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ABSTRACT: Radiolabelled monoclonal antibodies with affinity towards tumour-associated antigens may enhance the efficacy of cancer treatment with targeted radiotherapy. The humanized antibody nimotuzumab represents a promising vector to deliver radioactivity to tumours overexpressing epidermal growth factor receptor type 1 (ErbB1). We analysed the effect of radiolabelling nimotuzumab on its uptake in cancer cells and its biodistribution profile in preclinical experiments.
Nimotuzumab was labelled with 131I by oxidative iodination and with 177Lu using nimotuzumab conjugates with two different chelators (DTPA and DOTA) and two different spacers (p-SCN-Bn and NHS). For the receptor studies, two cell lines (HaCaT and A431) were used. Biodistribution studies were performed in male Wistar rats.
The choice of radiolabel and the manner of its attachment to nimotuzumab had little effect on the internalization of the antibody into ErbB1-expressing cell lines. However, the type of radiolabel, the way in which it was attached to nimotuzumab and the radiolabelling procedure, significantly affected the blood clearance, liver uptake and liver persistence of radiolabelled nimotuzumab. 131I-nimotuzumab had the longest elimination half-life and the lowest radioactivity uptake in the liver. 177Lu-labelled nimotuzumab exhibited a shorter elimination half-life, high radioactivity and long-term retention in the liver.
Journal of Labelled Compounds and Radiopharmaceuticals 05/2013; 56(5):280-288. · 0.91 Impact Factor
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ABSTRACT: The present study compares distribution and elimination characteristics of111In-DTPA-D-Phe1-octreotide and111In-DTPA-L-Phe1 octreotide in rats and evaluated the effect of the replacement of the terminal L-phenylalanine by D-phenylalanine on pharmacokinetic
profiles of the radiolabelled peptides. Both agents exhibited rapid radioactivity clearance from the blood and most organs
and tissues with no systematic and significant differences in activity accumulation. The long-term retention and high radioactivity
concentrations for both compounds under study were found in the kidneys and organs with a high density of somatostain receptors,
such as the pancreas and adrenals. The residence times in these organs were longer for111In-DTPA-D-Phe1-octreotid in comparison with111In-DTPA-L-Phe1-octreotide. The major elimination pathway for both radiolabelled peptides was relatively rapid excretion into the urine.
Analysis of the renal handling by an employment of the perfused rat kidney showed that both peptides were eliminated mainly
by the mechanism of glomerular filtration. Rat liver perfusion experiments confirmed a very low value of bile clearance of
radioactivity for both agents under study.
Keywords
111In-DTPA-D-Phe1-octreotide-DTPA-L-Phe1-octreotide-biodistribution-bioelimination
European Journal of Drug Metabolism and Pharmacokinetics 04/2012; 27(1):37-43. · 0.36 Impact Factor
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ABSTRACT: In this study, we investigated the relationship between affinity to somatostatin receptor subtype2 (SSTR(2)) and uptake of radioactivity from a group of radiolabeled somatostatin analogues in somatostatin receptor-rich tissues of rats. Organs with a high density of somatostin receptors (namely the adrenals and pancreas bearing mainly SSTR(2); this receptor subtype is also the most abundant in somatostatin receptor-positive tumors) were chosen as markers of specific binding of the peptides in vivo. Accumulations of radioactivity in these organs 24 h and 48 h after intravenous administration of six (111)In-labeled octreotide and octreotate derivatives with predominant affinity to SSTR(2) were correlated with affinity to SSTR(2) determined in vitro (IC(50) values). For correlation between adrenal uptake of radioactivity and IC(50), the best fit for exponential dependence was found; for that of pancreas, however, linear dependence was the most suitable. In cases where the values for the peptide with affinity to SSTR subtypes 2, 3 and 5, namely (111)In-DOTA-Nal(3)-octreotide were included in the group of studied agents, substantially less correlations were obtained. Our results showed that uptake of radioactivity in tissues with a high density of somatostatin receptors correlates with somatostatin receptor affinity of receptor-specific peptides; however, other factors (the affinity to particular receptor subtypes, the overall pharmacokinetic profile in the body etc.) may contribute to this observed relationship.
