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Zero-dimensional pores spanning only a few angstroms in size in two-dimensional materials such as graphene are some of the most promising systems for designing ion-ion selective membranes. However, the key challenge in the field is that so far a crack-free macroscopic graphene membrane for ion-ion separation has not been realized. Further, methods to tune the pores in the Å-regime to achieve a large ion-ion selectivity from the graphene pore have not been realized. Herein, we report an Å-scale pore size tuning tool for single layer graphene, which incorporates a high density of ion-ion selective pores between 3.5 and 8.5 Å while minimizing the nonselective pores above 10 Å. These pores impose a strong confinement for ions, which results in extremely high selectivity from centimeter-scale porous graphene between monovalent and bivalent ions and near complete blockage of ions with the hydration diameter, DH, greater than 9.0 Å. The ion diffusion study reveals the presence of an energy barrier corresponding to partial dehydration of ions with the barrier increasing with DH. We observe a reversal of K+/Li+ selectivity at elevated temperature and attribute this to the relative size of the dehydrated ions. These results underscore the promise of porous two-dimensional materials for solute-solute separation when Å-scale pores can be incorporated in a precise manner.
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Enhancing the kinetics of liquid-vapor transition from nanoscale confinements is an attractive strategy for developing evaporation and separation applications. The ultimate limit of confinement for evaporation is an atom thick interface hosting angstrom-scale nanopores. Herein, using a combined experimental/computational approach, we report highly enhanced water evaporation rates when angstrom sized oxygen-functionalized graphene nanopores are placed at the liquid-vapor interface. The evaporation flux increases for the smaller nanopores with an enhancement up to 35-fold with respect to the bare liquid-vapor interface. Molecular dynamics simulations reveal that oxygen-functionalized nanopores render rapid rotational and translational dynamics to the water molecules due to a reduced and short-lived water-water hydrogen bonding. The potential of mean force (PMF) reveals that the free energy barrier for water evaporation decreases in the presence of nanopores at the atomically thin interface, which further explains the enhancement in evaporation flux. These findings can enable the development of energy-efficient technologies relying on water evaporation.
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Predictable and tunable etching of angstrom-scale nanopores in single-layer graphene (SLG) can allow one to realize high-performance gas separation even from similar-sized molecules. We advance toward this goal by developing two etching regimes for SLG where the incorporation of angstrom-scale vacancy defects can be controlled. We screen several exposure profiles for the etchant, controlled by a multipulse millisecond treatment, using a mathematical model predicting the nucleation and pore expansion rates. The screened profiles yield a narrow pore-size-distribution (PSD) with a majority of defects smaller than missing 16 carbon atoms, suitable for CO2/N2 separation, attributing to the reduced pore expansion rate at a high pore density. Resulting nanoporous SLG (N-SLG) membranes yield attractive CO2 permeance of 4400 ± 2070 GPU and CO2/N2 selectivity of 33.4 ± 7.9. In the second etching regime, by limiting the supply of the etchant, the nanopores are allowed to expand while suppressing the nucleation events. Extremely attractive carbon capture performance marked with CO2 permeance of 8730 GPU, and CO2/N2 selectivity of 33.4 is obtained when CO2-selective polymeric chains are functionalized on the expanded nanopores. We show that the etching strategy is uniform and scalable by successfully fabricating high-performance centimeter-scale membrane.
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Nanotargeted liposomes may be modified with targeting peptide on the surface of a prepared liposome to endow specificity and elevate targeting efficiency. The aim of this study was to develop a radioactive targeted nanoparticle, the 111In-cyclic RGDfK-liposome, and its advantage of recognizing the αVß3 integrin was examined. The cyclic RGDfK modified liposomes were demonstrated the ability to bind the αVß3 integrin expressed on the surface of human melanoma cell in vitro and in vivo. The effects of the cyclic RGDfK-liposome on the functioning of phagocytes was also examined, showing no considerable negative effects on the engulfment of bacteria and the generation of reactive oxygen species. Based upon these findings, the cyclic RGDfK- liposome is said to be a promising agent for tumor imaging.
