RESUMEN
BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
Asunto(s)
Degeneración Hepatolenticular , Penicilamina , Humanos , Penicilamina/farmacología , Penicilamina/uso terapéutico , Trientina/farmacología , Trientina/uso terapéutico , Cobre , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos de Cobre/uso terapéutico , Degeneración Hepatolenticular/tratamiento farmacológico , Tomografía de Emisión de PositronesRESUMEN
TGF-ß plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-ß-driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-ß and a TGF-ß type 1 receptor inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab')2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-ß reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1-infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected macaques. This increase correlated with an increase in SIV RNA in the gut. Two of the 7 animals also exhibited increases in plasma VLs. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-ß signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
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Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Radioisótopos de Cobre/farmacología , Radioisótopos de Cobre/uso terapéutico , Antirretrovirales/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Macaca mulatta , Replicación Viral , Factor de Crecimiento Transformador beta , InmunidadRESUMEN
Copper-67 (T1/2 = 61.83 h, Eß-mean=141 keV, Iß-total=100%; Eγ = 184.577 keV, Iγ = 48.7%) is a promising radionuclide for theranostic applications especially in radio immunotherapy. However, one of the main drawbacks for its application is related to its limited availability. Various nuclear reaction routes investigated in the last years can result in 67Cu production, although the use of proton beams is the method of choice taken into account in this work. The goal of this work is a revision of the cross-sections aimed at 67Cu yield, which were evaluated for the 68Zn(p,2p)67Cu reaction route up to 80 MeV proton energy. A well-defined statistical procedure, i.e., the Simultaneous Evaluation on KALMAN (SOK), combined with the least-squares concept, was used to obtain the evaluated data together with the covariance matrix. The obtained evaluated data were also compared to predictions provided by the nuclear reaction model codes TALYS and EMPIRE, and a partial agreement among them has been found. These data may be useful for both existing and potential applications in nuclear medicine, to achieve an improvement and validation of the various nuclear reaction models, and may also find applications in other fields (e.g., activation analysis and thin layer activation).
Asunto(s)
Radioisótopos de Cobre/análisis , Medicina de Precisión , Isótopos de Zinc/análisis , Simulación por Computador , Radioisótopos de Cobre/uso terapéutico , Humanos , Medicina Nuclear , Protones , Isótopos de Zinc/uso terapéuticoRESUMEN
Copper-67 (t1/2 = 2.58 days) decays by ß- ([Formula: see text]: 562 keV) and γ-rays (93 keV and 185 keV) rendering it with potential for both radionuclide therapy and single-photon emission computed tomography (SPECT) imaging. Prompted by the recent breakthrough of 67Cu production with high specific activity, high radionuclidic purity, and sufficient quantities, the interest in the theranostic potential of 67Cu has been rekindled. This work addresses the practicability of developing 67Cu-labeled antibodies with substantially improved quality for cancer radioimmunotheranostics. Proof of concept is demonstrated with pertuzumab, a US-FDA-approved monoclonal antibody for combination therapies of HER2-positive breast cancer. With an average number of 1.9 chelators coupled to each antibody, we achieved a two-order of magnitude increase in radiolabeling efficiency compared to literature reports. In a preclinical therapeutic study, mice (n = 4-7/group) bearing HER2+ xenografts exhibited a 67Cu-dose dependent tumor-growth inhibition from 67Cu-labeled-Pertuzumab co-administered with trastuzumab. Furthermore, greater tumor size reduction was observed with 67Cu-labeled-pertuzumab formulations of higher specific activity. The potential of SPECT imaging with 67Cu radiopharmaceuticals was tested after 67Cu-labeled-Pertuzumab administration. Impressively, all tumors were clearly visualized by SPECT imaging with 67Cu-labeled-Pertuzumab even at day 5 post injection. This work demonstrates it is practical to use 67Cu radioimmunoconjugates for cancer radioimmunotheranostics.
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Radioisótopos de Cobre/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoterapia , Tomografía Computarizada de Emisión de Fotón Único , Animales , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Femenino , Humanos , Ratones SCID , Radioinmunoterapia , Receptor ErbB-2/metabolismo , Tomografía Computarizada por Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.