Anticancer research 03/2012; 32(3):761-6. · 1.73 Impact Factor
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ABSTRACT: Somatostatin receptor targeting is a valuable method to treat somatostatin receptor-positive tumours. In peptide receptor radionuclide therapy, it is essential to determine the highest activity that can be safely administered to the patient. As (90)Y emits no gamma rays, absorbed doses for (90)Y are usually estimated using the same peptide labelled with (111)In. The aim of the study was to determine if replacement of (90/88)Y by (111)In affects the biodistribution profile of five selected somatostatin analogues in preclinical experiments.
Radiolabelled peptides were administered intravenously to male Wistar rats.
The peptides under study labelled either with (111)In or with (88/90)Y showed similar distribution profiles in all tissues excepting the kidney. The kidney radioactivity uptake was significantly lower for (88/90)Y-labeled peptide in comparison with the one of (111)In.
We conclude that a radiation-absorbed dose after (90)Y-labelled somatostatin analogues appears to be lower than that predicted by the (111)In-labelled peptide.
Anticancer research 03/2012; 32(3):815-22. · 1.73 Impact Factor
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ABSTRACT: Radiolabeled cholecystokinin/gastrin (CCK) receptor-targeting peptides are promising compounds for radiodiagnosis and radiotherapy of certain malignancies. This study evaluated the pharmacokinetic profile of a CCK-2 receptor-specific peptide, Demogastrin 1, labeled with technetium-99m ((99m)Tc-Demogastrin 1), in rats. To investigate the fate of (99m)Tc-Demogastrin 1 in the rat, biodistribution and elimination studies in vivo were performed, and elimination parameters in perfused rat liver and kidney were determined. Biodistribution studies showed that (99m)Tc-Demogastrin 1 was rapidly cleared from the blood and most organs. A significant amount of radioactivity was detected in the CCK-2 receptor-rich organs, such as the stomach. Low radioactivity was found in the CCK-1 receptor-rich organs. Radioactivity in bowels and stomach declined relatively slowly. High and long-term retention of radioactivity in the kidneys was observed. Elimination of (99m)Tc-Demogastrin 1 via the bile was negligible. A high and rapid renal excretion was observed in elimination experiments in vivo. In the perfused kidney, glomerular filtration was found to be the main renal excretion mechanism of (99m)Tc-Demogastrin 1. Demogastrin 1 was distributed preferentially to the organs expressing CCK-2 receptors. The decisive elimination route of (99m)Tc-Demogastrin 1 in rats was urinary excretion. A high and prolonged renal retention may limit potential clinical use of the compound.
Cancer Biotherapy & Radiopharmaceuticals 03/2012; 27(2):169-74. · 1.44 Impact Factor
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ABSTRACT: Hyaluronan (HYA) is a high molecular weight glucosaminoglycan with a great perspective for medical applications. Because HYA is widespread in the body, it is difficult to determine the fate of exogenously administered HYA.
In this study, HYAof different molecular weights (0.1-1 MDa) was labelled with (99m)Tc, and the distribution profiles were determined after administrating the HYA to rats.
After the intravenous administration of (99m)Tc-HYA, a rapid decrease in the radioactivity of blood samples was observed, presumably because of (99m)Tc-HYA uptake by the liver; only minimal signs of liver radioactivity washout were detected. After the oral administration of (99m)Tc-HYA, no significant absorption to the central compartment was found. A preliminary study using (14)C-HYA exhibited a different distribution profile than (99m)Tc-HYA because of the different administered dose and the fate of the degradation products. Even with (14)C-HYA, only traces of radioactivity were absorbed after oral administration.
This paper provides quantitative information regarding the distribution parameters of radiolabelled HYA in preclinical experiments.
Pharmacological reports: PR 03/2012; 64(2):428-37. · 2.44 Impact Factor
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ABSTRACT: 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.
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.
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.
(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.
Cancer Biotherapy & Radiopharmaceuticals 06/2011; 26(3):287-97. · 1.44 Impact Factor
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ABSTRACT: Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA(0), Tyr(3), Thr(8)]-octreotide (DOTA-TATE) and [DOTA(0), 1-Nal(3)]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods.
The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells.
The renal clearance of (111)In-DOTA-NOC in the perfused rat kidney was significantly lower than that of (111)In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. (111)In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than (111)In-DOTA-TATE (ratio 3: 1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin > maleate > lysine. The uptake of the radiopeptides in the renal cells was temperature dependent.