Assuntos
Radioisótopos de Índio/química , Integrina alfaVbeta3/metabolismo , Lipossomos/química , Melanoma/metabolismo , Peptídeos Cíclicos/química , Animais , Adesão Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Peptídeos/química , Fagócitos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Microtomografia por Raio-XRESUMO
Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188Re achieved better therapeutic effect on lung cancer. Methods188Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated. NanoSPECT/CT images were taken to evaluate the distribution and tumor targeting of 188Re-cetuximab in mice. The anti-tumor effect of 188Re-cetuximab was assessed by the tumor growth inhibition, survival ratio. Results For nanoSPECT/CT imaging, a significant uptake in tumor was observed at 24 and 48 h following the injection of 188Re-cetuximab. The anti-tumor effect of 188Re-cetuximab was assessed by tumor growth inhibition and the survival ratio. The tumor-bearing mice treated with 188Re-cetuximab showed a better mean tumor growth inhibition rate (MGI = 0.049) and longer median survival time and lifespan (62.50 d; 70.07%) than those treated with 188Re-perrhenate and cetuximab only by single injection. A synergistic effect of tumor growth inhibition was observed with the combination index exceeding one for 188Re-cetuximab (CI = 6.135 and 9.276). Conclusion The tumor targeting and localization of 188Re-cetuximab were confirmed in this study. Synergistic therapeutic efficacy was demonstrated for the radioimmunotherapy of 188Re-cetuximab. The results of this study reveal the potential advantage and benefit obtained from 188Re-cetuximab for diagnosis and therapy of oncology applications in the future.
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Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Radioimunoterapia/métodos , Radioisótopos/uso terapêutico , Rênio/uso terapêutico , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacocinética , Apoptose , Proliferação de Células , Cetuximab/farmacocinética , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Radioisótopos/farmacocinética , Rênio/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIM: The biodistribution, pharmacokinetics and therapeutic evaluation of 188Re-human serum albumin microspheres (188Re-HSAM) by labeling with 188Re(I)-tricarbonyl ion (188Re(OH2)3(CO)3)+) were investigated in a GP7TB orthotopic hepatoma rat model. MATERIALS AND METHODS: Male F344 rats received intrahepatic inoculations with GP7TB 1 mm3 cubes. The efficacy of 188Re-HSAM was examined following a single-dose treatment via the intraarterial route. Rats were monitored for survival until death. RESULTS: The labeling efficiency of the 188Re-HSAM was about 80%. After intraarterial administration of 188Re-HSAM, radioactivity in tumors accumulated from 18.41±3.48 %ID/g at 1 h to 12.43±4.70 %ID/g at 24 h. The tumor/liver ratios ranged from 3.03 at 1 h to 1.89 at 72 h. The major uptake organs of 188Re-HSAM were liver (73.35%ID to 48.92%ID), tumor (10.54%ID to 3.51%ID) and kidney (7.48 %ID to 0.14%ID). The T1/2λz of 188Re-HSAM was 259.34 h after intraarterial injection. The AUC(0â96 h) of 188Re-HSAM was 0.69 h*% ID/g. In the efficacy study, the median survival time for the rat (n=6), that received normal saline was 80 d. The median survival times for the mice treated with 10 mCi (n=4), 5.2 mCi (n=6) and 2.9 mCi (n=3) of 188Re-HSAM were 130 d (p=0.003), 106 d (p=0.002) and 83.5 d (p=0.617), respectively. The increase in life span of 10 mCi, 5.2 mCi and 2.9 mCi of 188Re-HSAM were 62.5%, 32.5% and 4.4%, respectively. CONCLUSION: Administration of 188Re-HSAM demonstrated better survival time and therapeutic efficacy at the higher dose in the GP7TB hepatoma model. These results suggested that intraarterial administration of 188Re-HSAM could provide a benefit and promising strategy for delivery of radiotherapeutics in oncology applications.
