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BACKGROUND: Angiogenesis is a process that many tumors depend on for growth, development, and metastasis. Vascular endothelial growth factor (VEGF) is one of the major players in tumor angiogenesis in several tumor types, including melanoma. VEGF inhibition is achieved by bevacizumab, a humanized monoclonal antibody that binds with high affinity to VEGF and prevents its function. In order to successfully enable in vivo VEGF expression imaging in a murine melanoma model, we previously labeled bevacizumab with [99mTc]Tc. We observed that this was feasible, but it had prolonged blood circulation and delayed tumor uptake. OBJECTIVE: The aim of this study was to develop a radiolabeled Fab bevacizumab fragment, [99mTc]Tc-HYNICFab( bevacizumab), for non-invasive in vivo VEGF expression molecular imaging. METHODS: Flow cytometry was used to examine VEGF presence in the murine melanoma cell line (B16-F10). Bevacizumab was digested with papain for six hours at 37°C to produce Fab(bevacizumab), which was then conjugated to NHS-HYNIC-Tfa for radiolabeling with [99mTc]Tc. Stability and binding affinity assays were also evaluated. Biodistribution and single photon emission computed tomography/computed tomography (SPECT/CT) were performed at 1, 3, and 6 h (n = 4) after injection of [99mTc]Tc-HYNIC-Fab(Bevacizumab) in normal and B16-F10 tumor-bearing C57Bl/6J mice. RESULTS: Using flow cytometry, it was shown that the B16-F10 murine melanoma cell line has intracellular VEGF expression. Papain incubation resulted in the complete digestion of bevacizumab with good purity and homogeneity. The radiolabeling yield of [99mTc]Tc-HYNIC-Fab(bevacizumab) was 85.00 ± 6.06%, with a specific activity of 291.87 ± 18.84 MBq/mg (n=3), showing in vitro stability. Binding assays demonstrated significant intracellular in vitro VEGF expression. Fast blood clearance and high kidney and tumor uptake were observed in biodistribution and SPECT/CT studies. CONCLUSIONS: We present the development and evaluation of [99mTc]Tc-HYNIC-Fab(bevacizumab), a novel molecular VEGF expression imaging agent that may be used for precision medicine in melanoma and potentially in other VEGF-expressing tumors.
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Aim: ChiTn, a mouse/human chimeric anti-Tn monoclonal antibody, was radiolabeled with iodine-131 (131I) and technetium-99m (99mTc) to assess its biodistribution and internalization in Tn-expressing (Tn+) and wild-type (Tn-) LL/2 lung cancer cells. Results: Selective accumulation and gradual internalization of ChiTn were observed in Tn+ cells. Biodistribution in mice with both Tn+ or Tn- lung tumors indicated that the uptake of radiolabeled ChiTn within tumors increased over time. Dual-labeling experiments with 99mTc and 131I showed different biodistribution patterns, with 99mTc exhibiting higher values in the liver, spleen, and kidneys, while 131I showed higher uptake in the thyroid and stomach. However, tumor uptake did not significantly differ between Tn+ and Tn- tumors. To improve tumor targeting, Losartan, an antihypertensive drug known to enhance tumor perfusion and drug delivery, was investigated. Biodistribution studies in Losartan-treated mice revealed significantly higher radiolabeled ChiTn uptake in Tn+ tumors. No significant changes were observed in the uptake of the control molecule IgG-HYNIC™99mTc. Conclusions: These findings demonstrate the enhanced tumor targeting of radiolabeled ChiTn in Losartan-treated mice with Tn-expressing lung tumors. They highlight the potential of ChiTn as a theranostic agent for cancer treatment and emphasize the importance of Losartan as an adjunctive treatment to improve tumor perfusion and drug delivery.
