RESUMEN
Quantitation of Zn-DTPA (zinc diethylenetriamene pentaacetate, a metal chelate) in complex biological matrix is extremely challenging on account of its special physiochemical properties. This study aimed to develop a robust and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Zn-DTPA in human plasma and urine. The purified samples were separated on Proteonavi (250 × 4.6 mm, 5 µm; Shiseido, Ginza, Tokyo, Japan) and a C18 guard column. The mobile phase consisted of methanol-2 mm ammonium formate (pH 6.3)-ammonia solution (50:50:0.015, v/v/v), flow rate 0.45 mL/min. The linear concentration ranges of the calibration curves for Zn-DTPA were 1-100 µg/mL in plasma and 10-2000 µg/mL in urine. The intra- and inter-day precisions for quality control (QC) samples were from 1.8 to 14.6% for Zn-DTPA and the accuracies for QC samples were from -4.8 to 8.2%. This method was fully validated and successfully applied to the quantitation of Zn-DTPA in plasma and urine samples of a healthy male volunteer after intravenous infusion administration of Zn-DTPA. The result showed that the concentration of Zn-DTPA in urine was about 20 times that in plasma, and Zn-DTPA was completely (94.7%) excreted through urine in human.
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Cromatografía Liquida/métodos , Ácido Pentético/sangre , Ácido Pentético/orina , Espectrometría de Masas en Tándem/métodos , Adulto , Estabilidad de Medicamentos , Humanos , Modelos Lineales , Masculino , Ácido Pentético/química , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
This paper describes the evaluation of [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA-NCS) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA-NCS) as bifunctional chelators for 177Lu. While 177Lu-CHX-A''-DTPA-NCS could be obtained in high yields at equimolar ratios of lutetium to CHX-A''-DTPA-NCS, >95% yield of 177Lu-NOTA-NCS could be achieved at 1:2M ratio of lutetium to NOTA-NCS. Trace metals reduced the yields of 177Lu-NOTA-NCS significantly as compared to 177Lu-CHX-A''-DTPA-NCS. In vitro stability of 177Lu-CHX-A''-DTPA-NCS was also superior to 177Lu-NOTA-NCS. It could be concluded from this study that among the two chelators evaluated, CHX-A''-DTPA-NCS is more appropriate for preparation of 177Lu radiopharmaceuticals.
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Quelantes/química , Lutecio/química , Radioisótopos/química , Radiofármacos/química , Estabilidad de Medicamentos , Durapatita/química , Compuestos Heterocíclicos/sangre , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos con 1 Anillo , Humanos , Técnicas In Vitro , Lutecio/sangre , Ácido Pentético/análogos & derivados , Ácido Pentético/sangre , Ácido Pentético/química , Radioisótopos/sangre , Radiofármacos/sangre , Oligoelementos/químicaRESUMEN
Long-circulating liposomes (LCL) are often used as a drug carrier system to improve the therapeutic index of water-soluble drugs. To track these LCL in vivo, they can be radiolabelled with (111)In-oxine. For this labelling method, generally DTPA is encapsulated in the aqueous phase of LCL (DTPA-LCL). Alternatively, LCL can be labelled with (111)InCl3 after incorporation of DTPA-conjugated DSPE in the lipid bilayer (DTPA-DSPE LCL). Here, we compared the in vitro properties of DTPA-DSPE LCL with those of DTPA LCL and empty LCL. Additionally, we compared the in vivo performance of DTPA-DSPE LCL with those of DTPA LCL in mice. DTPA LCL (88 nm) and empty LCL (84 nm) were labelled with (111)In-oxine, and DTPA-DSPE LCL (83 nm) were labelled with (111)InCl3. Labelling efficiency at increasing specific activity was determined. In vitro stability of (111)In-labelled LCL was determined in human serum at 37 °C. The in vivo properties of (111)In-labelled LCL were determined in mice with a Staphylococcus aureus infection in the thigh muscle. Image acquisition, blood sampling and biodistribution studies were performed 1, 4 (blood sampling only), 24, 48 and 72 h p.i. of (111)In-labelled LCL. DTPA-DSPE LCL could be labelled efficiently at a much higher specific activity compared to DTPA LCL and empty LCL: > 90% at 15 GBq/mmol, > 90% at 150 MBq/mmol and 6065% at 150 MBq/mmol, respectively. (111)In-labelled DTPA-DSPE LCL and DTPA LCL were stable in human serum, regarding label retention, for at least 48 h at 37 °C (> 98% retention of the radiolabel). In contrast, only 68% radiolabel was retained in empty LCL after 48 h. In vivo targeting of (111)In-DTPA-DSPE LCL to the abscess was comparable to targeting of (111)In-DTPA LCL (3.5 ± 0.9%ID/g and 3.4 ± 0.9%ID/g abscess uptake respectively, 48 h p.i.). In conclusion, labelling of DTPA-DSPE LCL with (111)InCl3 represents a robust, easy and fast procedure which is preferred over the more laborious conventional labelling of DTPA-LCL with (111)In-oxine.