Both in vitro methods showed a higher renal accumulation of (111)In-DOTA-NOC in comparison with (111)In-DOTA-TATE. The renal uptake was partly decreased by inhibitors of receptor-mediated endocytosis and by a block of energy-dependent processes. A significant participation of active transport processes in renal accumulation of the studied peptides was confirmed.
Annals of Nuclear Medicine 12/2008; 22(10):859-67. · 1.50 Impact Factor
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ABSTRACT: In this study, we investigated the biodistribution and elimination characteristics of a new radiolabelled somatostatin analogue, 99mTc demotate 1, in rats by in-vivo biodistribution and elimination experiments, perfused rat liver and kidney experiments and micro-autoradiography of renal tissue.
Rapid clearance from blood and most organs was found. High and long-term uptake in organs with high density of somatostatin receptors (the adrenals and pancreas) and in stomach and intestine was reduced in non-radiolabelled octreotide pretreated animals. The predominant urine excretion was associated with an accumulation of 99mTc demotate 1 in the kidney, mainly in the renal cortex. This uptake was not affected by non-radiolabelled octreotide pretreatment.
99mTc demotate 1 is a prospective radiopharmaceutical for use in human medicine in somatostatin receptor-positive tumour imaging and its potential should be confirmed in further experiments and clinical trials.
Nuclear Medicine Communications 07/2005; 26(6):549-54. · 1.40 Impact Factor
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ABSTRACT: Pharmacokinetics together with in vivo metabolism and elimination of quinlukast, a potential anti-asthmatic and anti-inflammatory drug, were designed in rats. For this purpose, bile duct cannulated rats and an in situ perfused rat liver preparation were employed. 3H-radiolabelled compound was administered i.v. or loaded to the perfusion medium, respectively. Quinlukast represented the main form of radioactivity determined in plasma; in comparison with the parent drug metabolites were present in lower levels in the systemic circulation. The pharmacokinetic parameters related to the whole animal were calculated from quinlukast rat plasma concentration-time course. The distribution of quinlukast in the body was relatively fast (distribution half-life was approx. 6 min), the elimination half-life exceeded 2h. Binding of quinlukast to rat plasma proteins was very high (approx. 99.7%) and this binding influenced distribution volumes of quinlukast. Both the volume of the central compartment and the volume at a steady state were approx. 115 and 430 ml, respectively. The experiments showed that the biliary clearance was the major route of elimination of this compound from the systemic circulation of rats. In agreement with the determined elimination half-life approx. 42% of the radioactivity was found in the bile, with <0.5% appearing in the urine. The majority of the eliminated radioactivity in the bile was in the form of polar metabolites; only a small part of the parent compound was determined. Two hours after intravenous administration, polar metabolites - but no parent drug - were detected in the urine.
Journal of Pharmaceutical and Biomedical Analysis 06/2005; 38(2):313-9. · 2.97 Impact Factor
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ABSTRACT: An analytical method for the analysis of a novel antiasthmatic drug quinlukast and its metabolites in the plasma, bile and urine was developed. For the analysis, the solid phase extraction method and the C(8) RP-HPLC with radiometric detection of the drug were used. This method enables a quantitative determination of the agent and all of its metabolites (even of those with an unknown structure) in a biological system. The procedure is, therefore, suitable both for the pharmacokinetic analysis of quinlukast and the determination of its elimination pathways.
Journal of Pharmaceutical and Biomedical Analysis 05/2004; 35(1):177-83. · 2.97 Impact Factor
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ABSTRACT: The aim of this study was to compare renal handling and distribution of (99m)Tc-octreotide and (99m)Tc-EDDA/HYNIC-Tyr(3)-octreotide (HYNIC-TOC) in rats. In kidney perfusion experiments, the renal clearance value of (99m)Tc-octreotide was three times lower than that of (99m)Tc-EDDA/HYNIC-TOC. The predominant renal excretion of (99m)Tc-EDDA/HYNIC-TOC was associated with a high and long-term renal accumulation up to 48 hrs. Microautoradiographic results indicated that (99m)Tc-EDDA/HYNIC-TOC was retained mainly in the renal medulla within the cells of the collecting ducts and in the surrounding tissue. Lower positivity was found in the proximal and distal tubular cells. We conclude that the mechanism of renal accumulation of somatostatin analogues renal accumulation is complex and that proximal tubular reabsorption is probably not the main mechanism for uptake of (99m)Tc-EDDA/HYNIC-TOC in the kidneys. The presence of the somatostatin receptors, differences in the tonicity level within kidneys and other possible mechanisms could participate in their renal accumulation.