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Microesferas , Radioisótopos , Rênio , Albumina Sérica Humana/farmacocinética , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Radioisótopos/química , Ratos , Rênio/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Liver cancer is the second most common cause of death worldwide. This study was to investigate the SPECT/CT, ultrasound, biodistribution and therapeutic evaluation of 188Re-human serum albumin microspheres (188Re-HSAM) in the GP7TB orthotopic hepatoma rat model. MATERIALS AND METHODS: HSAM was labeled with 188Re by using a home-made kit and microwave system. The 188Re-HSAM was administered via intraarterial route. The in vivo distribution of 188Re-HSAM was determined by biodistribution analysis and nanoSPECT/CT system. In efficacy, tumor volumes were tracked longitudinally by three-dimensional ultrasound. RESULTS: The biodistribution and nanoSPECT/CT imaging showed that 188Re-HSAM could accumulate in liver and tumor. The correlation coefficient of tumor volumes done by three-dimensional ultrasound and at autopsy was 0.997. In efficacy, tumor volume in the normal saline-treated group was 1803.2 mm3 at 54 days after tumor inoculation. Tumor volumes in the 103.6 MBq and 240.5 MBq of 188Re-HSAM treated groups were 381 and 267.4 mm3 (p = 0.001 and 0.004), respectively. CONCLUSIONS: These results show that three-dimensional ultrasound with a high spatial resolution and contrast in soft tissue can become imaging modality in assessing tumor burden and tumor progression in an orthotopic rat model. The longitudinally therapeutic evaluation of 188Re-HSAM demonstrated dose-dependent tumor growth inhibition with increased dose in the GP7TB orthotopic hepatoma rat model.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Radioisótopos/administração & dosagem , Rênio/administração & dosagem , Rênio/farmacocinética , Animais , Apoptose/efeitos da radiação , Cápsulas/síntese química , Cápsulas/farmacocinética , Carcinoma Hepatocelular/diagnóstico por imagem , Linhagem Celular Tumoral , Injeções Intra-Arteriais , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Especificidade de Órgãos , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Ratos Endogâmicos F344 , Albumina Sérica/química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Nanomedicina Teranóstica , Distribuição Tecidual , Resultado do Tratamento , Carga Tumoral/efeitos da radiação , UltrassonografiaRESUMO
Zeolitic imidazolate frameworks (ZIFs) are an emerging class of microporous materials that possess an organic flexible scaffold and zeolite-like topology. The catalytic and molecular-separation capabilities of these materials have attracted considerable attention; however, crystal-shape engineering in ZIF materials remains in its infancy. This is the first study to report an effective method for tailoring the near-spherical crystal morphology of ZIF-8 using its leaf-like pseudopolymorph, ZIF-L. A thin, uniform layer of ZIF-8 is formed on ZIF-L through heterogeneous surface growth to produce a ZIF-L@ZIF-8 core-shell nanocomposite. This results in ZIF-8 with a crystal morphology comprising two-dimensional nanoflakes. We characterized the resulting core-shell crystals using a number of solid-state techniques, including powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, and nitrogen physisorption. Approximately 16 mass% of ZIF-8 in the core-shell composites heterogeneous surfacely grown on ZIF-L core crystals. We also investigated the effects of zinc salts, which were used as a source of zinc in the formation of the ZIF-L@ZIF-8 core-shell nanocomposites. Finally, we assessed the CO2 adsorption properties of ZIF-8, ZIF-L, and ZIF-L@ZIF-8 core-shell crystals, the results of which were used to deduce the dynamic and equilibrium adsorption characteristics of various microporous ZIF crystals. The core-shell materials present hybridized CO2 uptake and diffusivity of the parent crystals. The proposed method for the synthesis of core-shell nanocomposites using pseudopolymorphic crystals is applicable to other ZIF systems.