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Medios de Contraste/farmacocinética , Radioisótopos de Indio , Indio/farmacocinética , Músculo Esquelético/diagnóstico por imagen , Ácido Pentético/farmacocinética , Fosfatidiletanolaminas/farmacocinética , Infecciones Estafilocócicas/diagnóstico por imagen , Animales , Medios de Contraste/administración & dosificación , Medios de Contraste/química , Modelos Animales de Enfermedad , Femenino , Humanos , Indio/administración & dosificación , Indio/sangre , Indio/química , Marcaje Isotópico , Liposomas , Músculo Esquelético/metabolismo , Ácido Pentético/administración & dosificación , Ácido Pentético/sangre , Ácido Pentético/química , Fosfatidiletanolaminas/administración & dosificación , Fosfatidiletanolaminas/sangre , Fosfatidiletanolaminas/química , Infecciones Estafilocócicas/metabolismo , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único , Microtomografía por Rayos XRESUMEN
Diethylenetriaminepentaacetic acid (DTPA) is an FDA-approved chelating agent for enhancing the elimination of transuranic elements such as americium from the body. Early access to therapy minimizes deposition of these radionuclides in tissues such as the bone. Due to its poor oral bioavailability, DTPA is administered as an IV injection, delaying access. Therefore, a diethyl-ester analog of DTPA, named C2E2, was synthesized as a means to increase oral absorption. As a hexadentate ligand, it was hypothesized that C2E2 was capable of binding americium directly. Therefore, the protonation constants and americium stability constant for C2E2 were determined by potentiometric titration and a solvent extraction method, respectively. C2E2 was shown to bind americium with a log K of 19.6. The concentrations of C2E2, its metabolite C2E1, and DTPA required to achieve effective binding in rat, beagle, and human plasma were studied in vitro. Dose response curves for each ligand were established, and the 50% maximal effective concentrations were determined for each species. As expected, higher concentrations of C2E2 were required to achieve the same degree of binding as DTPA. The results indicated that chelation in beagle plasma is more representative of the human response than rats. Finally, the pharmacokinetics of C2E2 were investigated in beagles, and the data was fit to a two-compartment model with elimination from the central compartment, along with first-order absorption. Based on the in vitro data, a 100 mg kg dose of C2E2 can be expected to have an effective duration of action of 3.8 h in beagles.
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Americio/metabolismo , Quelantes/administración & dosificación , Ácido Pentético/análogos & derivados , Americio/aislamiento & purificación , Animales , Unión Competitiva , Disponibilidad Biológica , Quelantes/farmacocinética , Perros , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Ácido Pentético/administración & dosificación , Ácido Pentético/sangre , Ácido Pentético/farmacocinética , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
Glutamine may be a precursor for NO synthesis, which may play a crucial role in bacterial translocation (BT). The goal of the present study was to investigate the potential effects of glutamine on BT and the immunological response in an experimental model of NO synthase inhibition by NG-nitro-L-arginine methyl ester (l-NAME). Mice were randomly assigned to four groups: sham; intestinal obstruction (IO); IO+500 mg/kg per d glutamine (GLN); IO+GLN plus 10 mg/kg per d l-NAME (GLN/LN). The groups were pretreated for 7 d. BT was induced by ileal ligation and was assessed 18 h later by measuring the radioactivity of 99mTc-Escherichia coli in the blood and organs. Mucosal damage was determined using a histological analysis. Intestinal permeability (IP) was assessed by measuring the levels of 99mTc-diethylenetriaminepentaacetic acid in the blood at 4, 8 and 18 h after surgery. IgA and cytokine concentrations were determined by ELISA in the intestinal fluid and plasma, respectively. BT was increased in the GLN/LN and IO groups than in the GLN and sham groups. IP and intestinal mucosa structure of the sham, GLN and GLN/LN groups were similar. The GLN group had the highest levels of interferon-γ, while IL-10 and secretory IgA levels were higher than those of the IO group but similar to those of the GLN/LN group. The present results suggest that effects of the glutamine pathway on BT were mediated by NO. The latter also interferes with the pro-inflammatory systemic immunological response. On the other hand, IP integrity preserved by the use of glutamine is independent of NO.