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Radioisótopos de Cobre/farmacología , Radioisótopos de Cobre/uso terapéutico , Medicina de Precisión/métodos , Radioinmunoterapia/métodos , Animales , Anticuerpos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Reacción de Cicloadición , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoconjugados , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Radioisótopos/farmacología , Radioisótopos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of 64Cu and 67Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr3)-octreotate, called 64Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of 67Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, 177Lu-LuDOTA-Tyr3-octreotate (177Lu-LuTATE). Methods: The antitumor efficacy of various doses of 67Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with 177Lu-LuTATE. Results: Seven days after a single administration of 67Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of 177Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both 67Cu-CuSarTATE and 177Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of 67Cu-CuSarTATE or 177Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; 177Lu-LuTATE: 46 vs. 29 d [P = 0.040]). Conclusion: This study demonstrates that 67Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of 67Cu-CuSarTATE and 177Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of 67Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.
Asunto(s)
Radioisótopos de Cobre/uso terapéutico , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/radioterapia , Octreótido/análogos & derivados , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo , Animales , Transporte Biológico , Línea Celular Tumoral , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos BALB C , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Octreótido/metabolismo , Octreótido/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
We investigate the effects of an increase in the production of secondary electrons when a ß - source commonly used in internal radionuclide therapy, 67Cu, is radiolabelled to a super-paramagnetic iron oxide nanoparticle (SPION), with specific emphasis on the role of SPION cluster size and geometry. A positive relationship is found between the degree to which the nanoparticles are clustered and the associated radio-enhancement effects, with cluster population size playing a major role, as well as SPION separation within a cluster and the distance between clusters. Our simulation results indicate that SPIONs labelled with 67Cu can induce a nonlinear amplification in the number of secondary electrons produced of up to 4% in bulk, with localised regions of nearer inter-SPION separation producing an increase of over 400% for a 20 nm average SPION separation. Such variation in enhancement due to local concentration effects may help identify clinical strategies that enhance efficacy for a given radiation dosage, or achieve equal efficacy with reduced radiation dosage.
Asunto(s)
Partículas beta/uso terapéutico , Radioisótopos de Cobre/uso terapéutico , Radioterapia de Iones Pesados/métodos , Nanopartículas del Metal/uso terapéutico , Humanos , Método de MontecarloRESUMEN
We developed a new apparatus for the routine production of 64Cu in clinical use. The apparatus has many disposable parts that stabilize the product quality (such that there is a low deviation of the concentrations of impurity metals in the product) and reduce the work load of preparation for routine production. We also developed a new evaporator using near-infrared heaters for disposable use. We conducted a production test using the new apparatus and evaluated product quality. The product yield was 6.3⯱â¯0.32 GBq (end of bombardment) (Nâ¯=â¯4), the product quality in terms of the concentrations of impurity metals (Cu2+, Ni2+, Fe3+, Zn2+, Mn2+) was as good as that usually achieved, likely on the order of parts per billion, and the preparation time was reduced from 2 days to 1 day.