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Anticorpos Monoclonais , Radioisótopos do Iodo , Losartan , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Losartan/farmacologia , Losartan/farmacocinética , Losartan/administração & dosagem , Distribuição Tecidual , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Tecnécio , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Linhagem Celular Tumoral , Feminino , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Abstract The goal of this work is to identify new fatty acid-mimetic 99mTc-complexes to be used as myocardial imaging agents that allow studying heart abnormalities in high-risk patients. In this sense, we designed a fatty acid-mimetic substructure including an amide moiety that, among other properties, could improve myocardial residence time. A diamide with a chain length of 15 atoms and porting a 6-hydrazinonicotinyl (HYNIC) chelator, and an analog with a short carbon-chain, were prepared with convergent organic synthetic procedures and radiolabeled with 99mTc using tricine as the sole coligand. The in vivo proofs of concept were performed using healthy mice. The new 99mTc-complexes were obtained with adequate radiochemical purity. The lipophilicities were in agreement with the length of the chains. While both 99mTc-complexes showed uptake in the myocardial muscle, the designed radiopharmaceutical with the longest chain length had preferential target-uptake and target-retention compared to other complexes described in the bibliography. Further studies, involving imaging assays, synthetic modifications, and assay of new coligands for 99mTc-HYNIC complexes, are currently ongoing.
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Animais , Feminino , Camundongos , Compostos Radiofarmacêuticos/efeitos adversos , Ácidos Graxos/agonistas , Amidas/efeitos adversos , Cardiopatias Congênitas/classificaçãoRESUMO
BACKGROUND: Intraoperative parathyroid hormones have been used to establish operative success in patients with primary hyperparathyroidism. This study's aim was to assess the impact of estimated glomerular filtration rate and serum creatinine levels on the fulfillment of >50% drop and normalization of intraoperative parathyroid hormone levels. METHODS: Patients successfully treated for primary hyperparathyroidism were analyzed. The samples for parathyroid hormone were collected at baseline, 5-, 10-, and 30-minutes postexcision. The patients were classified as follows: (1) estimated glomerular filtration rate >60 mL/min, (2) estimated glomerular filtration rate <60 mL/min and serum creatinine levels <1.2 mg/dL, and (3) estimated glomerular filtration rate <60 mL/min and serum creatinine levels >1.2 mg/dL. Comparative analysis of patients achieving the >50% parathyroid hormone drop criterion and normalization of intraoperative parathyroid hormone was performed. RESULTS: One hundred-fourteen patients were distributed as follows: 88 patients (77.2%), 14 (12.3%), and 12 (10.5%) for groups 1, 2 and 3, respectively. No difference between groups in the proportion of patients fulfilling the >50% parathyroid hormone drop criterion was found. An abnormally elevated intraoperative parathyroid hormone level at 30-minute postexcision was observed in 0, 14.3, and 16.6% in groups 1, 2, and 3, respectively (P ≤ .0001). CONCLUSION: In the study, >50% parathyroid hormone drop criterion was equally achieved despite normal or reduced estimated glomerular filtration rate. When serum creatinine levels increased >1.2 mg/dL and estimated glomerular filtration rate declined <60 mL/min, the likelihood of reaching normal intraoperative parathyroid hormone levels postexcision was significantly lower.
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Hiperparatireoidismo Primário , Insuficiência Renal , Humanos , Hiperparatireoidismo Primário/cirurgia , Creatinina , Monitorização Intraoperatória , Estudos Retrospectivos , Paratireoidectomia , Hormônio Paratireóideo , Rim/fisiologiaRESUMO
Atmospheric nuclear tests (1945-1980) have led to radioactive fallout across the globe. French tests in Polynesia (1966-1974) may influence the signature of fallout in South America in addition to those conducted by USA and former USSR until 1963 in the Northern hemisphere. Here, we compiled the 240Pu/239Pu atom ratios reported for soils of South America and conducted additional measurements to examine their latitudinal distributions across this continent. Significantly lower ratio values were found in the 20-45° latitudinal band (0.04 to 0.13) compared to the rest of the continent (up to 0.20) and attributed to the contribution of the French atmospheric tests to the ultra-trace plutonium levels found in these soils. Based on sediment cores collected in lakes of Chile and Uruguay, we show the added value of measuring 240Pu/239Pu atom ratios to refine the age models of environmental archives in this region of the world.