Asunto(s)
Traslocación Bacteriana , Glutamina/metabolismo , Íleon/metabolismo , Mucosa Intestinal/metabolismo , Obstrucción Intestinal , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Animales , Traslocación Bacteriana/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Escherichia coli , Glutamina/farmacología , Íleon/efectos de los fármacos , Íleon/microbiología , Íleon/patología , Inmunoglobulina A/metabolismo , Inmunoglobulina A Secretora/metabolismo , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Obstrucción Intestinal/microbiología , Obstrucción Intestinal/patología , Ligadura , Masculino , Ratones , Ratones Endogámicos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/inmunología , Ácido Pentético/sangre , Permeabilidad , Transducción de SeñalRESUMEN
Dietary supplementation with l-arginine has been shown to improve the intestinal barrier in many experimental models. This study investigated the effects of arginine supplementation on the intestinal permeability and bacterial translocation (BT) induced by prolonged physical exercise under heat stress. Under anesthesia, male Swiss mice (5-wk-old) were implanted with an abdominal sensor to record their core body temperature (T(core)). After recovering from surgery, the mice were divided into 3 groups: a non-supplemented group that was fed the standard diet formulated by the American Institute of Nutrition (AIN-93G; control), a non-supplemented group that was fed the AIN-93G diet and subjected to exertional hyperthermia (H-NS), and a group supplemented with l-arginine at 2% and subjected to exertional hyperthermia (H-Arg). After 7 d of treatment, the H-NS and H-Arg mice were forced to run on a treadmill (60 min, 8 m/min) in a warm environment (34°C). The control mice remained at 24°C. Thirty min before the exercise or control trials, the mice received a diethylenetriamine pentaacetic acid (DTPA) solution labeled with technetium-99m ((99m)Tc-DTPA) or (99m)Tc-Escherichia coli by gavage to assess intestinal permeability and BT, respectively. The H-NS mice terminated the exercise with T(core) values of â¼40°C, and, 4 h later, presented a 12-fold increase in the blood uptake of (99m)Tc-DTPA and higher bacterial contents in the blood and liver than the control mice. Although supplementation with arginine did not change the exercise-induced increase in T(core), it prevented the increases in intestinal permeability and BT caused by exertional hyperthermia. Our results indicate that dietary l-arginine supplementation preserves the integrity of the intestinal epithelium during exercise under heat stress, acting through mechanisms that are independent of T(core) regulation.
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Arginina/uso terapéutico , Traslocación Bacteriana/efectos de los fármacos , Suplementos Dietéticos , Fiebre/complicaciones , Mucosa Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Animales , Arginina/farmacología , Temperatura Corporal/efectos de los fármacos , Escherichia coli , Fiebre/patología , Calor , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/microbiología , Intestinos/patología , Hígado/microbiología , Masculino , Ratones , Ratones Endogámicos , Ácido Pentético/sangre , Permeabilidad , Carrera/fisiología , Estrés FisiológicoRESUMEN
Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent that is used to facilitate the elimination of radionuclides such as americium from contaminated individuals. Its primary site of action is in the blood, where it competes with various biological ligands, including transferrin and albumin, for the binding of radioactive metals. To evaluate the chelation potential of DTPA under these conditions, the competitive binding of Am between DTPA and plasma proteins was studied in rat, beagle, and human plasma in vitro. Following incubation of DTPA and Am in plasma, the Am-bound ligands were fractionated by ultrafiltration and ion-exchange chromatography, and each fraction was assayed for Am content by gamma scintillation counting. Dose response curves of DTPA for Am binding were established, and these models were used to calculate the 90% maximal effective concentration, or EC90, of DTPA in each plasma system. The EC90 were determined to be 31.4, 15.9, and 10.0 µM in rat, beagle, and human plasma, respectively. These values correspond to plasma concentrations of DTPA that maximize Am chelation while minimizing excess DTPA. Based on the pharmacokinetic profile of DTPA in humans, after a standard 30 µmol kg intravenous bolus injection, the plasma concentration of DTPA remains above EC90 for approximately 5.6 h. Likewise, the effective duration of DTPA in rat and beagle were determined to be 0.67 and 1.7 h, respectively. These results suggest that species differences must be considered when translating DTPA efficacy data from animals to humans and offer further insights into improving the current DTPA treatment regimen.
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Americio/química , Quelantes/química , Ácido Pentético/sangre , Ácido Pentético/química , Americio/aislamiento & purificación , Animales , Perros , Humanos , Ratas , Especificidad de la EspecieRESUMEN
Diethylenetriamine pentaacetic acid penta-ethyl ester, designated as C2E5, was successfully incorporated into a nonaqueous gel for transdermal delivery. The thermal and rheological properties of a formulation containing 40% C2E5, 20% ethyl cellulose, and 40% Miglyol 840® prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity and flow properties. In vitro studies showed that C2E5 was steadily released from the gel at a rate suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved significantly higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The results suggest that transdermal delivery of a chelator prodrug is an effective radionuclide decorporation strategy by delivering chelators to the circulation with a pharmacokinetic profile that is more consistent with the biokinetic profile of transuranic elements in contaminated individuals.
