RESUMEN
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.
Asunto(s)
Ferroptosis , Radioisótopos de Yodo , Radiofármacos , Ferroptosis/efectos de los fármacos , Animales , Radiofármacos/química , Radiofármacos/uso terapéutico , Ratones , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/química , Línea Celular Tumoral , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Hierro/química , Ratones Endogámicos BALB C , Inmunoterapia/métodos , Radioinmunoterapia/métodos , Femenino , Neoplasias/terapiaRESUMEN
The potential of Strained-Promoted Sydnone-Alkyne Cycloaddition (SPSAC) for radioiodination was evaluated with model cyclooctyne-conjugated peptides. Starting with a series of sydnones with varying N3 and C4 substitution, a preliminary kinetic study with non-radioactive iodinated compounds highlighted the superiority of an arylsydnone substituted by a chlorine atom in C4 position. Interestingly, reaction rate up to 11 times higher than using an azide was achieved with the best system. Access to 125I-labelled sydnones was granted with high efficiency from arylboronic acid precursors by copper catalyzed nucleophilic substitution. Application of SPSAC on the model peptide in radiotracer conditions showed the same trend than in non-radioactive kinetic study and complete reactions could be achieved within less than an hour for the best systems. These results are favorable for use in the production of radiopharmaceuticals with heavy halogens and increase the diversity of available bioorthogonal reaction for nuclear imaging and therapy.
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Radioisótopos de Yodo , Radiofármacos , Sidnonas , Radioisótopos de Yodo/química , Radiofármacos/química , Radiofármacos/síntesis química , Sidnonas/química , Sidnonas/síntesis química , Sidnonas/farmacología , Estructura Molecular , Reacción de Cicloadición , Alquinos/química , Alquinos/síntesis química , Péptidos/química , Péptidos/síntesis química , CinéticaRESUMEN
This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.
Asunto(s)
Anastrozol , Neoplasias de la Mama , Epirrubicina , Radioisótopos de Yodo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteínas Proto-Oncogénicas c-akt , Radiofármacos , Epirrubicina/química , Epirrubicina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Humanos , Radioisótopos de Yodo/química , Radiofármacos/química , Radiofármacos/farmacología , Anastrozol/química , Anastrozol/uso terapéutico , Anastrozol/farmacología , Femenino , Ligandos , Unión Proteica , Simulación por ComputadorRESUMEN
To ensure the sustainable development of the nuclear industry, the effective capture of radioiodine from nuclear wastewater has attracted much attention. Herein, a novel MIL-88A(Al)/chitosan/graphene oxide (MCG) composite aerogel was prepared by using crosslinked chitosan and graphene oxide as the 3D network skeleton, and MIL-88A(Al) nanocrystalline particles were introduced into the skeleton by freeze-drying method. MIL-88A(Al) adsorption capacities for volatile and soluble iodine were 2.02 g g-1 and 850.00 mg g-1, respectively. Owing to the synergistic effect of MIL-88A(Al), GO, CS, and the hierarchically porous structures of the MCG aerogel, the adsorption capacities for volatile and soluble iodine by the MCG aerogel were increased to 2.62 g g-1 and 1072.60 mg g-1, respectively. Furthermore, the adsorption performance of the MCG aerogel for volatile and soluble iodine could be maintained at 83 % and 82 % after 5 cycles, suggesting excellent recoverability. Meanwhile, the adsorption mechanism studies showed the interactions between iodine and NH, AlO, and CO in MCG aerogel. Furthermore, the adsorption process is consistent with the Elovich kinetic and Sips isotherm models. MCG aerogels are potential candidates for enhanced radioiodine adsorption due to their high radioiodine capture performance and excellent recyclability.