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Plutônio , Monitoramento de Radiação , Poluentes Radioativos do Solo , Poluentes Radioativos da Água , Chile , Plutônio/análise , Radioisótopos/análise , Solo , Poluentes Radioativos do Solo/análise , Poluentes Radioativos da Água/análiseRESUMO
Abstract In recent years, nanocarriers have been studied as promising pharmaceutical tools for controlled drug-delivery, treatment-efficacy follow-up and disease imaging. Among them, X-shaped amphiphilic polymeric micelles (Tetronic®, poloxamines) display great potential due to their biocompatibility and non-toxic effects, among others. In the present work, polymeric micelles based on the T1307 copolymer were initially decorated with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-fluorophore in order to determinate its in vivo biodistribution on 4T1 tumor-bearing mice. However, unfavorable results with this probe led to two different strategies. On the one hand, the BODIPY-micelle-loaded, L-T1307-BODIPY, and on the other hand, the 99mTc-micelle-radiolabeled, L-T1307- 99m Tc, were analyzed separately in vivo. The results indicated that T1307 accumulates mainly in the stomach, the kidneys, the lungs and the tumor, reaching the maximum organ-accumulation 2 hours after intravenous injection. Additionally, and according to the results obtained for L-T1307- 99m Tc, the capture of the polymeric micelles in organs could be observed up to 24 hours after injection. The results obtained in this work were promising towards the development of new radiotracer agents for breast cancer based on X-shaped polymeric micelles.
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Animais , Feminino , Camundongos , Eficácia , Diagnóstico , Injeções Intravenosas/classificação , Micelas , Neoplasias/diagnóstico , Estômago/anormalidades , Preparações Farmacêuticas/análise , Estratégias de Saúde , Pulmão/anormalidadesRESUMO
Nanomedicine is a highly demanded discipline. Liposomes have seen an increased attention due to their physicochemical properties that allow them to act as nanocarriers of drugs and also of radioisotopes that can be used to diagnose and treat cancer. In order to obtain a novel permeability cancer imaging agent based on 99mTc-labeled liposomes, we describe microwave-assisted synthesis of stearyl 6-(benzylidenehydrazinyl) nicotinamide lipid, which was included in two formulations: nanometric hydrazinonicotinic acid (HYNIC) liposome and its PEGylated coated analogue, HYNIC-PEG liposome. Radiolabeling with 99mTc via stearyl 6-(benzylidenehydrazinyl) nicotinamide was found to be easy, reproducible, and stable, revealing high radiochemical purity (94 ± 1.7%) for both liposomal formulations. Biodistribution at 4 h and 24 h and scintigraphic images at 4 h were performed in normal and melanoma-bearing C57BL/6 mice. Biodistribution studies at 4 h showed tumor uptake of 99mTc-HYNIC liposome and 99mTc-HYNIC-PEG liposome (1.1 ± 0.6 and 2.5 ± 0.4, respectively) and also at 24 h p.i. (1.8 ± 0.5 and 3.0 ± 1.1, respectively). Scintigraphic images showed appreciable tumor uptake in melanoma tumor-bearing mice with both liposomal formulations. Our results show that 99mTc stearyl 6-(benzylidenehydrazinyl) nicotinamide liposomes can be used as diagnostic noninvasive in vivo tumor-targeting agents capable of evaluating tumor permeability and development who can be used in personalized chemotherapy planning.
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Melanoma Experimental/metabolismo , Niacinamida/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Animais , Linhagem Celular Tumoral , Lipossomos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/administração & dosagem , Niacinamida/química , Permeabilidade/efeitos dos fármacos , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Tecnécio/administração & dosagem , Tecnécio/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND: Multiple Myeloma (MM) is a malignant hematologic disorder and the second most common blood cancer. Interleukin-6 (IL-6) has been identified as a crucial factor for the proliferation and survival of MM cells and the overexpression of IL-6 receptor is being studied as a molecular target for therapeutic and diagnostic use in myelomas and other comorbidities. Tocilizumab is a humanized monoclonal antibody that binds IL-6R. OBJECTIVE: We aim to label and evaluate Fab(Tocilizumab) with 99mTechnetium or Cy7 as potential MM imaging agents. METHODS: IL-6R distribution was analyzed by Laser Confocal Microscopy (LCM) in MM cell lines. Fab(Tocilizumab) was produced by the digestion of Tocilizumab with papain for 24h at 37°C, derivatized with NHS-HYNIC-Tfa and radiolabeled with 99mTc. Radiochemical stability and in vitro cell assays were evaluated. Biodistribution and SPECT/CT were performed. Also, Fab(Tocilizumab) was labeled with Cy7 for in vivo fluorescence imaging up to 72h. RESULTS: LCM analysis demonstrates IL-6R distribution on MM cell lines. Incubation with papain resulted in complete digestion of Tocilizumab and exhibited a good purity and homogeneity. Radiolabeling with 99mTc via NHS-HYNIC-Tfa was found to be fast, easy, reproducible and stable, revealing high radiochemical purity and without interfering with IL-6R recognition. Biodistribution and SPECT/CT studies showed a quick blood clearance and significant kidney and MM engrafted tumor uptake. Cy7-Fab(Tocilizumab) fluorescent imaging allowed MM1S tumor identification up to 72h p.i. CONCLUSION: These new molecular imaging agents could potentially be used in the clinical setting for staging and follow-up of MM through radioactive whole-body IL-6R expression visualization in vivo. The fluorescent version could be used for tissue sample evaluation and to guide surgical excision, if necessary.