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Celulosa/análogos & derivados , Quelantes/administración & dosificación , Diglicéridos/química , Portadores de Fármacos , Ácido Pentético/análogos & derivados , Profármacos/administración & dosificación , Administración Cutánea , Animales , Biotransformación , Rastreo Diferencial de Calorimetría , Celulosa/química , Quelantes/química , Quelantes/farmacocinética , Química Farmacéutica , Preparaciones de Acción Retardada , Composición de Medicamentos , Femenino , Geles , Ácido Pentético/administración & dosificación , Ácido Pentético/sangre , Ácido Pentético/química , Ácido Pentético/farmacocinética , Profármacos/química , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Reología , Absorción Cutánea , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
The in vivo(212)Pb/(212)Bi generator is promising for application in targeted alpha therapy (TAT) of cancer. One main limitation of its therapeutic application is due to potential release of (212)Bi from the radioconjugate upon radioactive decay of the mother nuclide (212)Pb, potentially leading to irradiation of healthy tissue. The objective of the present work is to assess whether the chelate CHX-A''-DTPA (N-(2-aminoethyl)-trans-1,2-diaminocyclohexane-N,N',N''-pentaacetic acid) bound to a biological carrier molecule may be able to re-complex released (212)Bi under in vivo conditions to limit its translocation from the target site. CHX-A''-DTPA was bound to bovine gamma globulin (BGG) to mimic a model conjugate and the stability of the Bi-CHX-A''-DTPA-BGG conjugate was studied in blood serum by ultrafiltration. TRLFS experiments using Cm(III) as a fluorescent probe demonstrated that linking CHX-A''-DTPA to BGG does not affect the coordination properties of the ligand. Furthermore, comparable stability constants were observed between Bi(III) and free CHX-A''-DTPA, BGG-bound CHX-A''-DTPA and DTPA. The complexation constants determined between Bi(III) and the chelate molecules are sufficiently high to allow ultra trace amounts of the ligand to efficiently compete with serum transferrin controlling Bi(III) speciation in blood plasma conditions. Nevertheless, CHX-A''-DTPA is not able to complex Bi(III) generated in blood serum because of the strong competition between Bi(III) and Fe(II) for the ligand. In other words, CHX-A''-DTPA is not "selective" enough to limit Bi(iii) release in the body when applying the (212)Pb/(212)Bi in vivo generator.
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Bismuto/sangre , Quelantes/metabolismo , Isotiocianatos/sangre , Ácido Pentético/análogos & derivados , Ácido Pentético/sangre , Animales , Bovinos , Ácido Edético/sangre , Humanos , Técnicas In Vitro , gammaglobulinas/metabolismoRESUMEN
BACKGROUND: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed to address the systematic underestimation of the glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) Study equation in patients with a relatively well-preserved kidney function. The performance of the new equation for kidney transplant recipients (KTRs) is unknown. METHODS: We used the plasma clearance of (99m)Tc-diethylenetriamine pentaacetic acid to measure the GFR in a cohort of 207 stable KTRs and estimated the GFR with the new CKD-EPI equation. RESULTS: The mean bias for the CKD-EPI equation of -4.5 mL x min(-1) x (1.73 m(2))(-1) was lower than that of the 4-variable MDRD Study equation; however, the 2 equations showed similar variation of individual biases around the mean or median bias, so that only modest improvement was seen in the overall percentage of GFR estimates within 30% of the measured GFR (84% vs 77% for the CKD-EPI vs MDRD Study equations, respectively). In the cohort with a GFR >60 mL x min(-1) x (1.73 m(2))(-1) (n = 98), the CKD-EPI bias was much less than that of the MDRD Study equation [-7.4 mL x min(-1) x (1.73 m(2))(-1) vs -14.3 mL x min(-1) x (1.73 m(2))(-1)], and an accuracy of + or - 30% was seen for 89% of GFR estimates, compared with 77% with the MDRD Study equation. The variation of the individual biases around the mean bias remained substantial [SD = 13.7 mL x min(-1) x (1.73 m(2))(-1)]. CONCLUSIONS: The CKD-EPI equation shows improved estimation ability, and we recommend that it replace the MDRD Study equation as the currently preferred creatinine-based estimating equation for KTRs. The precision of GFR estimates obtained with the CKD-EPI equation remains suboptimal, however, and we recommend that research on other markers of GFR, such as cystatin C and beta-trace protein, be pursued.