Asunto(s)
Quitosano , Geles , Grafito , Radioisótopos de Yodo , Estructuras Metalorgánicas , Grafito/química , Quitosano/química , Adsorción , Porosidad , Radioisótopos de Yodo/química , Geles/química , Estructuras Metalorgánicas/química , Cinética , Purificación del Agua/métodosRESUMEN
Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [125I]INFT, for the potential improvement of binding properties to Tau in an Alzheimer's disease (AD) brain. Two new derivatives, namely [125I]ISAS and [125I]NIPZ, were designed, where binding energies at site 1 of Tau were -7.4 and -6.0 kcal/mole, respectively, compared to [125I]INFT (-7.6 kcal/mole). The radiosynthesis of [125I]ISAS and [125I]NIPZ was carried out by using iodine-125 and purified chromatographically to achieve >90% purity. In vitro binding affinities (IC50) for Tau were as follows: INFT = 7.3 × 10-8 M; ISAS = 4.7 × 10-8 M; NIPZ > 10-6 M. The binding of [125I]ISAS to gray matter (GM) correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. [125I]NIPZ did not bind to Tau, with similar levels of binding observed in GM and white matter (WM). Four radiotracers were compared and the rank order of binding to Tau was found to be [125I]IPPI > [125I]INFT > [125I]ISAS >>> [125I]NIPZ with GM/WM ratios of [125I]IPPI = 7.74 > [125I]INFT = 4.86 > [125I]ISAS = 3.62 >> [125I]NIPZ = 1.24. The predictive value of Chimera-AutoDock for structurally related compounds binding to the Tau binding sites (measured as binding energy) was good. A binding energy of less than -7 kcal/mole is necessary and less than -8 kcal/mole will be more suitable for developing imaging agents.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Radioisótopos de Yodo , Radiofármacos , Proteínas tau , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Proteínas tau/metabolismo , Proteínas tau/química , Humanos , Radioisótopos de Yodo/química , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radiofármacos/química , Radiofármacos/síntesis química , Modelos Moleculares , Unión Proteica , Sitios de Unión , Masculino , Anciano , Autopsia , FemeninoRESUMEN
Background: Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of specific antibodies in-vivo may be inferior to non-specific IgG in some cases. Objectives: To explore factors affecting labeled antibody visualization by PD-L1 specific and non-specific imaging of nude mouse tumors. Methods: TTU was observed in RKO model on Cerenkov luminescence (CL) and near-infrared fluorescence (NIRF) imaging of radionuclide 131I or NIRF dyes labeled Atezolizumab and IgG. A mixture of NIRF dyes labeled Atezolizumab and 131I-labeled IgG was injected, and TTU was observed in the RKO and HCT8 model by NIRF/CL dual-modality in-situ imaging. TTU were observed by 131I-labeled Atezolizumab and IgG in-vitro distribution. Results: Labeled IgG concentrated more in tumors than Atezolizumab. NIRF/CL imaging in 24 to 168 h showed that TTU gradually decreased over time, which decreased more slowly on CL imaging compared to NIRF imaging. The distribution data in-vitro showed that TTU of 131I-labeled IgG was higher than that of 131I-labeled Atezolizumab at any time point. Conclusion: Non-specific IgG may not be suitable as a control for Atezolizumab in comparing tumor PD-L1 expression in nude mice via labeled antibody optical imaging under certain circumstances.
Asunto(s)
Antígeno B7-H1 , Ratones Desnudos , Animales , Antígeno B7-H1/metabolismo , Humanos , Ratones , Línea Celular Tumoral , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/farmacocinética , Imagen Óptica/métodos , Radioisótopos de Yodo/química , Neoplasias/diagnóstico por imagen , Inmunoglobulina G/química , Inmunoglobulina G/metabolismo , Femenino , LuminiscenciaRESUMEN
Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO-, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In -vitro and -vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.
Asunto(s)
Radioisótopos de Yodo , Compuestos de Manganeso , Óxido Nítrico , Óxidos , Especies Reactivas de Oxígeno , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Humanos , Animales , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Óxidos/química , Óxidos/farmacología , Radioisótopos de Yodo/química , Apoptosis/efectos de los fármacos , Nanopartículas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Ratones Endogámicos BALB C , Terapia por Ultrasonido , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ondas Ultrasónicas , Línea Celular TumoralRESUMEN
Due to the rapid progression and aggressive metastasis of breast cancer, its diagnosis and treatment remain a great challenge. The simultaneous inhibition of tumor growth and metastasis is necessary for breast cancer to obtain ideal therapeutic outcomes. We herein report the development of radioactive hybrid semiconducting polymer nanoparticles (SPNH) for imaging-guided tri-modal therapy of breast cancer. Two semiconducting polymers are used to form SPNH with a diameter of around 60 nm via nano-coprecipitation and they are also labeled with iodine-131 (131I) to enhance the imaging functions. The formed SPNH show good radiolabeling stability and excellent photodynamic and photothermal effects under 808 nm laser irradiation to produce singlet oxygen (1O2) and heat. Moreover, SPNH can generate 1O2 with ultrasound irradiation via their sonodynamic properties. After intravenous tail vein injection, SPNH can effectively accumulate in the subcutaneous 4T1 tumors of living mice as verified via fluorescence and single photon emission computed tomography (SPECT) imaging. With the irradiation of tumors using an 808 nm laser and US, SPNH mediate photodynamic therapy (PDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) to kill tumor cells. Such a tri-modal therapy leads to an improved efficacy in inhibiting tumor growth and suppressing tumor metastasis compared to the sole SDT and combinational PDT-PTT. This study thus demonstrates the applications of SPNH to diagnose tumors and combine different therapies for effective breast cancer treatment.