RESUMO
OBJECTIVE: The present study relates to a method for preparing 188Re-labeled human serum albumin microspheres (HSAM) by 188Re(I)-tricarbonyl ion(188Re(OH2)3(CO)3)+). This radioactive particle can be subjected to radioembolization for liver tumor. METHODS: The particle sizes and conformations of HSA microspheres were analyzed by Particle sizes-Malvern mastersizer and Scanning Electron Microscope (SEM). For preparing 188Re(I)-tricarbonyl ion, the 188ReO4- was eluted from a 188W/188Re generator with saline. The radio labeling efficiency was analyzed with high-performance liquid chromatography (HPLC). Amino borane-reduced 188ReO4-was interacted with carbon oxide to form (188Re(OH2)3(CO)3]+). For preparing 188Re-HSA microspheres, the 188Re(I)-tricarbonyl ion was added into a vial with HSA microspheres. The in vitro stability was investigated. The rat was injected with 188Re-HSA microspheres via hepatic artery route. Nano-SPECT/CT Imaging was acquired after injection of 188Re-HSA microspheres. RESULTS: The shape of HSA microsphere was rough surfaced sphere or oval-shaped. The particle size was distributed between 20 and 35µm. In the RP-HPLC-UV chromatography, the yield of 188Re(I)-tricarbonyl ion was 75-80%. The labeling efficiency of 188Re-HSA microspheres in this method was more than 85%. After incubation, the 188Re(I)-tricarbonyl ion labeled HSA microspheres were found to be stable in vitro in normal saline and rat plasma. The result of Nano-SPECT/CT Imaging quantification analysis indicated that the percentage of injection dose %ID was maintained at 95% ID-88% ID from 2 to 72h after injection with 188Re- HSA microspheres. CONCLUSIONS: The method of 188Re(I)-tricarbonyl ion labeled HSA microspheres can proceed with high labeling yield. Furthermore, this method provided a convenient method for radio-labeling of HSA microspheres with 188Re as well as a kit for manufacturing.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Rênio/uso terapêutico , Albumina Sérica/farmacocinética , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Linhagem Celular Tumoral , Meios de Contraste , Humanos , Marcação por Isótopo/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Microesferas , Radioisótopos/uso terapêutico , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
Liposomes are good candidates as drug carriers and have been widely investigated in drug delivery systems. In this study, a new combination of bimodal 188Re-(DXR)-liposome-BBN radiochemotherapeutics was designed and studied for treating solid pancreatic tumor by intravenous administration. The in vivo nuclear microSPECT/CT imaging of tumor targeting, prolonged survival time and therapeutic efficacy were evaluated in AR42J malignant pancreatic solid tumor-bearing nude mice. MicroSPECT/CT imaging of 188Re-liposome-BBN pointed to significant targeting in tumors at 24 h after intravenous injection (SUV=2.13 ± 0.98). Co-injection of a blocking dose of cold BBN (4 mg/kg) inhibited the accumulation of 188Re-liposome-BBN in tumors (SUV=1.82 ± 0.31). For therapeutic efficacy, inhibition of tumor growth in mice treated with 188Re-DXR-liposome-BBN was precisely controlled [mean growth inhibition rate (MGI) = 0.092] and had longer survival time [life-span (LS) = 86.96%] than those treated with anticancer drug 188Re-liposome-BBN (MGI = 0.130; LS = 75%), Lipo-Dox-BBN (MGI = 0.666; LS = 3.61%) and untreated control mice. An additive tumor regression effect was observed (CI 0.946) for co-delivery of 188Re-DXR-liposome-BBN radiochemotherapeutics. These results point to the potential benefit of the 188Re-(DXR)-liposome-BBN radiochemotherapeutics for adjuvant cancer treatment with applications in oncology.
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Bombesina/uso terapêutico , Doxorrubicina/uso terapêutico , Neoplasias Pancreáticas/terapia , Rênio/uso terapêutico , Administração Intravenosa , Animais , Bombesina/farmacologia , Linhagem Celular Tumoral , Quimiorradioterapia , Doxorrubicina/farmacologia , Humanos , Camundongos , Imagem Multimodal , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Rênio/química , Rênio/farmacologia , Distribuição Tecidual , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
4-hydroxynonenal (4-HNE) is a major aldehyde produced during the lipid peroxidation of ω-6 polyunsaturated fatty acids. Recently, 4-HNE has been reported to contribute to the pathogenesis of neuronal diseases such as Alzheimer's disease. However, the role of 4-HNE in ischemic stroke is unclear yet. In this study, we found that plasma 4-HNE concentrations were higher in the genetic stroke-prone rats (stroke-prone spontaneously hypertensive rats) and experimental stroke rats with middle cerebral artery occlusion (MCAO). Moreover, administration of 4-HNE via intravenous injection before MCAO surgery not only enlarged cerebral ischemia-induced infarct area, but also increased oxidative stress in brain tissue, which was evidenced by the enhanced ROS/MPA levels, and the reduced GSH/GSSG ratio and MnSOD levels. Overexpression of aldehyde dehydrogenasesbcl-2 (ALDH2), an enzyme catalyses 4-HNE, rescued neuronal survival against 4-HNE treatment in PC12 cells. The plasma 4-HNE concentrations in patients with ischemic stroke were higher than those in control subjects. In a small sample population (N=60), the plasma 4-HNE concentration was positively correlated with the plasma homocysteine concentration, a risk factor for ischemic stroke. Taken together, our study suggests that the plasma 4-HNE level is a potential biomarker for ischemic stroke.