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Tasa de Filtración Glomerular , Trasplante de Riñón , Ácido Pentético/sangre , Tecnecio/sangre , Adulto , Estudios de Cohortes , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVES: To examine the feasibility and accuracy of glomerular filtration rate (GFR) measurements in infants with sickle cell anemia (SCA). STUDY DESIGN: The NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled trial (BABY HUG) tests the hypothesis that hydroxyurea can prevent chronic organ damage in SCA. GFR elevation is a coprimary endpoint, measured quantitatively by technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) plasma clearance and estimated by the Schwartz equation with height and creatinine. RESULTS: Baseline DTPA GFR measurement was attempted in 191 infants; 176 of 184 completed studies (96%) were interpretable. Average age (mean +/- 1SD) was 13.7 +/- 2.6 months. Average DTPA GFR was 125.2 +/- 34.4 (range 40.2-300.9, normal 91.5 +/- 17.8 mL/min/1.73m(2)), while Schwartz estimates were higher at 184.4 +/- 55.5 mL/min/1.73m(2). DTPA GFR was correlated with Schwartz GFR (r(2) = 0.0658, P = .0012); also with age, weight, height, and kidney volume (all P < .002); but not with hemoglobin, HbF, white blood cell count, reticulocytes, medical events, or splenic function. CONCLUSIONS: Quantitative GFR measurement is feasible but variable among infants with SCA. Schwartz GFR estimates are not highly correlated with quantitative DTPA GFR values. Baseline GFR measurements suggest that renal dysfunction in SCA, evidenced by glomerular hyperfiltration, begins during infancy.
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Anemia de Células Falciformes/fisiopatología , Riñón/fisiopatología , Bazo/fisiopatología , Creatinina/sangre , Tasa de Filtración Glomerular , Humanos , Lactante , Ácido Pentético/sangreRESUMEN
N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGDfK conjugates targeting the alpha(v)beta(3) integrin have shown increased accumulation in solid tumors and promise for selective delivery of radiotherapeutics to sites of angiogenesis- or tumor-expressed alpha(v)beta(3) integrin. An unresolved issue in targeting radiotherapeutics to solid tumors is toxicity to non-target organs. To reduce toxicity of radiolabeled conjugates, we have synthesized HPMA copolymer-RGDfK conjugates with varying molecular weight and charge content to help identify a polymeric structure that maximizes tumor accumulation while rapidly clearing from non-targeted organs. Endothelial cell binding studies showed that copolymer conjugates of approximately 43, 20 and 10 kD actively bind to the alpha(v)beta(3) integrin. Scintigraphic images showed rapid clearance of indium-111 ((111)In) radiolabeled conjugates from the blood pool and high kidney accumulation within 1 h in tumor bearing mice. Biodistribution data confirms images with high accumulation in kidney (max 210% ID/g for 43 kD conjugate) and lower tumor accumulation (max 1.8% ID/g for 43 kD conjugate). While actively binding to the alpha(v)beta(3) integrin in vitro, HPMA copolymer-RGDfK conjugates with increased negative charge through increased CHX-A''-DTPA chelator content in the side chains causes increased kidney accumulation with a loss of tumor accumulation in vivo.
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Acrilamidas/farmacocinética , Carcinoma Pulmonar de Lewis/metabolismo , Portadores de Fármacos , Integrina alfaVbeta3/metabolismo , Isotiocianatos/farmacocinética , Riñón/metabolismo , Ácido Pentético/análogos & derivados , Péptidos Cíclicos/farmacocinética , Acrilamidas/administración & dosificación , Acrilamidas/sangre , Acrilamidas/síntesis química , Animales , Unión Competitiva , Carcinoma Pulmonar de Lewis/diagnóstico por imagen , Línea Celular Tumoral , Química Farmacéutica , Células Endoteliales/metabolismo , Femenino , Humanos , Radioisótopos de Indio , Inyecciones Intravenosas , Isotiocianatos/administración & dosificación , Isotiocianatos/sangre , Isotiocianatos/síntesis química , Riñón/diagnóstico por imagen , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Peso Molecular , Trasplante de Neoplasias , Ácido Pentético/administración & dosificación , Ácido Pentético/sangre , Ácido Pentético/síntesis química , Ácido Pentético/farmacocinética , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/sangre , Péptidos Cíclicos/síntesis química , Cintigrafía , Distribución TisularRESUMEN
A high-molecular weight tetrametallic supramolecular complex [(Ln-DTPA-phen)3Fe]- (Ln = Gd, Eu, La) has been obtained upon self-assembly around one iron(II) ion of three 1,10-phenantroline-based molecules substituted in 5'-position with the polyaminocarboxylate diethylenetriamine-N,N,N',N',N'-pentaacetate, DTPA-phen(4-). The ICP-MS measurements indicated that the lanthanide:iron ratio is 3:1. Photoluminescence spectra of [Eu-DTPA-phen](-) and of [(Eu-DTPA-phen)3Fe]- are nearly identical, implying that the first coordination sphere of the lanthanide(III) ion has not been changed upon coordination of phenantroline unit to iron(II) ion. NMRD measurements revealed that at 20 MHz and 310 K the relaxivity of the [(Gd-DTPA-phen)3Fe]- is equal to 9.5 +/- 0.3 s(-1) mM(-1) of Gd (28.5 s(-1) per millimole per liter of complex) which is significantly higher than that for Gd-DTPA (3.9 s(-1) mM(-1)). The pharmacokinetic parameters of [(Gd-DTPA-phen)3Fe]- in rats indicate that the elimination of [(Gd-DTPA-phen)3Fe]- is significantly slower than that of Gd-DTPA and is correlated with a reduced volume of distribution. The low volume of distribution and the longer elimination time (T(e1/2)) suggest that the agent is confined to the blood compartment, so it could have an important potential as a blood pool contrast agent. The biodistribution profile of [(Gd-DTPA-phen)3Fe]- 2 h after injection indicates significantly higher concentrations of [(Gd-DTPA-phen)3Fe]- as compared with Gd-DTPA in kidney, liver, lungs, heart and spleen. The images obtained on rats by MR angiography show the enhancement of the abdominal blood vessels. The signal intensity reaches a maximum of 55% at 7 min post-contrast and remains around 25% after 90 min. MRI-histomorphological correlation studies of [Gd-DTPA-phen]- and [(Gd-DTPA-phen)3Fe]- showed that both agents displayed potent contrast enhancement in organs including the liver. The necrosis avidity tests indicated that, in contrast to the [Gd-DTPA-phen](-) precursor complex, the supramolecular complex [(Gd-DTPA-phen)3Fe]- exhibits necrosis avidity.