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Neoplasias de la Mama , Radioisótopos de Yodo , Nanopartículas , Fotoquimioterapia , Polímeros , Semiconductores , Animales , Nanopartículas/química , Ratones , Femenino , Polímeros/química , Radioisótopos de Yodo/química , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Ratones Endogámicos BALB C , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Tamaño de la Partícula , Tomografía Computarizada de Emisión de Fotón Único , Terapia Fototérmica , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patologíaRESUMEN
Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Humanos , Animales , Ratones , Floxuridina/química , Floxuridina/farmacología , Radioisótopos de Yodo/química , Clorhidrato de Erlotinib/química , Clorhidrato de Erlotinib/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Radiofármacos/química , Radiofármacos/farmacología , Línea Celular Tumoral , Distribución Tisular , Ratones Desnudos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Ratones Endogámicos BALB C , FemeninoRESUMEN
Brachytherapy stands as an essential clinical approach for combating locally advanced tumors. Here, an injectable brachytherapy hydrogel is developed for the treatment of both local and metastatic tumor. Fe-tannins nanoparticles are efficiently and stably radiolabeled with clinical used therapeutic radionuclides (such as 131I, 90Y, 177Lu, and 225Ac) without a chelator, and then chemically cross-linked with 4-armPEG-SH to form brachytherapy hydrogel. Upon intratumoral administration, magnetic resonance imaging (MRI) signal from ferric ions embedded within the hydrogel directly correlates with the retention dosage of radionuclides, which can real-time monitor radionuclides emitting short-range rays in vivo without penetration limitation during brachytherapy. The hydrogel's design ensures the long-term tumor retention of therapeutic radionuclides, leading to the effective eradication of local tumor. Furthermore, the radiolabeled hydrogel is integrated with an adjuvant to synergize with immune checkpoint blocking therapy, thereby activating potent anti-tumor immune responses and inhibiting metastatic tumor growth. Therefore, this work presents an imageable brachytherapy hydrogel for real-time monitoring therapeutic process, and expands the indications of brachytherapy from treatment of localized tumors to metastatic tumors.
Asunto(s)
Braquiterapia , Hidrogeles , Braquiterapia/métodos , Animales , Hidrogeles/química , Ratones , Imagen por Resonancia Magnética , Humanos , Línea Celular Tumoral , Femenino , Nanopartículas/química , Nanopartículas/uso terapéutico , Quelantes/química , Radioisótopos de Yodo/química , Ratones Endogámicos BALB C , Radioisótopos/químicaRESUMEN
In aquatic settings, radioactive iodine from nuclear waste can exist as iodate (IO3-). This study explored the efficiency and mechanism of IO3- adsorption by minimally modified anthocyanin-based adsorbents. Pomegranate peels and mangosteen pericarps were selected from an initial screening test and could remove over 70% of 10 mg/L IO3-. The adsorbents yielded adsorption capacity (q) of 9.59 mg/g and 2.31 mg/g, respectively, at room temperature. At 5 °C, q values increased to 14.5 and 5.13 mg/g, respectively. Pomegranate peels showed superior performance, with approximately 4 times the anthocyanin content of mangosteen pericarps. Both adsorbents took 120 min to reach adsorption equilibrium, and no desorption was observed after 8 days (I-131 half-time). Confirmation of physisorption was indicated by the fit of the pseudo-first-order reaction model, negative entropy (exothermic), and negative activation energy (Arrhenius equation). IO3- inclusion was confirmed through adsorbent surface modifications in scanning electron microscope images, the increased iodine content post-adsorption in energy-dispersive X-ray spectroscopy analysis, and alterations in peaks corresponding to anthocyanin-related functional groups in Fourier transform infrared spectroscopy analysis. X-ray absorption near-edge spectroscopy at 4564.54 eV showed that iodine was retained in the form of IO3-. Through the computational analysis, electrostatic forces, hydrogen bonds, and π-halogen interactions were deduced as mechanisms of IO3- adsorption by anthocyanin-based adsorbents. Anthocyanin-rich fruit wastes emerged as sustainable materials for eliminating IO3- from water.