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Aldeídos/sangue , Peroxidação de Lipídeos , Acidente Vascular Cerebral/sangue , Idoso , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Aldeídos/administração & dosagem , Animais , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sobrevivência Celular , Homocisteína/sangue , Humanos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Células PC12 , Ratos , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/patologiaRESUMO
Intragastric growth of Helicobacter pylori and non-Helicobacter microorganisms is thought to be associated with elevated levels of pro-inflammatory cytokines and the production of NO these effects can lead to chronic inflammation. Microorganisms can activate the expression of iNOS and the production of NO by macrophages through stimulation with bacterial LPS. Helicobacter pylori can evade these vigorous immune responses, but the underlying mechanism remains unknown. In this study, we used a murine model of macrophage infection to demonstrate that H. pylori inhibits LPS-induced expression of iNOS and production of NO by macrophages. Suppression of LPS-induced NO production by macrophages led to elevated survival of H. pylori in a trans-well system. This effect was abrogated in macrophages from iNOS(-/-) mice. Analysis of iNOS mRNA and protein levels revealed that H. pylori inhibits iNOS expression at both transcriptional and post-transcriptional levels, and that these effects occurred with live bacteria. Furthermore, the effect of H. pylori involved down-regulation of the mitogen-activated protein kinase pathway and the translocation of active NF-κB into the nucleus. Taken together, our results reveal a new mechanism by which H. pylori modulates the innate immune responses of the host and maintains a persistent infection within the stomach.
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Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Macrófagos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Animais , Evasão da Resposta Imune , Terapia de Imunossupressão , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases , Macrófagos/imunologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genéticaRESUMO
The biodistribution, pharmacokinetics, dosimetry and comparative therapeutic efficacy of intravenously administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposome ((188)Re-liposome) and 5-FU were investigated in a CT26-luc lung-metastatic model. After intravenous administration of (188)Re-liposome, tumor accumulation from the radioactivity was observed. Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC((0â∞)), MRT((0â∞)) and Cl of (188)Re-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for (188)Re-liposome in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed doses for (188)Re-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after (188)Re-liposome [80% maximum tolerated dose (MTD); 29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. Consequently, radiotherapeutics of (188)Re-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the (188)Re-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration of (188)Re-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications.
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Adenocarcinoma/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Neoplasias Pulmonares/metabolismo , Radioisótopos/farmacocinética , Rênio/farmacocinética , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Medula Óssea/metabolismo , Neoplasias do Colo/patologia , Fluoruracila/uso terapêutico , Injeções Intravenosas , Lipossomos , Fígado/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Radioisótopos/uso terapêutico , Rênio/uso terapêutico , Distribuição Tecidual , Resultado do TratamentoRESUMO
Liposomal doxorubicin (Lipo-DOX) has been widely and successfully used in chemotherapy for breast cancer patients. Since our previous studies found that 188Rhenium (188Re)-N,N-bis (2-mercaptoethyl)-N',N'-diethy-lethylenediamine (BMEDA)-labeled pegylated liposomes (188Re-liposomes) have radiotherapeutic potential in a colon cancer model, and little information is available to make a comparison of the therapeutic efficacy of internal radiotherapy and chemotherapy, this study evaluates the therapeutic efficacy of 188Re-liposomes and Lipo-DOX, in a 4T1 murine orthotopic breast cancer model. MicroSPECT/CT imaging showed that the highest uptake of 188Re-liposomes was found at 24 h after intravenous administration. The results of a bio-distribution assay also demonstrated that the highest uptake of 188Re-liposomes in a tumor was 3.03±0.29 (%ID/g) at 24 h, and that the highest tumor to muscle ratio was approximately 17 at 48 h. According to measurements of body weight and survival rate, the maximum tolerated doses (MTD) of 188Re-liposomes and Lipo-DOX were 37 MBq and 25 mg/kg, respectively. In a study of therapeutic efficacy, mice with 4T1 orthotopic breast tumors that were treated with 188Re-liposomes (4/5 MTD, 29.6 MBq) or Lipo-DOX (4/5 MTD, 20 mg/kg), showed a significant inhibition of tumor growth. In the small tumor model (50 mm3), the lifespan of 4T1 tumor-bearing mice treated with 188Re-liposomes and Lipo-DOX was increased by 21.7 and 169.6%, respectively, compared to those treated with normal saline. In the large tumor model (300 mm3), the lifespan of the 188Re-liposomes and the Lipo-DOX treated group was also increased by 35.2 and 141.2%, respectively. In this study, it was found that Lipo-DOX is better than 188Re-liposomes, for the treatment of 4T1 breast cancer. A further investigation of combined therapy, in a breast cancer model, using 188Re-liposomes and Lipo-Dox, to determine whether a synergistic effect exists, is ongoing in our laboratory.