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Anticorpos Monoclonais Humanizados/química , Carbocianinas/química , Imagem Molecular , Mieloma Múltiplo/diagnóstico por imagem , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/química , Humanos , Receptores de Interleucina-6/análiseRESUMO
Aptamers are oligonucleotides that have the characteristic of recognizing a target with high affinity and specificity. Based on our previous studies, the aptamer probe Sgc8-c-Alexa647 is a promising tool for molecular imaging of PTK7, which is an interesting biomarker in cancer. In order to improve the delivery of this probe as well as create a novel drug delivery nanosystem targeted to the PTK7 receptor, we evaluate the co-association between the probe and preformed nanostructures. In this work, preformed pegylated liposomes (PPL) and linear and branched pristine polymeric micelles (PMs), based on PEO-PPO-PEO triblock copolymers were used: poloxamer F127® and poloxamines T1307® and T908®. For it, Sgc8-c-Alexa647 and its co-association with the different nanostructures was exhaustively analyzed. DLS analysis showed nanometric sizes, and TEM and AFM showed notable differences between free- and co-associated probe. Likewise, all nanosystems were evaluated on A20 lymphoma cell line overexpressing PTK7, and the confocal microscopy images showed distinctness in cellular uptake. Finally, the biodistribution in BALB/c mice bearing lymphoma-tumor and pharmacokinetic study revealed an encouraging profile for T908-probe. All data obtained from this work suggested that PMs and, more specifically T908 ones, are good candidates to improve the pharmacokinetics and the tumor uptake of aptamer-based probes.
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2-Amino-7-fluorophenazine 5,10-dioxide (FNZ) is a bioreducible prodrug, poorly soluble in water, with potential anticancer activity on hypoxic-tumors. This poor solubility limits its potential applications in clinic. Amphiphilic pristine polymeric micelles (PMs) based on triblock copolymers Pluronic® and Tetronic®, glycosylated derivatives and their mixtures with preformed-liposomes (LPS), were analyzed as strategies to improve the bioavailability of FNZ. FNZ encapsulations were performed and the obtaining nanostructures were characterized using UV-visible spectroscopy (UV-VIS), Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS). The most promising nanoformulations were analyzed for their potential toxicity and pharmacologically, at 20 mg/kg FNZ-doses, in a stage-IV murine metastatic-breast tumor model. The results revealed that the solubility of the encapsulated-FNZ increased up to 14 times and the analysis (UV-VIS, DLS and TEM) confirmed the interaction between vehicles and FNZ. In all the cases appropriate encapsulation efficiencies (greater than 75%), monodisperse nanometric particle sizes (PDI = 0.180-0.335), adequate Z-potentials (-1.59 to -26.4 mV), stabilities and spherical morphologies were obtained. The in vitro profile of FNZ controlled releases corresponded mainly to a kinetic Higuchi model. The in vitro/in vivo biological studies revealed non-toxicity and relevant tumor-weight diminution (up to 61%).