Asunto(s)
Antocianinas , Yodatos , Adsorción , Antocianinas/química , Antocianinas/aislamiento & purificación , Yodatos/química , Frutas/química , Radioisótopos de Yodo/química , Contaminantes Radiactivos del Agua/química , Purificación del Agua/métodosRESUMEN
Background: Radionuclides have important roles in clinical tumor radiotherapy as they are used to kill tumor cells or as imaging agents for drug tracing. The application of radionuclides has been developing as an increasing number of nanomaterials are used to deliver radionuclides to tumor areas to kill tumor cells. However, promoting the efficient combination of radionuclides and nanocarriers (NCs), enhancing radionuclide loading efficiency, and avoiding environmental pollution caused by radionuclide overuse are important challenges that hinder their further development. Methods: In the present study, a new small molecule compound (3-[[(2S)-2-hydroxy-3-(4-hydroxyphenyl)-1-carbonyl] amino]-alanine, abbreviation: HN, molecular formula: C12H16N2O5) was synthesized as a linker between radionuclide iodine-125 (125I) and NCs to enable a more efficient binding between NCs and radionuclides. Results: In vitro evidence indicated that the linker was able to bind 125I with higher efficiency (labeling efficiency >80%) than that of tyrosine, as well as various NCs, such as cellulose nanofibers, metal oxide NCs, and graphene oxide. Single-photon emission computed tomography/computed tomography imaging demonstrated the biological distribution of 125I-labeled NCs in different organs/tissues after administration in mice. Conclusion: These results showed an improvement in radionuclide labeling efficiency for nanocarriers and provided an approach for nanocarrier image tracing.
Asunto(s)
Radioisótopos de Yodo , Neoplasias , Ratones , Animales , Radioisótopos de Yodo/química , Neoplasias/tratamiento farmacológico , Modelos Animales de Enfermedad , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
The high rate of incidence and mortality caused by breast cancer encourage urgent research to immediately develop new diagnostic and therapeutic agents for breast cancer. Alpha mangostin (AM) is a natural compound reported to have anti-breast cancer properties. Its electron-donating groups structure allows it to be labeled with an iodine-131 radioisotope to develop a candidate of a diagnostic and therapeutic agent for breast cancer. This study aims to prepare the [131I]Iodine-α-mangostin ([131I]I-AM) and evaluate its stability, lipophilicity, and cellular uptake in breast cancer cell lines. The [131I]I-AM was prepared by direct radiosynthesis with Chloramine-T method in two conditions (A: AM dissolved in NaOH, B: AM dissolved in ethanol). Reaction time, pH, and mass of the oxidizing agent were optimized as crucial parameters that affected the radiosynthesis reaction. Further analysis was conducted using the radiosynthesis conditions with the highest radiochemical purity (RCP). Stability tests were carried out at three storage conditions, including -20, 2, and 25 °C. A cellular uptake study was performed in T47D (breast cancer cell line) and Vero cells (noncancerous cell line) at various incubation times. The results show that the RCP values of [131I]I-AM under conditions A and B were 90.63 ± 0.44 and 95.17 ± 0.80% (n = 3), respectively. In the stability test, [131I]I-AM has an RCP above 90% after three days of storage at -20 °C. A significant difference was obtained between [131I]I-AM uptake in T47D and Vero cells. Based on these results, [131I]I-AM has been prepared with high RCP, stable at -20 °C, and specifically uptaken by breast cancer cell lines. Biodistribution evaluations in animals are recommended as further research in developing [131I]I-AM as a diagnostic and therapeutic agent for breast cancer.
