RESUMEN
Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with ß--emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radiolabeling, whereas a notable increase in lipophilicity of the resulting 90Y radiocomplex was observed. As a result, the compound could be extracted in Lipiodol® and encapsulated in biodegrable pegylated poly(malic acid) nanoparticles demonstrating the potential of lipophilic pyclen-dipicolinate derivatives as platforms for the design of radiopharmaceuticals for the treatment of liver or brain cancers by internal radiotherapy.
Asunto(s)
Compuestos de Azabiciclo/química , Radiofármacos/química , Radioterapia/métodos , Radioisótopos de Itrio/química , Aceite Etiodizado/química , Ligandos , Ácidos Picolínicos/químicaRESUMEN
In randomized clinical trials, no survival benefit has been observed for selective internal radiation therapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess, through a metaanalysis, whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is noninferior to sorafenib and to compare safety profiles for patients with advanced HCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify randomized clinical trials comparing SIRT, as monotherapy or followed by sorafenib, with sorafenib monotherapy among patients with advanced HCC. The main outcomes were OS and frequency of treatment-related severe adverse events (≥grade 3). The per-protocol population was the primary analysis population. A noninferiority margin of 1.08 in terms of hazard ratio was prespecified for the upper boundary of 95% confidence interval for OS. Prespecified subgroup analyses were performed. Results: Three randomized clinical trials, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411 of 635 (64.7%) patients allocated to SIRT and 522 of 608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was noninferior to sorafenib (10.2 and 9.2 mo [hazard ratio, 0.91; 95% confidence interval, 0.78-1.05]). Treatment-related severe adverse events were reported in 149 of 515 patients (28.9%) who received SIRT and 249 of 575 (43.3%) who received sorafenib only (P < 0.01). Conclusion: SIRT as initial therapy for advanced HCC is noninferior to sorafenib in terms of OS and offers a better safety profile.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/radioterapia , Microesferas , Sorafenib/uso terapéutico , Radioisótopos de Itrio/uso terapéutico , Humanos , Resultado del Tratamiento , Radioisótopos de Itrio/químicaRESUMEN
Development of a complex based on iron oxide nanoparticles (IONPs) for diagnosis and dual magnetic hyperthermia/radionuclide cancer therapy accomplishing high yields of radiolabeling and great magnetic heat induction is still a challenge. We report here the synthesis of citric acid, poly(acrylic acid) (PAA) and poly(ethylene glycol) coated IONPs and their labeling with three radionuclides, namely, technetium (99mTc), yttrium (90Y), and lutetium (177Lu), aiming at potential use in cancer diagnosis and therapy. Polyol-synthesized IONPs are a flowerlike structure with 13.5 nm spherically shaped cores and 24.8 nm diameter. PAA-coated nanoparticles (PAA@IONP) showed the best characteristics such as easy radiolabeling with very high yields (>97.5%) with all three radionuclides, and excellent in vitro stabilities with less than 10% of radionuclides detaching after 24 h. Heating ability of PAA@IONP in an alternating external magnetic field showed intrinsic loss power value of 7.3 nH m2/kg, which is one of higher reported values. Additionally, PAA@IONP itself presented no significant cytotoxicity to the CT-26 cancer cells, reaching IC50 at 60 µg/mL. However, under the external magnetic field, they show hyperthermia-mediated cells killing, which correlated with the magnetic field strength and time of exposure. Since PAA@IONP are easy to prepare, biocompatible, and with excellent magnetic heat induction, these nanoparticles radiolabeled with high-energy beta emitters 90Y and 177Lu have valuable potential as agent for dual magnetic hyperthermia/radionuclide therapy, while radiolabeled with 99mTc could be used in diagnostic imaging.