Asunto(s)
Radioisótopos de Cobre/aislamiento & purificación , Radiofármacos/aislamiento & purificación , Tecnología Radiológica/instrumentación , Resinas de Intercambio de Catión , Cromatografía por Intercambio Iónico/instrumentación , Radioisótopos de Cobre/normas , Radioisótopos de Cobre/uso terapéutico , Monitoreo del Ambiente , Diseño de Equipo , Humanos , Isótopos/aislamiento & purificación , Metales Pesados/análisis , Níquel/aislamiento & purificación , Control de Calidad , Radiofármacos/normas , Radiofármacos/uso terapéuticoRESUMEN
The growing advancement in nuclear medicine challenges researchers from several different fields to integrate imaging and therapeutic modalities in a theranostic radiopharmaceutical, which can be defined as a molecular entity with readily replaceable radioisotope to provide easy switch between diagnostic and therapeutic applications for efficient and patient-friendly treatment of diseases. For such a reason, the diagnostic and therapeutic potential of all five medical radionuclides of copper have thoroughly been investigated as they boost the hope for development of successful radiotheranostics. To facilitate the mutual understanding between all different specialists working on this multidisciplinary field, we summarized the recent updates in copper-based nuclear medicine, with specific attention to the potential theranostic applications. Thereby, this review paper is focused on the current achievements in the copper-related complementary fields, such as synthetic and nuclear chemistry, biological assessment of radiopharmaceuticals, design and development of nanomaterials for multimodal theranostic implications. This work includes: i) description of available copper radionuclide production methods; ii) analyses of the synthetic strategies for development of improved copper radiopharmaceuticals; iii) summary of reported clinical data and recent preclinical studies from the last five years on biological applicability of copper radiopharmaceuticals; and iv) illustration of some sophisticated multimodal nanotheranostic agents that comprise several imaging and therapeutic modalities. Significant advancement can be seen in the synthetic procedures, which enables the broader implication of pretargeting approaches via bioorthogonal click reactions, as well as in the nanotechnology methods for biomimetic construction of biocompatible multimodal copper theranostics. All this gives the hope that personalized treatment of various diseases can be achieved by copper theranostics in the near future.
Asunto(s)
Radioisótopos de Cobre/uso terapéutico , Radiofármacos/uso terapéutico , Nanomedicina Teranóstica , Animales , Radioisótopos de Cobre/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Radiofármacos/química , Relación Estructura-ActividadRESUMEN
We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve the pharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatment efficacy.
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Clorofila/análogos & derivados , Radioisótopos de Cobre/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Clorofila/química , Clorofila/farmacocinética , Clorofila/uso terapéutico , Radioisótopos de Cobre/química , Radioisótopos de Cobre/farmacocinética , Masculino , Ratones , Ratones Desnudos , Imagen Óptica/métodos , Péptidos/química , Péptidos/farmacocinética , Péptidos/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Porfirinas/química , Porfirinas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/patología , Nanomedicina Teranóstica/métodosRESUMEN
Ongoing studies of physiological and pathological processes have led to a corresponding need for new radiopharmaceuticals, especially when studies are limited by the absence of a particular radiolabeled target. Thus, the development of new radioactive tracers is highly relevant and can represent a significant contribution to efforts to elucidate important phenomena in biology. Currently, theranostics represents a new frontier in the fields of medicine and nuclear medicine, with the same compound being used for both diagnosis and treatment. In the human body, copper (Cu) is the third most abundant metal and it plays a crucial role in many biological functions. Correspondingly, in various acquired and inherited pathological conditions, such as cancer and Alzheimer's disease, alterations in Cu levels have been found. Moreover, a wide spectrum of neurodegenerative disorders are associated with higher or lower levels of Cu, as well as inappropriately bound or distributed levels of Cu in the brain. In human cells, the membrane protein, hCtr1, binds Cu in its Cu(I) oxidation state in an energy-dependent manner. Copper-64 (64Cu) is a cyclotron-produced radionuclide that has exhibited physical properties that are complementary for diagnosis and/or therapeutic purposes. To date, very few reports have described the clinical development of 64Cu as a radiotracer for cancer imaging. In this review, we highlight recent insights in our understanding and use of 64CuCl2 as a theranostic agent for various types of tumors. To the best of our knowledge, no adverse effects or clinically observable pharmacological effects have been described for 64CuCl2 in the literature. Thus, 64Cu represents a revolutionary radiopharmaceutical for positron emission tomography imaging and opens a new era in the theranostic field.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Radioisótopos de Cobre/uso terapéutico , Neoplasias/tratamiento farmacológico , Radiofármacos/uso terapéutico , Nanomedicina Teranóstica , Animales , HumanosRESUMEN