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Doxorrubicina/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/radioterapia , Radioisótopos/administração & dosagem , Rênio/administração & dosagem , Animais , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Feminino , Injeções Intravenosas/métodos , Lipossomos , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Radioisótopos/farmacocinética , Rênio/farmacocinética , Taxa de Sobrevida , Distribuição TecidualRESUMO
BACKGROUND: Nanoliposomes are designed as carriers capable of packaging drugs through passive targeting tumor sites by enhanced permeability and retention (EPR) effects. In the present study the biodistribution, pharmacokinetics, micro single-photon emission computed tomography (micro-SPECT/CT) image, dosimetry, and therapeutic efficacy of (188)Re-labeled nanoliposomes ((188)Re-liposomes) in a C26 colonic peritoneal carcinomatosis mouse model were evaluated. METHODS: Colon carcinoma peritoneal metastatic BALB/c mice were intravenously administered (188)Re-liposomes. Biodistribution and micro-SPECT/CT imaging were performed to determine the drug profile and targeting efficiency of (188)Re-liposomes. Pharmacokinetics study was described by a noncompartmental model. The OLINDA|EXM computer program was used for the dosimetry evaluation. For therapeutic efficacy, the survival, tumor, and ascites inhibition of mice after treatment with (188)Re-liposomes and 5-fluorouracil (5-FU), respectively, were evaluated and compared. RESULTS: In biodistribution, the highest uptake of (188)Re-liposomes in tumor tissues (7.91% ± 2.02% of the injected dose per gram of tissue [%ID/g]) and a high tumor to muscle ratio (25.8 ± 6.1) were observed at 24 hours after intravenous administration. The pharmacokinetics of (188)Re-liposomes showed high circulation time and high bioavailability (mean residence time [MRT] = 19.2 hours, area under the curve [AUC] = 820.4%ID/g*h). Micro-SPECT/CT imaging of (188)Re-liposomes showed a high uptake and targeting in ascites, liver, spleen, and tumor. The results were correlated with images from autoradiography and biodistribution data. Dosimetry study revealed that the (188)Re-liposomes did not cause high absorbed doses in normal tissue but did in small tumors. Radiotherapeutics with (188)Re-liposomes provided better survival time (increased by 34.6% of life span; P < 0.05), tumor and ascites inhibition (decreased by 63.4% and 83.3% at 7 days after treatment; P < 0.05) in mice compared with chemotherapeutics of 5-fluorouracil (5-FU). CONCLUSION: The use of (188)Re-liposomes for passively targeted tumor therapy had greater therapeutic effect than the currently clinically applied chemotherapeutics drug 5-FU in a colonic peritoneal carcinomatosis mouse model. This result suggests that (188)Re-liposomes have potential benefit and are safe in treating peritoneal carcinomatasis of colon cancer.
Assuntos
Fluoruracila/farmacocinética , Lipossomos/farmacocinética , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Rênio/farmacocinética , Animais , Ascite/metabolismo , Ascite/patologia , Fluoruracila/uso terapêutico , Injeções Intravenosas , Estimativa de Kaplan-Meier , Lipossomos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Peritoneais/química , Neoplasias Peritoneais/patologia , Doses de Radiação , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Rênio/uso terapêutico , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Microtomografia por Raio-X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging demonstrated the change of glucose consumption of tumor cells, but problems with specificity and difficulties in early detection of tumor response to chemotherapy have led to the development of new PET tracers. Fluorine-18-fluorothymidine ((18)F-FLT) images cellular proliferation by entering the salvage pathway of DNA synthesis. In this study, we evaluate the early response of colon carcinoma to the chemotherapeutic drug, lipo-Dox, in C26 murine colorectal carcinoma-bearing mice by (18)F-FDG and (18)F-FLT. The male BALB/c mice were bilaterally inoculated with 1 × 10(5) and 1 × 10(6) C26 tumor cells per flank. Mice were intravenously treated with 10 mg/kg lipo-Dox at day 8 after (18)F-FDG and (18)F-FLT imaging. The biodistribution of (18)F-FDG and (18)F-FLT were followed by the microPET imaging at day 9. For the quantitative measurement of microPET imaging at day 9, (18)F-FLT was superior to (18)F-FDG for early detection of tumor response to Lipo-DOX at various tumor sizes (P < 0.05). The data of biodistribution showed similar results with those from the quantification of SUV (standard uptake value) by microPET imaging. The study indicates that (18)F-FLT/microPET is a useful imaging modality for early detection of chemotherapy in the colorectal mouse model.