Asunto(s)
Compuestos Férricos/química , Magnetismo , Nanopartículas/química , Radiofármacos/química , Resinas Acrílicas/química , Animales , Partículas beta , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ácido Cítrico/química , Hipertermia Inducida , Lutecio/química , Campos Magnéticos , Ratones , Nanopartículas/toxicidad , Neoplasias/diagnóstico por imagen , Tamaño de la Partícula , Polietilenglicoles/química , Radioisótopos/química , Radiofármacos/farmacología , Radiofármacos/uso terapéutico , Tecnecio/química , Radioisótopos de Itrio/químicaRESUMEN
PURPOSE: Beta particles emitted by radioisotopes used in targeted radionuclide therapies (TRT) create Bremsstrahlung (BRS) which may affect SPECT quantification when imaging these isotopes. The purpose of the current study was to investigate the characteristics of Bremsstrahlung produced in tissue by three ß-emitting radioisotopes used in TRT. METHODS: Monte Carlo simulations of (177)Lu, (188)Re, and (90)Y sources placed in water filled cylinders were performed. BRS yields, mean energies and energy spectra for (a) all photons generated in the decays, (b) photons that were not absorbed and leave the cylinder, and (c) photons detected by the camera were analyzed. Next, the results of simulations were compared with those from experiments performed on a clinical SPECT camera using same acquisition conditions and phantom configurations as in simulations. RESULTS: Simulations reproduced relatively well the shapes of the measured spectra, except for (90)Y which showed an overestimation in the low energy range. Detailed analysis of the results allowed us to suggest best collimators and imaging conditions for each of the investigated isotopes. Finally, our simulations confirmed that the BRS contribution to the energy spectra in quantitative imaging of (177)Lu and (188)Re could be ignored. CONCLUSIONS: For (177)Lu and (188)Re, BRS contributes only marginally to the total spectra recorded by the camera. Our analysis shows that MELP and HE collimators are the best for imaging these two isotopes. For (90)Y, HE collimator should be used.
Asunto(s)
Lutecio/química , Radioisótopos/química , Radioisótopos/uso terapéutico , Renio/química , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Radioisótopos de Itrio/química , Simulación por Computador , Humanos , Método de Montecarlo , Fantasmas de Imagen , Tomografía de Emisión de Positrones , Agua/químicaRESUMEN
Intra-arterial radionuclide therapies serve essentially as internal radiation treatment options for both primary and metastatic liver tumors, which imply delivering implantable radioactive microspheres into branches of hepatic arteries that feed liver tumors to provide a high dose of targeted radiation to tumor tissue, while sparing the healthy liver tissue from hazardous effects of radiation. The principle of this therapeutic option depends on the unique preferential arterial supply of malignant liver tumors in contrast with mostly portal venous supply of normal hepatocytes as well as excess amount of arterial neovascularization in the tumor bed. Therefore, intra-arterial radionuclide therapy can provide very high radiation exposure to tumor tissue, which is impossible to reach with external radiation therapy due to serious side effects and moreover, radiation can be targeted to tumor tissue selectively with less side effects. Yttrium-90 (Y-90), a high-energetic beta emitter is the most preferred radionuclide, which is used to label microspheres. Two types of Y-90 microspheres are commercially available that are made of resin and glass. Many studies in the literature have demonstrated that Y-90 microsphere therapy is an efficient and safe locoregional therapeutic option for unresectable primary and metastatic liver tumors such as hepatocellular carcinoma and liver metastases from colorectal cancer and breast cancer as well as neuroendocrine tumors. Furthermore, limited number of studies has reported its use in some relatively uncommon metastatic liver tumors from melanoma, pancreatic, renal, and lung cancer. Besides Y-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, Rhenium-188 microspheres, Holmium-166 chitosan, and Holmium-166 microspheres have been introduced as alternative radiopharmaceuticals for intra-arterial therapy for liver tumors.
