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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 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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Macrocyclic chelators for metal-radionuclides
Málková, Michaela ; Hermann, Petr (advisor) ; Příhoda, Jiří (referee) ; Komárek, Pavel (referee)
5 Abstract in English Complexation properties of structurally related macrocyclic polyazachelators with different metal ions suitable for a medicinal use were studied. In the present work, a study of chelators formally derived from H4dota (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) by replacement of one or four carboxylic groups with a phosphorus acid moiety(ies) was performed. Three new chelators were studied: H4do3apABn (10-{[(4-aminobenzyl)hydroxyphosphoryl]methyl}- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), H5do3apPrA (10-{[(2-carboxyethyl)hydroxyphosphoryl]methyl}- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), H4dotpOEt [1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrakis(methylphosphonic acid monoethylester)] In addition new data on stability constants of transition metal complexes of H5do3ap, 10-[(dihydroxyphosphoryl)methyl]- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, are presented. The achieved results suggest that all studied chelators form complexes with di- and trivalent metal ions with sufficient thermodynamic stability and kinetic inertness for the potential medicinal applications. The formation rate of complexes of the monophosphonic/inic chelators is comparable to that of the H4dota complexes. The formation rate of the complexes depends highly on...
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OSCE as a mediator of the conflict in Transnistria
Komárek, Pavel ; Karlas, Jan (advisor) ; Ditrych, Ondřej (referee)
The thesis deals with the mediation role of the OSCE in the conflict in Transnistria. The aim of the work is to assess success of the OSCE mission and analyse the main factors that influence the success. Contingency model is used for the analysis, based on an assumption that a conflict is a dynamic process, and during its analysis and search for a solution we have to view it as a complex, in as wide a context as possible. Via contingency model, it is possible to explain the success of the mediation mission on the basis of an analysis of two types of independent variables - contextual and process. Contingency model differs from other approaches in mediation, being specific because it does not automatically suppose certain success of mediator's work. Thanks to its complexity, it therefore offers a convenient analytical framework that makes it possible to study the success of mediation in various contexts. Although the OSCE has achieved a lot and has had a positive impact on the evolution of the conflict as well as the overall situation in the region, the main aim of the mission - i.e. the arrangement of finding a stable political settlement of the conflict - has not been reached yet. Also, the OSCE has not managed to accomplish another two very delicate goals: to contribute by its activities to the...
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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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Sortimenty severoamerických aster rodu Symphyotrichum a jejich hodnocení v podmínkách středoevropského termofytika
Komárek, Pavel
This thesis deals with the evaluation renge of North American asters species Symphyotrichum Ness. Furthmore by their history, morphological, physiological, cultivation and introductionhistorical aspect. In this thesis was evaluated 85 kind and varieties of the genus Symphyotrichum Ness and existing range of collection ZF MENDELU expanded to 138 pieces autumn asters. Part of this work is to compare varieties of these specials and recommendations for the best of them, for gardeners, and for use in urban greenery.
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Mechanisms of membrane transport of radiolabeled receptor-specific peptides in the kidney
Volková, Marie ; Trejtnar, František (advisor) ; Mičuda, Stanislav (referee) ; Komárek, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: PharmDr. Marie Volková Supervisor: doc. PharmDr. František Trejtnar, CSc. Title of doctoral thesis: Mechanisms of membrane transport of radiolabeled receptor-specific peptides in the kidney Radiolabelled receptor-specific peptides are a useful tool for radiodiagnostic and radiotherapy of some neuroendocrine tumours. Despite many recent developments in this radiopharmaceutical group, there is still a lack of relevant information about the mechanisms determining the pharmacokinetics and describing interactions with membrane transport systems. These transporters may be responsible for undesirable renal accumulation and subsequent radiotoxic kidney damage, which significantly limited the use of radiopeptides in nuclear medicine. The aim of our work was to assess the role of several transport mechanisms that can be potentially involved in the transmembrane transport of radiopeptides in the renal tissue. We mainly focused on studying the role of megalin mediated active endocytosis, fluid phase endocytosis and important human renal SLC transporters - hOAT1 and hOCT2. Simultaneously, the potential transport of selected radiometabolites of these peptides was studied in vitro and their...
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