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Yodo , Neoplasias , Animales , Chlorocebus aethiops , Radioisótopos de Yodo/química , Distribución Tisular , Células Vero , Línea Celular TumoralRESUMEN
The accumulation of radiolabeled phosphonium cations in cells is dependent on the mitochondrial membrane potential (MMP). However, the efflux of these cations from tumor cells via P-glycoprotein (P-gp) limits their clinical application as MMP-based imaging tracers. In the present study, we designed (E)-diethyl-4-[125I]iodobenzyl-4-stilbenylphosphonium ([125I]IDESP), which contains a stilbenyl substituent, as a P-gp inhibitor to reduce P-gp recognition, and evaluated its biological properties in comparison with 4-[125I]iodobenzyl dipropylphenylphosphonium ([125I]IDPP). The in vitro cellular uptake ratio of [125I]IDESP in P-gp expressing K562/Vin cells to the parent (P-gp negative) K562 cells was significantly higher than that of [125I]IDPP. The efflux rate of [125I]IDESP was not significantly different between K562 and K562/Vin, while [125I]IDPP was rapidly effluxed from K562/Vin compared with K562, and the efflux of [125I]IDPP from K562/Vin was inhibited by the P-gp inhibitor, cyclosporine A. The cellular uptake of [125I]IDESP was well correlated with the MMP levels. These results suggested that [125I]IDESP was accumulated in cells depending on the MMP levels, without being effluxed via P-gp, while [125I]IDPP was rapidly effluxed from the cells via P-gp. Despite having suitable in vitro properties for MMP-based imaging, [125I]IDESP showed rapid blood clearance and lower tumor accumulation than [125I]IDPP. Improvement in the normal tissue distribution of [125I]IDESP is required to develop an agent for use in in vivo MMP-based tumor imaging.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Radioisótopos de Yodo , Potencial de la Membrana Mitocondrial , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Resistencia a Antineoplásicos , Glicoproteínas , Radioisótopos de Yodo/química , Radioisótopos de Yodo/farmacología , Células K562 , Potencial de la Membrana Mitocondrial/fisiología , Ensayo de Unión Radioligante/métodosRESUMEN
Grout materials are commonly used to immobilize low-level radioactive waste. Organic moieties can be unintentionally present in common ingredients used to make these grout waste forms, which may result in the formation of organo-radionuclide species. These species can positively or negatively affect the immobilization efficiency. However, the presence of organic carbon compounds is rarely considered in models or characterized chemically. Here, we quantify the organic pool of grout formulations with and without slag, as well as the individual dry ingredients used to make the grout samples (ordinary Portland cement (OPC), slag and fly ash), including total organic carbon (TOC) and black carbon, followed by aromaticity evaluation and molecular characterization via Electro Spray Ionization Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry (ESI-FTICRMS). All dry grout ingredients contained significant amounts of organic carbon, ranging from 550 mg/kg to 6250 mg/kg for the TOC pool, with an averaged abundance of 2933 ± 2537 mg/kg, of which 60 ± 29% was composed of black carbon. The significant abundance of a black carbon pool implies the presence of the aromatic-like compounds, which was further identified by both phosphate buffer-assisted aromaticity evaluation (e.g., >1000 mg-C/kg as aromatic-like carbon in the OPC) and dichloromethane (DCM) extraction with ESI-FTICRMS analysis. Besides aromatic-like compounds, other organic moieties were also detected in the OPC, such as carboxyl-containing aliphatic molecules. While the organic compound only consists of minor fractions of the grout materials investigated, our observations of the presence of various radionuclide-binding organic moieties suggests the potential formation of organo-radionuclides, such as radioiodine, which might be present at lower molar concentrations than TOC. Evaluating the role of organic carbon complexation in controlling the disposed radionuclides, especially for those radionuclides with strong association with organic carbon, has important implications for the long-term immobilization of radioactive waste in grout systems.
Asunto(s)
Monitoreo de Radiación , Residuos Radiactivos , Radioisótopos de Yodo/química , Carbono , Espectrometría de MasasRESUMEN
The alpha particle-emitting radionuclide astatine-211 (211At) is of interest for targeted radiotherapy; however, low in vivo stability of many 211At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG4-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with 125I and 211At. Oxidization of the [125I]iodo- and [211At]astato-benzamidyl-dPEG4-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized 125I- and 211At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [211At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [211At]NaAtO3 and [125I]NaIO3. Comparison of the tissue concentrations of the isolated material from the oxidized [211At]benzamide derivative with those of [211At]astatate indicated the species obtained after isolation was likely [211At]astatate.