INTRODUCTION: The high diagnostic potential of 64Cu-PSMA PET-CT imaging was clinically investigated in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local disease. The aim of our study is to assess the uptake behavior in the clinical setting of 64Copper Prostate-Specific Membrane Antigen (64Cu PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) in prostate cancer. METHODS: A retrospective study was performed in 23 patients with intermediate, high risk and progressive disease at primary staging of prostate cancer. All patients underwent 64Cu-PSMA PET. Overall, 250 MBq (4 MBq per kg bodyweight, range 230-290 MBq) of 64Cu-NODAGA PSMA was intravenously applied. PET images were performed 30 min (pelvis and abdomen) and 1-2 h post-injection (skull base to mid-thigh). Maximum standardized uptake values (SUVmax) were measured in the organs with high physiological uptake such as liver and kidney, and, additionally, background activity was measured in the gluteal area and in suspected tumor lesions using a HERMES workstation. RESULTS: PSMA uptake was detected in prostate bed in nine patients, in six patients in distant metastases (bone, lung and liver) and in nine patients in lymph nodes. Of 23 patients, 5 (20.8%) did not show any focal pathological uptake in the whole body. The number of sites (prostate bed, lymph nodes, distant metastases) with positive PSMA uptake was significantly associated with PSA values before imaging (P = 0.0032). The 64Cu PSMA uptake increased significantly from 30 min to 1-3 h post-injection (Wilcoxon signed rank test, P = 0.002). CONCLUSIONS: 64Cu NODAGA-PSMA PET is a promising imaging tool in the detection of residual disease in patients with recurrent or primary progressive prostate cancer. Furthermore, the increased tracer uptake over time indicates in vivo stability of the diagnostic radiopharmaceutical.
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Acetatos/uso terapéutico , Antígenos de Superficie/uso terapéutico , Radioisótopos de Cobre/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Radiofármacos/uso terapéutico , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Copper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly 64Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [64Cu2+] ions. For example, it has been demonstrated that administration of ionic [64Cu2+] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of 64Cu-radiopharmaceuticals in molecular imaging and cancer therapy.
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Radioisótopos de Cobre/uso terapéutico , Imagen Molecular/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Radiofármacos/uso terapéutico , Nanomedicina Teranóstica , Animales , Humanos , Neoplasias/patología , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: Positron emission tomography (PET) is an instrumental diagnostic modality developed around the positron-emitting radioisotopes of biologically important elements such as carbon, oxygen and nitrogen (11C, 15O, 13N). Among longer-lived PET radionuclides, 18F is by far the most commonly used radiotracer, extensively used for tumour imaging with FDG ([18F]-fluorodeoxyglucose) and also frequently investigated in the development of novel radiopharmaceuticals. Many other positron- emitting radionuclides with higher atomic numbers and longer half-lives have been investigated for both imaging and therapeutic purposes, including the halogens (124I, 120I, 76Br) and a number of metal radionuclides. The radio-copper has attracted considerable attention, because they include isotopes which, due to their emission properties, offer themselves as agents of both diagnostic imaging (60Cu, 61Cu, 62Cu, 64Cu) and in vivo targeted radiation therapy (64Cu and 67Cu). OBJECTIVES: Although the use of this radionuclide has grown exponentially over the last decade, academic institutions have largely been responsible for its production and for the development of the vast majority of radiopharmaceutical based on these nuclides. A number of compounds labelled with Cuisotopes have been proposed, not only for imaging purposes but also for therapy. The aim of the present paper is to provide an overview on the clinical results obtained in human beings with copper radionuclides. CONCLUSION: Several preliminary studies and clinical trials evaluated the potential clinical role of copper radioisotopes for diagnostic and therapeutic purposes. 64Cu seems to be the most suitable radioisotope for future clinical applications due to its longer half-life (12.7 h) and its commercial availability. Future clinical applications of copper radioisotopes could be enhanced by the possibility of radioligand therapy with the beta-emitting 67Cu, creating a new "theranostics pair".
