu-DOTA- [Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu-PCTA-[Lys3]bombesin, and 177 Lu- DOTA-MG47) to plasma proteins by equilibrum dialysis in 37řC, particularly using plasma samples of beef, rabbit, rat and human. Within this group, these substances were compared interspecifically. The substances 177 Lu-DOTA-[Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu- PCTA-[Lys3]bombesin, and 177 Lu-DOTA-MG47 are the newly developed receptor- specific radiolabeled peptides. For all the newly collected data, the interspecific comparison and subsequent statistical evaluation was performed. The indicated bombesin derivates were compared and statistically analyzed even between themselves. During the interspecies comparisons and the determination of the statistical significance of the data, there were found statistically significant and statistically highly significant differences between some of the examined samples. A highly significant difference was found during comparing with samples of 177 Lu-NOTA- [Lys3]bombesin and statistical evaluation, there was found a statistically highly significant difference. Despite the differences found, it is clear that the plasma binding concerning...
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Study of plasma protein binding of new radiopharmaceuticals
Šejnová, Barbora ; Lázníček, Milan (advisor) ; Melicharová, Ludmila (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ Department of Pharmacology and Toxicology DIPLOMA THESIS: Study of plasma protein binding of new radiopharmaceuticals SUMMARY: The binding ability of two receptor specific peptides - 111 In - DOTA - minigastrin 45 and 177 Lu - DOTA - bombesin - was studied by methods of equilibrium dialysis at 37řC and ultrafiltration in terms of interspecies comparison. Among selected animal species (rat, rabbit, bovine, human) was plasma protein binding completely different. Higher binding was observed for 111 In - DOTA - minigastrin 45. In comparison of both methods - higher values of binding were measured for both peptides and all species by ultrafiltration than by equilibrium dialysis. KEYWORDS: radiopharmaceuticals, plasma protein binding, equilibrium dialysis, ultrafiltration, 111 In - DOTA - minigastrin 45, 177 Lu - DOTA - bombesin Barbora Šejnová Hradec Králové 2011
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Determination of plasma protein binding of new radiopharmaceuticals for Alzheimer's disease imaging
Hyršová, Lucie ; Lázníček, Milan (advisor) ; Melicharová, Ludmila (referee)
CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Lucie Hyršová Supervisor: Prof. PharmDr. Ing. Milan Lázníček CSc. Title of thesis: Determination of plasma protein binding of new radiopharmaceuticals for Alzheimer`s disease imaging Summary: Determination of plasma protein binding of new potential drugs belongs to basic parameters which are made at early stages of clinical trials. The drug-protein binding affects all the pharmacokinetic factors and it influences pharmacodynamics as well. The aim of this thesis is to examine binding of 99m Tc-5C-2-BOC and 99m Tc-5C-5-BOC which are potential radiodiagnostics of Alzheimer`s disease, is investigated in this work. Blood plasma of four species (namely human, rabbit, bovine and sewer rat`s plasma) is tested and findings are mutually compared. The binding in both cases is determined by means of two methods - equilibrium dialysis and ultrafiltration. The binding of both substances is the lowest in human and bovine plasma with the use of equilibrium dialysis. The binding of 99m Tc-5C-2-BOC determined by ultrafiltration is the lowest in bovine plasma and a slightly higher in human one, the binding of 99m Tc-5C-5-BOC is the lowest in human plasma. These findings show that binding on plasma proteins...
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