Asunto(s)
Benzamidas , Radioisótopos de Yodo , Aminoácidos , Animales , Ésteres , Radioisótopos de Yodo/química , Marcaje Isotópico/métodos , Ratones , Distribución TisularRESUMEN
Environmental damage from serious nuclear accidents should be urgently restored, which needs the removal of radioactive species. Radioactive iodine isotopes are particularly problematic for human health because they are released in large amounts and retain radioactivity for a substantial time. Herein, we prepare platinum-coated iron nanoparticles (Fe@Pt) as a highly selective and reusable adsorbent for iodine species, i.e., iodide (I-), iodine (I2), and methyl iodide (CH3I). Fe@Pt selectively separates iodine species from seawater and groundwater with a removal efficiency ≥ 99.8%. The maximum adsorption capacity for the iodine atom of all three iodine species was determined to be 25 mg/g. The magnetic properties of Fe@Pt allow for the facile recovery and reuse of Fe@Pt, which remains stable with high efficiency (97.5%) over 100 uses without structural and functional degradation in liquid media. Practical application to the removal of radioactive 129I and feasibility for scale-up using a 20 L system demonstrate that Fe@Pt can function as a reusable adsorbent for the selective removal of iodine species. This systematic procedure is a standard protocol for designing highly active adsorbents for the clean separation and removal of various chemical species dissolved in wastewater.
Asunto(s)
Yodo , Neoplasias de la Tiroides , Contaminantes Químicos del Agua , Adsorción , Humanos , Yoduros , Radioisótopos de Yodo/química , Agua/química , Contaminantes Químicos del Agua/químicaRESUMEN
This work focuses on tracking ulcerative colitis in mice. High labeling yield and radiochemical purity were achieved for the formation of a [125/131 I]balsalazide radiotracer at optimum conditions of oxidizing agent content (chloramines-T [Ch-T], 75 µg), substrate amount (100 µg), pH of reaction mixture (6), reaction time (30 min), and temperature (37°C), using radioactive iodine-125 (200-450 MBq). The radiolabeled compound, [125/131 I]balsalazide, was stable in serum and saline solution during 24 h. Balsalazide is acting as a peroxisome proliferator-activated receptor (PPARγ). Biodistribution studies were carried in normal and ulcerated colon mice. High uptake of 75 ± 1.90% injected dose/g organ (ID/g) observed in ulcerated mice confirmed the suitability of [131 I]balsalazide as a novel radiotracer for ulcerative colitis imaging in mice.
Asunto(s)
Colitis Ulcerosa , Neoplasias de la Tiroides , Animales , Colitis Ulcerosa/diagnóstico por imagen , Radioisótopos de Yodo/química , Mesalamina , Ratones , Fenilhidrazinas , Distribución TisularRESUMEN
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.
Asunto(s)
Acrilamidas/química , Compuestos de Anilina/química , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Radiofármacos/química , Acrilamidas/síntesis química , Acrilamidas/farmacocinética , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Radioisótopos de Bromo/química , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Halogenación , Humanos , Radioisótopos de Yodo/química , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Despite the growing interest in radioiodine and 211 At-labeled radiopharmaceuticals, the search for radiolabeling reactions has been somewhat neglected, resulting in a limited number of available radiosynthetic strategies. Herein we report a comparative study of nucleophilic 125 I and 211 At-labeling of aryliodonium ylides. Whereas radioiodination efficiency was low, 211 At-labeling performed efficiently on a broad scope of precursors. The most activated aryliodonium ylides led rapidly to quantitative reactions at room temperature in acetonitrile. For deactivated precursors, heating up to 90 °C in glyme and addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as radical scavenger appeared essential to avoid precursor degradation and to achieve high radiochemical yields and molar activity. The approach was applied successfully to the preparation of 4-[211 At]astatophenylalanine (4-APA), an amino acid derivative increasingly studied as radiotherapeutic drug for cancers. This validated aryliodonium ylides as a valuable tool for nucleophilic 211 At-labeling and will complement the short but now growing list of available astatination reactions.