Rostoucí incidence karcinomu prostaty je – především s ohledem na snadno vyčerpatelné způsoby terapie při progresi tohoto onemocnění do metastatického kastračně rezistentního stadia – hlavní hnací silou pro rozvoj nových léčebných modalit. Radioligandová terapie je jednou z možností, ke které by bylo možné se uchýlit. Tento způsob léčby využívá ligandy schopné cílit na konkrétní buněčné struktury, a dopravit tak zdroj ionizujícího záření přímo k nádorovým buňkám. Radiofarmakum tak působí radiační poškození přímo nádorovým buňkám při minimálním ozáření zdravé tkáně. Lutecium (177Lu) vipivotid tetraxetan (přípravek Pluvicto) patří mezi radiofarmaka, která je dnes možné použít k radioligandové léčbě, konkrétně k terapii metastatického kastračně rezistentního karcinomu prostaty u pacientů, u kterých jiné léčebné postupy již selhaly. Tento článek si klade za cíl shrnout dosavadní poznatky o výzkumu a možnostech použití tohoto radiofarmaka.

The increasing incidence of prostate cancer, especially with regard to the easily exhausted methods of therapy when once developed to the metastatic castration-resistant stage, is the main driving force for the development of new treatment modalities. Radioligand therapy is one option that one can resort to. This therapy uses ligands capable of targeting specific cell structures, thereby delivering a source of ionizing radiation directly to the tumour cells. The radiopharmaceutical thus causes radiation damage directly to the tumour cells with minimal irradiation of healthy tissue. Lutetium ( 177 Lu) vipivotide tetraxetan (Pluvicto) belongs to the radiopharmaceuticals that can be used today for radioligand therapy, specifically for the treatment of metastatic castration-resistant prostate cancer in cases when other treatments have already failed. This article aims to summarize the current knowledge about research and use of this radiopharmaceutical.

• MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• lutecium * farmakokinetika   farmakologie   terapeutické užití   účinky záření   MeSH
• nádory prostaty rezistentní na kastraci MeSH
• nádory prostaty * terapie   MeSH
• prostatický specifický antigen MeSH
• protokoly protinádorové léčby MeSH
• radiofarmaka aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• radioligandová zkouška metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [(89)Sr]SrCl2 and [(153)Sm]Sm-EDTMP. No-carrier-added (n.c.a.) (177)Lu is remarkably suitable for an application in this scope. METHODS: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. (177)Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [(177)Lu]citrate. RESULTS: Radiolabelling yields for [(177)Lu]Lu-DOTA and [(177)Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All (177)Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. (177)Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [(177)Lu]Lu-DO2A(P(BP))2; SUVfemur = 5.41 ± 0.46 for [(177)Lu]Lu-DOTA(M(BP))2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [(177)Lu]Lu-DO2A(P(BP))2; SUVblood = 1.43 ± 0.32 for [(177)Lu]Lu-DOTA(M(BP))2). CONCLUSIONS: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

• Publikační typ
• časopisecké články MeSH

OBJECTIVE: [ 177 Lu]Lu-PSMA radioligand therapy (PSMA-RLT) is a promising therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) and offers a survival benefit particularly to patients with only lymph node metastases. We therefore sought to evaluate the clinical outcome of this therapy in such a cohort. METHODS: Of all prostate cancer patients admitted to our department between September 2015 and March 2019 to receive 1-4 courses of PSMA-RLT (each course consisted of three cycles of highly standardized PSMA-RLT every 4 weeks), only 10 consecutive men were found to have nodal metastases only and were analyzed retrospectively. RESULTS: Nine out of 10 patients responded to their first PSMA-RLT course with a mean prostate-specific antigen (PSA) decline of 71.8 ± 25.2%, seven of them demonstrated a PSA decline of ≥50%. Collectively, seven of eight patients responded to further PSMA-RLT courses with a total PSA reduction of 59.8 ± 30.0%, five of which showed a PSA reduction of ≥50%. One patient experienced complete remission. Median progression-free survival was 85 weeks (range 14-255 weeks) and median overall survival was not reached during the median observation time of 209 weeks (30-298 weeks). Univariate Cox-regression identified initial PSA decline as the only predictive parameter for progression-free survival ( P = 0.047). CONCLUSION: mCRPC patients with only lymph node metastases showed favorable survival and excellent response to PSMA-RLT, leading to transient partial remission of the disease in most of them.