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Arterias/efectos de la radiación , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/radioterapia , Radioterapia/métodos , Radioisótopos de Itrio/uso terapéutico , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioisótopos de Itrio/químicaRESUMEN
Bispecific antibodies (BsAb) have proven to be useful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g., of streptavidin-antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive [GD2(+)] tumors. For this purpose, an IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with ß-particle-emitting radiometals such as (177)Lu and (90)Y. A three-step regimen, including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with (177)Lu (as (177)Lu-DOTA-Bn; t1/2 = 6.71 days), was optimized in immunocompromised mice carrying subcutaneous human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were approximately 85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indices (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5/group; tumor volume, 240 ± 160 mm(3)) with three successive PRIT cycles (total (177)Lu: â¼33 MBq; tumor dose â¼3,400 cGy), revealed complete tumor response in 5 of 5 animals, with no recurrence up to 28 days after treatment. Tumor ablation was confirmed histologically in 4 of 5 mice, and normal organs showed minimal overall toxicities. All nontreated mice required sacrifice within 12 days (>1.0-cm(3) tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(+)-NB in mice while sparing kidney and bone marrow.
Asunto(s)
Anticuerpos Biespecíficos/farmacología , Gangliósidos/inmunología , Inmunoglobulina G/inmunología , Radiofármacos/farmacología , Animales , Anticuerpos Biespecíficos/inmunología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Fragmentos de Inmunoglobulinas/inmunología , Fragmentos de Inmunoglobulinas/farmacología , Lutecio/administración & dosificación , Lutecio/química , Ratones , Ratones Desnudos , Octreótido/análogos & derivados , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Radioinmunoterapia , Radiofármacos/química , Radiofármacos/inmunología , Distribución Aleatoria , Ensayos Antitumor por Modelo de Xenoinjerto , Radioisótopos de Itrio/administración & dosificación , Radioisótopos de Itrio/químicaRESUMEN
We report a practical and high-yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, and 3p-C-DEPA for radiolabeling kinetics with (90)Y and (177)Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with (90)Y and (177)Lu. (90)Y-3p-C-NETA-trastuzumab and (177)Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of (177)Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. (177)Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using (90)Y and (177)Lu and has the potential to replace DOTA and DTPA analogues in current clinical use.
Asunto(s)
Quelantes/química , Lutecio/química , Radioinmunoterapia , Radioisótopos de Itrio/química , Anticuerpos Monoclonales Humanizados/química , Evaluación Preclínica de Medicamentos , Cinética , Ligandos , TrastuzumabRESUMEN
The human E. coli heat-stable enterotoxin (ST(h), amino acid sequence N1SSNYCCELCCNPACTGCY19) binds specifically to the guanylate cyclase C (GC-C) receptor, which is present in high density on the apical surface of normal intestinal epithelial cells as well as on the surface of human colon cancer cells. Analogs of ST(h) are currently being used as vectors targeting human colon cancers. Previous studies in our laboratory have focused on development of 111Indium-labeled ST(h) analogs for in vivo imaging applications. Here, we extend the scope of this work to include targeting of the therapeutic radionuclides 90Y and 177Lu. The peptide DOTA-F19-ST(h)(1-19) was synthesized using conventional Fmoc-based solid-phase techniques and refolded in dilute aqueous solution. The peptide was purified by RP-HPLC and characterized by MALDI-TOF MS and in vitro receptor binding assay. The DOTA-conjugate was metallated with nonradioactive Lu(III)Cl3 and Y(III)Cl3, and IC50 values of 2.6+/-0.1 and 4.2+/-0.9 nM were determined for the Lu- and Y-labeled peptides, respectively. 177Lu(III)Cl3 and 90Y(III)Cl3 labeling yielded tracer preparations that were inseparable by C18 RP-HPLC, indicating that putative differences between Lu-, Y- and In coordination spheres are not observed in the context of labeled ST(h) peptides. In vivo biodistribution studies of the 177Lu-labeled peptide in severe combined immunodeficient (SCID) mice bearing T-84 human cancer tumor xenografts showed rapid clearance from the bloodstream, with >90 %ID in the urine at 1 h pi. Localization of the tracer within tumor xenografts was 1.86+/-0.91 %ID/g at 1 h pi, a value higher than for all other tissues with the exception of kidney (2.74+/-0.24 %ID/g). At 24 h pi, >98 %ID was excreted into the urine, and 0.35+/-0.23 %ID/g remained in tumor, again higher than in all other tissues except kidney (0.91+/-0.46 %ID/g). Biodistribution results at 24 h pi for the 90Y-labeled peptide mirrored those for the 177Lu analog, in agreement with the identical behavior of the labeled analogs by C18 RP-HPLC. These results demonstrate the ability of 177Lu- and 90Y-labeled ST(h) molecules to specifically target GC-C receptors expressed on T-84 human colon cancer cells.