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Radioisótopos de Cobre/química , Radioisótopos de Cobre/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/uso terapéutico , Semivida , HumanosRESUMEN
Developing tumor-homing nanoparticles with integrated diagnostic and therapeutic functions, and meanwhile could be rapidly excreted from the body, would be of great interest to realize imaging-guided precision treatment of cancer. In this study, an ultrasmall coordination polymer nanodot (CPN) based on the coordination between tungsten ions (WVI) and gallic acid (W-GA) was developed via a simple method. After polyethylene glycol (PEG) modification, PEGylated W-GA (W-GA-PEG) CPNs with an ultrasmall hydrodynamic diameter of 5 nm were rather stable in various physiological solutions. Without the need of chelator molecules, W-GA-PEG CPNs could be efficiently labeled with radioisotope 64Cu2+, enabling positron emission tomography (PET) imaging, which reveals efficient tumor accumulation and rapid renal clearance of W-GA-PEG CPNs upon intravenous injection. Utilizing the radio-sensitizing function of tungsten with strong X-ray absorption, such W-GA-PEG CPNs were able to greatly enhance the efficacy of cancer radiotherapy in inhibiting the tumor growth. With fast clearance and little long-term body retention, those W-GA-PEG CPNs exhibited no appreciable in vivo toxicity. This study presents a type of CPNs with excellent imaging and therapeutic abilities as well as rapid renal clearance behavior, promising for further clinic translation.
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Neoplasias de la Mama/radioterapia , Complejos de Coordinación/química , Radioisótopos de Cobre/química , Ácido Gálico/análogos & derivados , Nanopartículas/química , Polietilenglicoles/química , Tungsteno/química , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/uso terapéutico , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/uso terapéutico , Femenino , Ácido Gálico/farmacocinética , Ácido Gálico/uso terapéutico , Riñón/metabolismo , Ratones , Nanopartículas/uso terapéutico , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Tungsteno/farmacocinética , Tungsteno/uso terapéuticoRESUMEN
OBJECTIVE: Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale production of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets αVß3 integrin (αVß3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound. MATERIALS AND METHODS: Cu, produced through the Ni(α, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liquid chromatography and/or thin-layer chromatography. Mice with subcutaneous αVß3-positive U87MG-glioblastoma xenografts received a single intravenous injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle solution. The tumor volumes were measured, side effects were assessed in terms of body weight, routine hematology, and hepatic and renal functions, and the mouse radiation dosimetry was estimated. RESULTS: Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochemical purity of 97.9±2.4% and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that observed upon vehicle or peptide control administration, with an estimated tumor-absorbed dose of 0.712 Gy. No significant toxicity was observed in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice. CONCLUSION: Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVß3 integrin-targeted internal radiotherapy.
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Radioisótopos de Cobre/uso terapéutico , Glioblastoma/radioterapia , Integrina alfaVbeta3/antagonistas & inhibidores , Oligopéptidos/uso terapéutico , Radiofármacos/uso terapéutico , Animales , Línea Celular Tumoral , Radioisótopos de Cobre/química , Radioisótopos de Cobre/toxicidad , Estabilidad de Medicamentos , Femenino , Humanos , Marcaje Isotópico/métodos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Oligopéptidos/química , Oligopéptidos/toxicidad , Compuestos Organometálicos/química , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/toxicidad , Radiofármacos/química , Radiofármacos/toxicidad , Dosificación Radioterapéutica , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/metabolismo , Cobre/metabolismo , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/radioterapia , Radioisótopos de Cobre/uso terapéutico , Humanos , Neoplasias Hepáticas/terapia , Ratones , Imagen Molecular , Tomografía de Emisión de Positrones , Radiofármacos/uso terapéutico , Nanomedicina TeranósticaRESUMEN
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [(64)Cu]CuCl2. To evaluate the potential theranostic role of [(64)Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [(64)Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.