Nuclear Medicine and Biology 03/2004; 31(2):231-9. · 3.02 Impact Factor
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ABSTRACT: Renal elimination of two renal radiodiagnostic agents, (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) and [(131)I]-o-iodohippurate (OIH) has been studied using the method of the perfused rat kidney. The experiments showed significant differences between renal handling of (99m)Tc-MAG3 and OIH in the perfused rat kidney. While the renal clearance for (99m)Tc-MAG3 was relatively stable, the renal clearance values of OIH rapidly decreased after the OIH administration in a bolus dose. The infusion administration of OIH resulted in stable clearance values during the perfusion. The OIH/(99m)Tc-MAG3 renal clearance ratio was 2.47. Both compounds were bound to proteins in the perfusate to a considerable extent. An analysis of renal handling showed that contribution of tubular secretion to the total excretion was 95% for OIH, and 97% for (99m)Tc-MAG3.
Nuclear Medicine and Biology 02/2003; 30(1):45-9. · 3.02 Impact Factor
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ABSTRACT: Due to their high CCK-2/gastrin receptor selectivity, high affinity, and rapid background clearance, radiolabeled minigastrins (MG) are emerging as promising new tools in the diagnosis and therapy of CCK-2/gastrin receptor-positive tumors. In this study, the pharmacokinetic profile, particularly the excretion mode, of two 111In-labeled minigastrins was compared in rats. The first tracer, 111In-MG-0 is based on (D)Glu1-MG, while the second, 111In-MG-11, is its des-(Glu)5-derivative, expected to be less retained in renal tissue.
The fate of 111In-MG-0 and 111In-MG-11 in the body of rats was investigated during biodistribution and bioelimination experiments, while the respective elimination parameters were determined in perfused rat liver and kidney models.
During biodistribution both compounds were rapidly cleared from the blood and most non-target organs whereas activity levels in the bowel and stomach declined slowly. The overall contribution of hepatobiliary excretion of 111In-MG-0 and 111In-MG-11 was relatively small. In the perfused rat liver their elimination into the bile was negligible. In contrast, renal excretion was the major excretion pathway for both analogs, mainly via glomerular filtration. However, kidney levels were substantially higher and retention was more prolonged in the case of 111In-MG-0 as compared to 111In-MG-11.
The presence of the (Glu)5-chain in 111Ln-MG-0 appears to be implicated in the prolonged radioactivity retention in the kidney of rats.
Anticancer research 27(2):907-12. · 1.73 Impact Factor
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ABSTRACT: The present study compares distribution and elimination characteristics of 111In-DTPA-D-Phe1-octreotide and 111In-DTPA-L-Phe1-octreotide in rats and evaluated the effect of the replacement of the terminal L-phenylalanine by D-phenylalanine on pharmacokinetic profiles of the radiolabelled peptides. Both agents exhibited rapid radioactivity clearance from the blood and most organs and tissues with no systematic and significant differences in activity accumulation. The long-term retention and high radioactivity concentrations for both compounds under study were found in the kidneys and organs with a high density of somatostatin receptors, such as the pancreas and adrenals. The residence times in these organs were longer for 111In-DTPA-D-Phe1-octreotide in comparison with 111In-DTPA-L-Phe1-octreotide. The major elimination pathway for both radiolabelled peptides was relatively rapid excretion into the urine. Analysis of the renal handling by an employment of the perfused rat kidney showed that both peptides were eliminated mainly by the mechanism of glomerular filtration. Rat liver perfusion experiments confirmed a very low value of bile clearance of radioactivity for both agents under study.
European Journal of Drug Metabolism and Pharmacokinetics 27(1):37-43. · 0.36 Impact Factor
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ABSTRACT: Somatostatin analogues labelled with radiometals or radiohalogens are useful for the imaging and treatment of somatostatin receptor-containing tumours. In this study, the procedures for the radioiodination of glucose-Tyr3-octreotate (gluc-Tyr3-tate) and radiolabelling of DOTA-Tyr3-octreotate (DOTA-Tyr3-tate) with 111In, 177Lu and 125I were compared and their metabolism in rats was analyzed. The usefulness of high performance liquid chromatography (HPLC) analysis and instant thin-layer chromatography on silica gel (ITLC-SG) for both radiochemical purity determination and analysis of metabolism in urine was investigated. MATERIALS AND METHODs: For labelling with radiometals, the formation of a complex with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) functionality of the peptide was employed. Radioiodination was performed by the chloramime-T method. The radiochemical purity of radiolabelled peptides and the analyses of rat urine were determined by HPLC and/or ITLC-SG methods. Male Wistar rats were used in the elimination studies.