Asunto(s)
Toxinas Bacterianas/farmacocinética , Neoplasias del Colon/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Escherichia coli , Lutecio/farmacocinética , Péptidos Natriuréticos/metabolismo , Radioisótopos de Itrio/farmacocinética , Animales , Toxinas Bacterianas/química , Toxinas Bacterianas/uso terapéutico , Línea Celular Tumoral , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/radioterapia , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Femenino , Calor , Humanos , Marcaje Isotópico/métodos , Lutecio/química , Lutecio/uso terapéutico , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos ICR , Radioisótopos/química , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Cintigrafía , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Receptores de Superficie Celular/metabolismo , Distribución Tisular , Radioisótopos de Itrio/química , Radioisótopos de Itrio/uso terapéuticoRESUMEN
86Y is an attractive PET radionuclide due to its intermediate half-life. (86)Y was produced via the 86Sr(p,n)86Y nuclear reaction. Enriched SrCO3 or SrO was irradiated with 2-6 microA of beam current for <4 h on a CS-15 cyclotron. It was shown that the SrO target could withstand at least 6 microA of beam current, a significant improvement over a maximum of 2 microA on the SrCO3 target. Average yields of 4.5 mCi/microA.h were achieved with SrO, which represent 71% of the theoretical yield, compared to 2.3 mCi/microA.h with SrCO3. The radioisotopic contaminants were (86m)Y (220%), 87Y (0.27%), (87m)Y (0.43%) and 88Y (0.024%). 86Y was isolated in an electrochemical cell consisting of three Pt electrodes. The solution was electrolyzed at 2000 mA (40 min) using two Pt plate electrodes. A second electrolysis (230 mA for 20 min) was performed using one Pt plate and a Pt wire. On average, 97.1% of the 86Y was recollected on the Pt wire after a second electrolysis. The (86)Y was collected from the Pt wire using 2.8 M HNO3/EtOH (3:1). After evaporation, 86Y was reconstituted in 100 microl of 0.1 M HCl. Target materials were recovered as SrCO3 and then converted to SrO by thermal decomposition at 1150 degrees C. Specific activity of 86Y was determined to be 29+/-19 mCi/microg via titration of 86Y(OAc)3 with DOTA or DTPA. We have established techniques for the routine, economical production of high purity, high specific activity 86Y on a small biomedical cyclotron that are translatable to other institutions.
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Ciclotrones , Estabilidad de Medicamentos , Radiofármacos/análisis , Radiofármacos/síntesis química , Coloración y Etiquetado/métodos , Radioisótopos de Itrio/análisis , Radioisótopos de Itrio/química , Ingeniería Biomédica/métodos , Evaluación Preclínica de Medicamentos , Cinética , Garantía de la Calidad de Atención de Salud/métodos , Control de CalidadRESUMEN
The article reviews the background and current status of pretargeting for cancer imaging and therapy with radionuclides. Pretargeting procedures were introduced approximately 20 years ago as an alternative to directly radiolabeled antibodies. Because they were multistep processes, they were met with resistance but have since progressed to simple and improved procedures that could become the next generation of imaging and therapy with radionuclides. The separation of the radiolabeled compound from the antibody-targeting agent affords pretargeting procedures considerable flexibility in the radiolabeling process, providing opportunities for molecular imaging using gamma- or positron-emitting radionuclides and a variety of beta- and alpha-emitting radionuclides of therapeutic applications. Pretargeting methods improve tumor/nontumor ratios, exceeding that achieved with directly radiolabeled Fab' fragments, particularly within just a few hours of the radionuclide injection. In addition, tumor uptake exceeds that of a Fab' fragment by as much as 10-fold, giving pretargeting a greatly enhanced sensitivity for imaging. Advances in molecular biology have led to the development of novel binding proteins that have further improved radionuclide delivery in these systems. Studies in a variety of hematologic and solid tumor models have shown advantages of pretargeting compared with directly radiolabeled IgG for therapy, and there are several clinical studies under way that are also showing promising results. Thus, the next generation of targeting agents will likely employ pretargeting approaches to optimize radionuclide delivery for a wide range of applications.