• MeSH
• dipeptidy terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické terapeutické užití   MeSH
• lidé MeSH
• lutecium terapeutické užití   MeSH
• lymfatické metastázy MeSH
• nádory prostaty rezistentní na kastraci * patologie   MeSH
• prostatický specifický antigen * MeSH
• radionuklidy MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The humanized monoclonal antibody Nimotuzumab (h-R3) has demonstrated an exceptional and better clinical profile than other monoclonal antibodies for immunotherapy of epidermal growth factor receptor-overexpressing tumors. This work deals with the preparation and radiolabeling optimization of (177)Lu-Nimotuzumab and their preclinical evaluation. METHODS: Nimotuzumab was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), testing different molar ratios. The immunoconjugates were characterized. The radiolabeling with (177)Lu was optimized. Radioimmunoconjugates stability was tested in 2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA) excess and human serum. In vitro studies were performed in tumor model cell lines. Receptor-specific binding was tested by competitive inhibition. (177)Lu-Nimotuzumab in vivo studies were conducted in healthy and xenograft animals. RESULTS: Nimotuzumab conjugates were obtained with high purity. Radiolabeling yield and specific activities ranged from 63.6% to 94.5% and from 748 to 1142 MBq/mg, respectively. The stability in DTPA excess and human serum was 95.9% and 93.2% after 10 days, respectively. The radioimmunoconjugate showed specific receptor binding in tumor cell lines. Biodistribution in healthy animals showed the typical behavior of the immunoconjugates based on monoclonal antibodies. The study in xenografts mice demonstrated uptake of (177)Lu-Nimotuzumab in the tumor and reticuloendothelial organs. CONCLUSIONS: (177)Lu-Nimotuzumab was obtained with high purity and specific activities under optimal conditions without significant loss in immunoreactivity and might be a potential radioimmunoconjugate for radioimmunotherapy of tumors with epidermal growth factor receptor overexpression.

• MeSH
• časové faktory MeSH
• chelátory farmakologie   MeSH
• erbB receptory biosyntéza   MeSH
• heterocyklické sloučeniny farmakologie   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• imunokonjugáty terapeutické užití   MeSH
• isothiokyanatany farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• lutecium terapeutické užití   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory terapie   MeSH
• potkani Wistar MeSH
• radioimunoterapie metody   MeSH
• radionuklidy terapeutické užití   MeSH
• regulace genové exprese u nádorů MeSH
• transplantace nádorů MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. METHODS: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin ((177)Lu-DOTA-[Tyr(3)]octreotate, (177)Lu-DOTA-[1-Nal(3)]octreotide), gastrin ((177)Lu-DOTA-sargastrin) and bombesin ((177)Lu-DOTA-[Pro(1),Tyr(4)]bombesin, (177)Lu-DOTA-[Lys(3)]bombesin, (177)Lu-PCTA-[Lys(3)]bombesin) analogues were involved in the study. RESULTS: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. CONCLUSION: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested (177)Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process.

• MeSH
• biologický transport MeSH
• bombesin chemie   metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• endocytóza * MeSH
• gastriny chemie   metabolismus   MeSH
• HeLa buňky MeSH
• izotopové značení MeSH
• lidé MeSH
• lutecium * MeSH
• peptidové hormony chemie   metabolismus   MeSH
• prasata MeSH
• přenašeče organických aniontů nezávislé na sodíku metabolismus   MeSH
• protein 1 přenášející organické anionty metabolismus   MeSH
• somatostatin chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

The epidermal growth factor receptor (EGFR) is a rational target of anticancer therapies due to its overexpression in a variety of malignant epithelial tumors. Nevertheless, this antigen is also present in normal tissues. Consequently, monoclonal antibodies which selectively bind to EGFR-overexpressing tumors will be choice drug candidates for development of radioimmunoconjugates (RIC). Nimotuzumab (h-R3) and trastuzumab are monoclonal antibodies (mAbs) which would preferentially target tissues with EGFR and HER2 overexpression, respectively. In this chapter, we describe preparation and evaluation of the targeting properties of RIC formed by (177)Lu/(90)Y and monoclonal antibodies which selectively target EGFR- and HER2/c-neu-overexpressing tissues. mAbs were labeled with n.c.a. (177)Lu/(90)Y using bifunctional chelating agents. RIC binding properties and toxicity were evaluated in vitro using cell lines with varying antigen expression. In vivo tumor targeting properties of RIC were evaluated in mice bearing colorectal (SNU-C2B) and A431 tumor xenografts. RICs were prepared with specific activities up to 2 GBq/mg without significant loss in biological activity. (90)Y-h-R3/trastuzumab increased cell growth inhibition compared with unmodified mAbs or (90)YCl(3) alone in cell lines with overexpression of the target antigen. (177)Lu-h-R3 showed significantly higher uptake in A431 (22.8 ± 3.1% ID/g) than in SNU-C2B (8.8 ± 4.1% ID/g) xenografts at 72 h post injection, indicating strong association between tumor uptake and EGFR expression levels.

• MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• imunokonjugáty farmakokinetika   terapeutické užití   MeSH
• izotopové značení MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• lutecium terapeutické užití   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• potkani Wistar MeSH
• radioimunoterapie MeSH
• radioizotopy ytria terapeutické užití   MeSH
• radionuklidy terapeutické užití   MeSH
• receptor erbB-2 antagonisté a inhibitory   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite.

• MeSH
• buňky MDCK MeSH
• fenylalanin analogy a deriváty   chemie   farmakokinetika   MeSH
• gastriny chemie   farmakokinetika   MeSH
• HeLa buňky MeSH
• komplexní sloučeniny chemie   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• oligopeptidy chemie   farmakokinetika   MeSH
• potkani Wistar MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• psi MeSH
• radiofarmaka chemie   farmakokinetika   MeSH
• somatostatin analogy a deriváty   chemie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakt z konference MeSH

• MeSH
• lutecium aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• příprava léků metody   MeSH
• radiofarmaka MeSH