Assuntos
Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Didesoxinucleosídeos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias do Colo/metabolismo , Didesoxinucleosídeos/farmacocinética , Doxorrubicina/administração & dosagem , Fluordesoxiglucose F18/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Molecular imaging with promise of personalized medicine can provide patient-specific information noninvasively, thus enabling treatment to be tailored to the specific biological attributes of both the disease and the patient. This study was to investigate the characterization of DO3A-CH(2)CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA) in vitro, MicroSPECT/CT imaging, and biological activities of (111)In-AMBA in PC-3 prostate tumor-bearing SCID mice. The uptake of (111)In-AMBA reached highest with 3.87 ± 0.65% ID/g at 8 h. MicroSPECT/CT imaging studies suggested that the uptake of (111)In-AMBA was clearly visualized between 8 and 48 h postinjection. The distribution half-life (t(1/2α)) and the elimination half-life (t(1/2ß)) of (111)In-AMBA in mice were 1.53 h and 30.7 h, respectively. The C(max) and AUC of (111)In-AMBA were 7.57% ID/g and 66.39 h % ID/g, respectively. The effective dose appeared to be 0.11 mSv/MBq(-1). We demonstrated a good uptake of (111)In-AMBA in the GRPR-overexpressed PC-3 tumor-bearing SCID mice. (111)In-AMBA is a safe, potential molecular image-guided diagnostic agent for human GRPR-positive tumors, ranging from simple and straightforward biodistribution studies to improve the efficacy of combined modality anticancer therapy.
Assuntos
Radioisótopos de Índio/farmacocinética , Imagem Molecular/métodos , Oligopeptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Animais , Bombesina/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Meia-Vida , Humanos , Marcação por Isótopo , Masculino , Camundongos , Camundongos SCID , Radiometria/métodos , Compostos Radiofarmacêuticos/farmacocinética , Receptores da Bombesina/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transplante HeterólogoRESUMO
AMBA (DO3A-CH(2)CO-G-(4-aminobenzoyl)-QWAVGHLM-NH(2)) is a bombesin (BN)-like peptide having high affinity with gastrin-releasing peptide receptors (GRPr).(177)Lu-AMBA is currently undergoing clinical trial as a systemic radiotherapy for hormone refractory prostate cancer (HRPC) patients. This study evaluated the biodistribution, pharmacokinetics, bioluminescent imaging (BLI) and microSPECT/CT imaging of (177)Lu-AMBA in PC-3M-luc-C6 luciferase-expressing human prostate tumour-bearing mice. Plasma stability of (177)Lu-AMBA could be maintained up to 55.67±6.07% at 24 h in a protection buffer. High positive correlations of PC-3M luc-C6 tumour growth in SCID mice between caliper measurement and BLI were observed (R(2)=0.999). Both the biodistribution and microSPECT/CT imaging in PC-3M-luc-C6 bearing-tumour mice showed that (177)Lu-AMBA in tumour uptake could be retained for 24 h. The distribution half-life (t(1/2α)) and the elimination half-life (t(1/2ß)) of (177) Lu-AMBA in mice were 0.52 h and 26.6 h, respectively. These results indicated that BLI could be used to monitor the growth of tumour. High uptake of (177)Lu-AMBA in PC-3M-luc-C6 tumour-bearing mice by microSPECT/CT imaging can further evaluate the potential of (177)Lu-AMBA therapy for PC-3M-luc-C6 tumours.