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Medios de Contraste/farmacocinética , Gadolinio/farmacocinética , Hierro/farmacocinética , Abdomen/irrigación sanguínea , Animales , Vasos Sanguíneos , Medios de Contraste/administración & dosificación , Gadolinio/sangre , Hierro/sangre , Ligandos , Hígado/diagnóstico por imagen , Hígado/patología , Sustancias Macromoleculares/síntesis química , Angiografía por Resonancia Magnética , Masculino , Necrosis , Ácido Pentético/sangre , Ácido Pentético/síntesis química , Ácido Pentético/química , Ácido Pentético/farmacocinética , Protones , Radiografía , Ratas , Ratas WistarRESUMEN
The physiological effects of a novel MRI contrast agent, Gd(ABE-DTTA), were investigated in dogs, monitoring parameters in blood samples. Each animal (n = 8 in the short-term, n = 4 in the long-term group) underwent isoflurane anesthesia followed by the generation of myocardial infarction and received a contrast agent at the MRI effective dose. Blood samples were collected 24 and 48 h, and 7, 14, 28, 35, 49 and 56 days after contrast agent administration. No significant changes exceeding the normal range were detected in any of the investigated parameters except in alanine aminotransferase (ALT). ALT enzyme activity increased in the short-term group 24 and 48 h after agent administration as expected from the effect of isoflurane anesthesia. Between days 7 and 56 no elevation in ALT was observed. In dogs no substantial short- or long-term effect was observed on the investigated, physiological parameters after Gd(ABE-DTTA) administration at the MRI effective dose.
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Medios de Contraste/farmacología , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos/farmacología , Alanina Transaminasa/sangre , Amilasas/sangre , Amilasas/metabolismo , Anestésicos por Inhalación/administración & dosificación , Animales , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Medios de Contraste/química , Medios de Contraste/toxicidad , Perros , Evaluación Preclínica de Medicamentos/métodos , Electrólitos/sangre , Recuento de Eritrocitos , Isoflurano/administración & dosificación , Pruebas de Función Renal/métodos , Recuento de Leucocitos , Pruebas de Función Hepática/métodos , Masculino , Estructura Molecular , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/diagnóstico , Compuestos Organometálicos/sangre , Compuestos Organometálicos/química , Ácido Pentético/sangre , Ácido Pentético/química , Ácido Pentético/farmacología , Factores de TiempoRESUMEN
111In-DTPA octreotide (DTPAOC) has been used for detecting somatostatin receptor positive tumor for years. In-111 DOTA-Tyr3-octreotide (DOTATOC) is newly developed for diagnostic and therapeutic purposes. In this study, we compared the biodistribution and tumor uptake ratio after injection of In-111 DTPAOC and In-111 DOTATOC in rats. Twelve rats bearing pancreatic tumors were divided into two groups: six rats were sacrificed at 4 hr after injection of 3.7 MBq of In-111 DTPAOC and another 6 rats were sacrificed at the same time after injection of 3.7 MBq of In-111 DOTATOC. Samples of various organs were obtained and counted to calculate the tissue concentration. In addition, 12 rats bearing pancreatic tumors were scanned at 4, 24, and 48 hr after injection of 37 MBq of In-111 DTPAOC or In-111 DOTATOC. The tumor uptake ratios (T/N ratio) were calculated. The biodistribution data showed that the activity in the tumor as well as in the kidney was significantly higher in the In-111 DOTATOC group than in the In-111 DTPAOC group, although both radiopharmaceuticals had the expected high affinity to the tumor. The T/N ratios in the In-111 DOTATOC group were also significantly higher than those in the In-111 DTPAOC group at 24 hr after injection. We conclude that In-111 DOTATOC showed lower clearance than In-111 DTPAOC in the rats bearing pancreatic tumors, although both of these radiopharmaceuticals showed expected high tumor uptake.