DOTA-Tyr3-tate was simply radiolabelled with radiometals with high yield and high radiochemical purity. Stopping of the reaction was a critical step for radioiodination, therefore labelling of gluc-Tyr3-tate and DOTA-Tyr3-tate with 125I was not so simple and the reaction product had to be purified by preparative HPLC analysis. Whereas 111In-DOTA-Tyr3-tate and 177Lu-DOTA-Tyr3-tate were eliminated in rat urine in a practically unchanged form, a significant proportion of metabolites was observed with radioiodinated peptides, particularly at longer time intervals.
Labelling of DOTA-Tyr3-tate with radiometals is simple and the radiochemical purity of prepared compounds is very high, while iodination of the peptides demands purification of the product by preparative HPLC. The analysis of rat urine showed that excretion of radioiodinated peptides included a significant proportion of metabolites.
Anticancer research 27(6B):3941-6. · 1.73 Impact Factor
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ABSTRACT: Somatostatin receptors are known to be present at a high density in a large number of tumors while (111)In-DTPA-octreotide has been routinely used in oncology for imaging somatostatin receptor-positive tumors and metastases. Lanreotide is another somatostatin receptor-specific peptide, shown to be effective in controlling the growth of some human tumors. The aim of this study was to label lanreotide with 99mTc by a direct labeling method and to evaluate the distribution and elimination characteristics of the labeled agent in rats. (111)In-octreotide was used as the reference radiopharmaceutical. For both radiolabeled-peptides the activity in blood and most organs decreased relatively rapidly with time. On the other hand, 99mTc-lanreotide was excreted mainly by the gastrointestinal tract to feces while (111)In-DTPA-octreotide was eliminated mostly into urine. The rat liver perfusion experiments showed that bile clearance of 99mTc-lanreotide was about three-order times higher than for (111)In-DTPA-octreotide. Analysis of the elimination mechanisms of 99mTc-lanreotide and (111)In-DTPA-octreotide in the perfused rat kidney confirmed that both peptides were eliminated mostly by glomerular filtration. Different protein binding of the agents ((111)In-DTPA-octreotide was only weakly bound, whereas 99mTc-lanreotide was strongly bound to proteins) resulted in substantially lower renal clearance of 99mTc-lanreotide when compared with (111)In-DTPA-octreotide. The results indicated that 99mTc-lanreotide could be of value for the scintigraphic imaging of specific tumors.
Anticancer research 22(4):2125-30. · 1.73 Impact Factor
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ABSTRACT: In this study, some important biological characteristics of two radiolabelled somatostatin analogues 111In-DOTA-1-Nal3-octreotide (DOTA-NOC) and 111In-DOTA-Tyr3-octreotate (DOTA-TATE) were compared.
Rats were used for in vivo biodistribution experiments and in vitro cell models (OK and AR42J cell lines) were used for simulating the internalization in the kidney and in subtype 2 somatostatin receptor (SSTR2)-positive tissues, respectively.
Significantly higher radioactivity concentrations in rat organs with high density of somatostatin receptors after 111In-DOTA-NOC administration in comparison with 111In-DOTA-TATE were observed. The predominant urine excretion was associated with accumulation of the radioactivity in the kidney, where higher retention of 111In-DOTA-TATE compared to 111In-DOTA-NOC was detected. In the OK cell line the opposite results were found. No significant differences in the in vitro internalization and externalization of radioactivity to AR42J cell line were found for either peptide suggesting their same affinity for SSTR2.
Preclinical experiments indicated that 111In-DOTA-NOC is a very promising peptide for somatostatin receptor-positive tumour visualization. The conflict between the in vitro and in vivo kidney handling showed that the transfer of results from in vitro to in vivo conditions and their interpretation should be performed very carefully because both types of experiments can be affected by different factors, making their simple comparison difficult.
Anticancer research 28(4B):2189-95. · 1.73 Impact Factor