Asunto(s)
Neoplasias/tratamiento farmacológico , Radioinmunoterapia/métodos , Radioisótopos/administración & dosificación , Animales , Anticuerpos Monoclonales/química , Avidina/química , Biotina/química , Calibración , Línea Celular Tumoral , Medios de Contraste/farmacología , ADN/química , ADN Complementario/metabolismo , Sistemas de Liberación de Medicamentos , Femenino , Rayos gamma , Humanos , Inmunoglobulina G/química , Inmunoglobulina G/uso terapéutico , Imagen por Resonancia Magnética , Ratones , Ratones Desnudos , Modelos Biológicos , Trasplante de Neoplasias , Neoplasias/metabolismo , Oligonucleótidos/química , Radioinmunodetección , Radioisótopos/química , Cintigrafía/métodos , Proteínas Recombinantes/química , Estreptavidina/química , Factores de Tiempo , Ultrasonido , Radioisótopos de Itrio/químicaRESUMEN
Ethiodol (or lipiodol) is selectively retained in hepatocellular carcinoma and is used as a vehicle to deliver radioactive agents following intraarterial hepatic infusion. We prepared the lipophilic complex 90Y-oxine with a radiolabeling efficiency of 97.6+/-1.1%. After extraction into ethiodol, a stability test in serum at 37 degrees C showed that 87.8% of the 90Y remained ethiodol-bound for 7 days. Bremsstrahlung imaging of a rabbit for 48 h confirmed that the homogeneous mixture of radiolabeled 90Y-oxine and ethiodol stayed in the targeted liver lobe. This radiopharmaceutical is thus a potential candidate for the treatment of non-resectable liver cancer.
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Aceite Etiodizado/química , Neoplasias Hepáticas Experimentales/radioterapia , Oxiquinolina/química , Radiofármacos/uso terapéutico , Radioisótopos de Itrio/administración & dosificación , Radioisótopos de Itrio/química , Angiografía , Animales , Cromatografía en Capa Delgada , Estabilidad de Medicamentos , Aceite Etiodizado/administración & dosificación , Aceite Etiodizado/farmacocinética , Arteria Hepática , Radioisótopos de Indio/química , Inyecciones Intraarteriales , Marcaje Isotópico/métodos , Hígado/diagnóstico por imagen , Especificidad de Órganos , Oxiquinolina/administración & dosificación , Oxiquinolina/sangre , Oxiquinolina/farmacocinética , Conejos , Cintigrafía , Radioisótopos de Itrio/sangre , Radioisótopos de Itrio/farmacocinéticaRESUMEN
Microspheres made from Y2O3-Al2O3-SiO2 (YAS) glasses, which contain radioactive Y-90, are currently being used to treat liver cancer in humans, where their chemical durability is of prime importance. In deionized water or saline at 37 degrees C, the weight percent Yttrium (Y) dissolved from eight different YAS glasses ranged from only 0.02-0.13% of the total Y present and their dissolution rate was barely measurable, < or = 1.0 x 10(-9) g/cm2-min. The most chemically durable YAS glass was 17Y2O3-19Al2O3-64SiO2, mol%. The small amount of Y released from microspheres, 25-35 microns diameter, of this glass after corrosion in saline or deionized water at 37 degrees C was essentially the same as for bulk glass samples. Based on their excellent chemical durability, it is concluded that YAS glass microspheres are suitable for in vivo use.