Assuntos
Oligopeptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Animais , Linhagem Celular Tumoral , Humanos , Marcação por Isótopo , Medições Luminescentes/métodos , Lutécio , Masculino , Camundongos , Camundongos SCID , Oligopeptídeos/sangue , Neoplasias da Próstata/sangue , Radioisótopos , Compostos Radiofarmacêuticos/sangue , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transplante HeterólogoRESUMO
Nanoliposome can be designed as a drug delivery carrier to improve the pharmacological and therapeutic properties of drug administration. (188)Re-labeled nanoliposomes are useful for diagnostic imaging as well as for targeted radionuclide therapy. In this study, the in vivo nuclear imaging, pharmacokinetics and biodistribution of administered nanoliposomes were investigated as drug and radionuclide carriers for targeting solid tumor via intravenous (i.v.) administration. The radiotherapeutics ((188)Re-liposome) and radiochemotherapeutics ((188)Re-DXR-liposome) were i.v. administered to nude mice bearing human HT-29 colorectal adenocarcinoma xenografts. (188)Re-liposome and (188)Re-DXR-liposomes show similar biodistribution profile; both have higher tumor uptake, higher blood retention time, and lower excretion rate than (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylenediamine (BMEDA). In contrast to tumor uptake, the area under the curve (AUC) value of tumor for (188)Re-liposome and (188)Re-DXR-liposome was 16.5- and 11.5-fold higher than that of free (188)Re-BMEDA, respectively. Additionally, (188)Re-liposome and (188)Re-DXR-liposome had a higher tumor-to-muscle ratio at 24 h (14.4+/-2 .7 and 17.14+/-4.1, respectively) than (188)Re-BMEDA (1.6+/-0.1). The tumor targeting and distribution of (188)Re-(DXR)-liposome (representing (188)Re-DXR-liposome and (188)Re-liposome) can also be acquired by signal photon-emission computed tomography/computed tomography images as well as whole body autoradiograph. These results suggest that (188)Re-(DXR)-liposomes are potentially promising agents for passive targeting treatment of malignant disease.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Doxorrubicina/análogos & derivados , Nanopartículas/administração & dosagem , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Rênio/farmacocinética , Adenocarcinoma/diagnóstico por imagem , Animais , Neoplasias Colorretais/diagnóstico por imagem , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Células HT29 , Humanos , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Camundongos , Camundongos Nus , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transplante HeterólogoRESUMO
Gastrin-releasing peptide receptors (GRPRs) are overexpressed on a variety of human tumors, such as prostate, breast, and lung cancer. Bombesin (BN) is a 14-amino-acid peptide with high affinity for these GRPRs. We synthesized DTPA-Q-K-Y-G-N-Q-W-A-V-G-H-L-M, a 13-amino-acid peptide chelated with diethylenetriaminepentaacetic acid (DTPA), and radiolabeled this BN analog with 111InCl(3). Biologic activity of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was evaluated in PC-3 prostate tumor-bearing severely compromised immunodeficient (SCID) mice. The purity of synthesized [DTPA(1), Lys(3), Tyr(4)]-BN was greater than 95%. The radiolabeling efficiency of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN was 96.9% +/- 2.46%. The IC(50) and K(i) of [DTPA(1), Lys(3), Tyr(4)]-BN in the human bombesin 2 receptor were 1.05 +/- 0.46 and 0.83 +/- 0.36 nM, respectively. The K(d) of 111In-[DTPA(1), Lys(3), Tyr(4)]-BN in GRPR-expressing PC-3 tumor cells was 22.9 +/- 6.81 nM. Both biodistribution and micro-SPECT/CT (single-photon emission computed tomography/computed tomography) imaging studies with 111In-[DTPA(1), Lys(3), Tyr(4)]-BN demonstrated the highest uptake at 8 hours postinjection. The Pearson correlation analysis showed a positive correlation of tumor uptake between biodistribution and micro-SPECT/CT semiquantification imaging analysis (r = 0.832). Our results revealed 111In-[DTPA(1), Lys(3), Tyr(4)]-BN has high affinity with BN type 2 receptor. The results demonstrated a good uptake in the GRPR-overexpression of PC-3 tumor-bearing SCID mice. 111In-[DTPA(1), Lys(3), Tyr(4)]-BN is a potential agent for imaging GRPR-positive tumors in humans.