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Radioisótopos de Indio/farmacocinética , Tumores Neuroendocrinos/metabolismo , Octreótido/análogos & derivados , Neoplasias Pancreáticas/metabolismo , Ácido Pentético/análogos & derivados , Radiofármacos/farmacocinética , Animales , Radioisótopos de Indio/sangre , Radioisótopos de Indio/metabolismo , Masculino , Octreótido/sangre , Octreótido/metabolismo , Octreótido/farmacocinética , Ácido Pentético/sangre , Ácido Pentético/metabolismo , Ácido Pentético/farmacocinética , Radiofármacos/sangre , Radiofármacos/metabolismo , Ratas , Ratas Endogámicas Lew , Distribución TisularRESUMEN
UNLABELLED: The high renal uptake of radiolabeled somatostatin analogs is dose limiting. Lowering this uptake permits higher radioactivity doses and, thus, tumor doses to be administered. We tested the effects of the microtubule drug colchicine on renal uptake of [(111)In-DTPA(0)]octreotide. Also, the effects of fructose were tested. METHODS: Organ radioactivity 24 h after injection of [(111)In-DTPA(0)]octreotide was determined in rats. RESULTS: Coinjection of 1 mg of colchicine per kilogram did not influence renal uptake of [(111)In-DTPA(0)]octreotide, whereas this dose administered 5 h before [(111)In-DTPA(0)]octreotide resulted in significant renal uptake reduction (63%). D-Lysine plus colchicine reduced the uptake by 76% (P < 0.01 vs. D-lysine alone). Liver and blood radioactivity levels were significantly elevated by colchicine. Fructose did not affect the biodistribution of [(111)In-DTPA(0)]octreotide. CONCLUSION: Renal uptake of [(111)In-DTPA(0)]octreotide is dependent on microtubule function in rats. The addition of colchicine to amino acid protocols may permit administration of higher doses, improving the therapeutic window of peptide receptor radionuclide therapy.
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Adenosina Trifosfato/metabolismo , Colchicina/farmacología , Fructosa/farmacología , Riñón/diagnóstico por imagen , Riñón/metabolismo , Octreótido/análogos & derivados , Octreótido/farmacocinética , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Animales , Relación Dosis-Respuesta a Droga , Riñón/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Octreótido/sangre , Especificidad de Órganos , Ácido Pentético/sangre , Renografía por Radioisótopo , Radiofármacos/sangre , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Distribución TisularRESUMEN
For purpose of reducing renal accumulation of radioactivity of a known radiopharmaceutical agent, i.e., (111)In-DTPA (diethylenetriaminepentaacetic acid)-D-Phe(1)-octreotide, a derivative in which p-carboxy-L-phenylalanine is substituted for D-Phe(1) was synthesized. Biodistribution study of the resultant compound having carboxy-substituted L-Phe(1) revealed that the renal accumulation was significantly lower than that of control compound having unsubstituted L-Phe(1), demonstrating that the presence of negative charge on the N-terminal amino acid of octreotide is effective to reduce the renal accumulation. This effect can be attributed to the reduction of lipophilicity and also the repulsive force arisen from the negative charge of renal brush border membrane.
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Riñón/metabolismo , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Fenilalanina/química , Radiofármacos/farmacocinética , Animales , Estabilidad de Medicamentos , Radioisótopos de Indio , Inyecciones Intravenosas , Riñón/diagnóstico por imagen , Ratones , Ratones Endogámicos , Ácido Pentético/sangre , Ácido Pentético/química , Cintigrafía , Radiofármacos/sangre , Radiofármacos/química , Factores de Tiempo , Distribución TisularRESUMEN
The biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes (IDLPL) and unencapsulated 111In-DTPA administered by the intraperitoneal (i.p.) and i.v. routes in non-tumour-bearing mice were compared. Mice received i.p. or i.v. injections of 0.37 MBq 111In-DTPA either encapsulated in liposomes or as an unencapsulated agent. A variety of tissues were dissected from 5 min to 192 h to determine the biodistribution and pharmacokinetics. Injection of IDLPL via the i.p. route caused a 74-fold increase in the area under the concentration (AUC) versus time curve in the peritoneum compared to unencapsulated 111In-DTPA. Similarly, the AUC for all the intra-abdominal tissues was increased significantly (20-427-fold). When i.p. IDLPLs were compared directly with i.v. IDLPLs, more modest changes were seen. There were increases in AUC for peritoneum (1.4-fold), ovary (1.3-fold), stomach (2.9-fold), pancreas (3.6-fold). small intestine (1.5-fold). colon (1.2-fold), gallbladder (5.1-fold) and adrenal gland (2.1-fold). These data support the development of i.p. liposomal chemotherapy for the treatment of intraperitoneal malignant disease.