Asunto(s)
Encéfalo/patología , Radioisótopos de Cobre/uso terapéutico , Glioblastoma/radioterapia , Nanomedicina Teranóstica , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de la radiación , Línea Celular Tumoral , Terapia Combinada , Glioblastoma/diagnóstico por imagen , Glioblastoma/patología , Humanos , Ratones , Distribución Tisular , Tomografía Computarizada por Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Delta-like ligand 4 (Dll4) expressed in tumor cells plays a key role to promote tumor growth of numerous cancer types. Based on a novel antihuman Dll4 monoclonal antibody (61B), we developed a (64)Cu-labeled probe for positron emission tomography (PET) imaging of tumor Dll4 expression. In this study, 61B was conjugated with the (64)Cu-chelator DOTA through lysine on the antibody. Human IgG (hIgG)-DOTA, which did not bind to Dll4, was also prepared as a control. The Dll4 binding activity of the probes was evaluated through the bead-based binding assay with Dll4-alkaline phosphatase. The resulting PET probes were evaluated in U87MG glioblastoma and HT29 colorectal cancer xenografts in athymic nude mice. Our results demonstrated that the 61B-DOTA retained (77.2 ± 3.7) % Dll4 binding activity of the unmodified 61B, which is significantly higher than that of hIgG-DOTA (0.06 ± 0.03) %. Confocal microscopy analysis confirmed that 61B-Cy5.5, but not IgG-Cy5.5, predominantly located within the U87MG and HT29 cells cytoplasm. U87MG cells showed higher 61B-Cy5.5 binding as compared to HT29 cells. In U87MG xenografts, 61B-DOTA-(64)Cu demonstrated remarkable tumor accumulation (10.5 ± 1.7 and 10.2 ± 1.2%ID/g at 24 and 48 h postinjection, respectively). In HT29 xenografts, tumor accumulation of 61B-DOTA-(64)Cu was significantly lower than that of U87MG (7.3 ± 1.3 and 6.6 ± 1.3%ID/g at 24 and 48 h postinjection, respectively). The tumor accumulation of 61B-DOTA-(64)Cu was significantly higher than that of hIgG-DOTA-(64)Cu in both xenografts models. Immunofluorescence staining of the tumor tissues further confirmed that tumor accumulation of 61B-Cy5.5 was correlated well with in vivo PET imaging data using 61B-DOTA-(64)Cu. In conclusion, 61B-DOTA-(64)Cu PET probe was successfully synthesized and demonstrated prominent tumor uptake by targeting Dll4. 61B-DOTA-(64)Cu has great potential to be used for noninvasive Dll4 imaging, which could be valuable for tumor detection, Dll4 expression level evaluation, and Dll4-based treatment monitoring.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Glioblastoma/metabolismo , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Proteínas de Unión al Calcio , Línea Celular Tumoral/trasplante , Radioisótopos de Cobre/uso terapéutico , Femenino , Células HT29/trasplante , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/inmunología , Ratones , Ratones Desnudos , Microscopía Confocal , Trasplante de Neoplasias , Tomografía de Emisión de PositronesRESUMEN
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies. The aggressive behavior of ATC and its resistance to traditional treatment limit the efficacy of radiotherapy, chemotherapy, and surgery. The purpose of this study is aimed at enhancing the therapeutic efficacy of radiotherapy (RT) combined with photothermal therapy (PTT) in murine orthotopic model of ATC, based on our developed single radioactive copper sulfide (CuS) nanoparticle platform. We prepare a new dual-modality therapy for ATC consisting of a single-compartment nanoplatform, polyethylene glycol-coated [(64)Cu]CuS NPs, in which the radiotherapeutic property of (64)Cu is combined with the plasmonic properties of CuS NPs. Mice with Hth83 ATC were treated with PEG-[(64)Cu]CuS NPs and/or near infrared laser. Antitumor effects were assessed by tumor growth and animal survival. We found that in mice bearing orthotopic human Hth83 ATC tumors, micro-PET/CT imaging and biodistribution studies showed that about 50% of the injected dose of PEG-[(64)Cu]CuS NPs was retained in tumor 48 h after intratumoral injection. Human absorbed doses were calculated from biodistribution data. In antitumor experiments, tumor growth was delayed by PEG-[(64)Cu]CuS NP-mediated RT, PTT, and combined RT/PTT, with combined RT/PTT being most effective. In addition, combined RT/PTT significantly prolonged the survival of Hth83 tumor-bearing mice compared to no treatment, laser treatment alone, or NP treatment alone without producing acute toxic effects. These findings indicate that this single-compartment multifunctional NPs platform merits further development as a novel therapeutic agent for ATC.