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Radioisótopos de Indio/farmacocinética , Ácido Pentético/farmacocinética , Glándulas Suprarrenales/metabolismo , Animales , Área Bajo la Curva , Química Farmacéutica , Colon/metabolismo , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Femenino , Vesícula Biliar/metabolismo , Mucosa Gástrica/metabolismo , Radioisótopos de Indio/administración & dosificación , Radioisótopos de Indio/sangre , Radioisótopos de Indio/orina , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Intestino Delgado/metabolismo , Liposomas , Ratones , Ovario/metabolismo , Páncreas/metabolismo , Ácido Pentético/administración & dosificación , Ácido Pentético/sangre , Ácido Pentético/orina , Peritoneo/metabolismo , Organismos Libres de Patógenos Específicos , Distribución TisularRESUMEN
The aim of this work was to synthesize [166Dy]Dy/166Ho-DTPA-Biotin to evaluate its potential as a new radiopharmaceutical for targeted radiotherapy. Dysprosium-166 (166Dy) was obtained by neutron irradiation of enriched 164Dy(2)O(3) in a Triga Mark III reactor. The labeling was carried out in aqueous media at pH 8.0 by addition of [166Dy]DyCl(3) to diethylenetriaminepentaacetic-alpha,omega-bis(biocytinamide) (DTPA-Biotin). Radiochemical purity was determined by high-performance liquid chromatography (HPLC) and TLC. The biological integrity of labeled biotin was studied evaluating its avidity for avidin in an agarose column and by size-exclusion HPLC analysis of the radiolabeled DTPA-Biotin with and without the addition of avidin. Stability studies against dilution were carried out by diluting the radiocomplex solution with saline solution and with human serum at 37 degrees C for 24 h. The [166Dy]Dy/166Ho-labeled biotin was obtained with a 99.1+/-0.6% radiochemical purity. In vitro studies demonstrated that [166Dy]Dy/166Ho-DTPA-Biotin is stable after dilution in saline and in human serum and no translocation of the daughter nucleus occurs subsequent to beta(-) decay of 166Dy that could produce release of 166Ho(3+). Avidity of labeled biotin for avidin was not affected by the labeling procedure. Biodistribution studies in normal mice showed that the [166Dy]Dy/166Ho-DTPA-Biotin has a high renal clearance. In conclusion, the radiolabeled biotin prepared in this investigation has adequate properties to work as a stable in vivo generator system for targeted radiotherapy.
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Biotina/análogos & derivados , Biotina/química , Disprosio/química , Holmio/química , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Radiofármacos/química , Animales , Biotina/sangre , Biotina/farmacocinética , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Estabilidad de Medicamentos , Femenino , Inyecciones Intravenosas , Marcaje Isotópico , Ratones , Ratones Endogámicos BALB C , Ácido Pentético/sangre , Ácido Pentético/farmacocinética , Radioisótopos/química , Radiofármacos/sangre , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
RATIONALE AND OBJECTIVES: A molecular-based computed tomographic (CT) contrast agent with prolonged vascular residence time is needed for vascular and tumor imaging. No particulate agents have reached clinical practice due to nonspecific macrophage activation. The authors' objective was to synthesize a water-soluble macromolecular agent. MATERIALS AND METHODS: Dysprosium-DTPA-dextran was synthesized through activation of the hydroxyl units of dextran PM40 with allylbromine and subsequent reaction with amino ethanethiol to produce amino-terminated leashes. These leashes were then coupled to DTPA by means of the mixed anhydride method. Complexation of dysprosium by DTPA-dextran was achieved in an acidic solution of 0.2 M dysprosium chloride. One rabbit with a VX2 tumor was imaged with [Dy]DTPA-dextran (0.5 mL, 3.1 g, 1.15 mmol of dysprosium per kilogram). Transaxial scans were acquired through the liver and tumor for 45 minutes. A second healthy rabbit was imaged with Optiray-320 (6.0 mL, 5.0 mmol of iodine per kilogram) at 1-minute intervals for 10 minutes and again at 20 minutes. RESULTS: Each dextran PM40 molecule (diameter, 8.8 nm) contained 95 [Dy]DTPA groups, increasing its average molecular weight from 40,500 to 101,537 g/mol. The baseline-corrected inferior vena cava (IVC) enhancement for [Dy]DTPA-dextran decreased, with an 8-minute half-time during the first 15 minutes followed by a nearly zero slope for the rest of the observation period. The IVC remained brighter than liver throughout the observation period. The solid portion of the tumor was enhanced by 5-10 CT numbers, rendering areas of necrosis more apparent. The baseline-corrected IVC curve for Optiray-320 also demonstrated two phases, with half-times of 2.5 and 45 minutes. The IVC became less dense than liver within 5-8 minutes. CONCLUSION: [Dy]DTPA-dextran is water soluble and can be synthesized without intermolecular cross-linking to carry a high load of dysprosium. It provides blood pool enhancement characteristics with a long intravascular dwell time.