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The presence of a high number of macrophages within solid tumors is often significantly associated with poor prognosis and predict treatment failure for chemotherapy and radiotherapy. Macrophages are innate immune cells capable of performing diverse functions depending on the different signals from the microenvironment. The classically activated macrophage is commonly present during the early stages of tumor development while alternatively activated macrophages are associated with more advanced tumors. The distinction of the antitumoral macrophages from the pro-tumoral macrophages is not absolute. However, they have different cell surface markers such as mannose receptor (MRC1 or CD206) abundantly expressed by macrophages treated with interleukin-4 (IL-4). The important roles of macrophages in cancers suggest that it is important to develop novel therapies that target these cells. In the present study, we designed a probe using Polyamidoamine (PAMAM) fifth-generation (G5) dendrimers conjugated with mannose, Cyanine 7 (Cy7), and hydrazinonicotinamide (HYNIC) for target macrophages with high expression of MRC1 in the tumor. The intracellular uptake of 99mTc-HYNIC-dendrimer-mannose-Cy7 through the interaction with MRC1 in bone marrow-derived macrophages (BMDMs) untreated or treated with lipopolysaccharides (LPS) + interferon (IFN)γ or IL-4 was analyzed. Our results show that high-density mannose dendrimers are preferentially bound by macrophages treated by IFNγ and LPS that express lower levels of MRC1 than for macrophages treated by IL-4 that express high levels of MRC1. Furthermore, the intracellular 99mTc-HYNIC-dendrimer-mannose-Cy7 uptake in BMDMs was not inhibited in the presence of free mannose or glucose. This result suggests that 99mTc-HYNIC-dendrimer-mannose-Cy7 is not internalized via macrophage MRC1. Based on these findings, we concluded that MRC1 expression does not determine the uptake of high-density mannose dendrimers.
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Benzotiazóis/química , Carbocianinas/química , Dendrímeros/química , Macrófagos/metabolismo , Manose/química , Niacinamida/análogos & derivados , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/metabolismo , Animais , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/química , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
About 95 % of people diagnosed with glioblastoma die within five years. Glioblastoma is the most aggressive central nervous system tumour. It is necessary to make progress in the glioblastoma treatment so that advanced chemotherapy drugs or radiation therapy or, ideally, two-in-one hybrid systems should be implemented. Tyrosine kinase receptors-inhibitors and boron neutron capture therapy (BNCT), together, could provide a therapeutic strategy. In this work, sunitinib decorated-carborane hybrids were prepared and biologically evaluated identifying excellent antitumoral- and BNCT-agents. One of the selected hybrids was studied against glioma-cells and found to be 4â times more cytotoxic than sunitinib and 1.7â times more effective than 10 B-boronophenylalanine fructose complex when the cells were irradiated with neutrons.
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Antineoplásicos , Terapia por Captura de Nêutron de Boro , Neoplasias Encefálicas , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma , Preparações Farmacêuticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Boro , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Camundongos , FenilalaninaRESUMO
Background: Aptamers represent an emerging class of oligonucleotides that have the ability to bind ligands with high affinity. Sgc8-c aptamer recognizes PTK7, a member of the catalytically defective receptor protein tyrosine kinase family that is upregulated in various cancers, including hemato-oncological malignancies. Herein, an Sgc8-c-NOTA-radiolabeled probe was prepared for theranostic purpose. Materials and Methods: In this work, an Sgc8-c-radiolabeled probe against PTK7 was prepared, and biological evaluations-pharmacokinetic studies, biodistribution analysis, and in vivo molecular imaging-were performed. To obtain the radiolabeled probe, a modified 5'-amino-derivative of the Sgc8-c aptamer was bound to the metal chelator NOTA, and subsequently labeled with 67Ga with high yield and radiochemical purity. The precursor, Sgc8-c-NOTA, the radio probe Sgc8-c-NOTA-67Ga, and its nonradioactive complex, Sgc8-c-NOTA-69/71Ga, were purified by reverse-phase high-performance liquid chromatography and characterized by electrospray ionization mass spectrometry. The binding ability of Sgc8-c-NOTA-67Ga was studied in vitro against purified PTK7 receptor. In addition, the binding was also evidenced against the hemato-oncological A20 cell line, derived from B lymphocytes, and the corresponding A20-green fluorescent protein (GFP)-transfected cells. The proof of concept was performed on A20-GFP tumor-bearing mice, in which the biodistribution of the radiolabeled probe was evaluated through imaging, using X-ray, fluorescence, and γ modalities. The specific uptake of the probe was confirmed by blocking with the Sgc8-c aptamer in an in vivo competition assay. Results: The biodistribution results showed considerable uptake in tumor since 2 h, with highest at 48 h postinjection. However, the blood and muscle ID/g (injected dose per gram of tissue) activities were decreasing with time and tumor/no-target ratios increasing to 20 at 24 h postinjection. These results are consistent with the in vivo images. Conclusions: This study supports the utility of Sgc8-c-NOTA radiolabeled as a theranostic agent.
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Aptâmeros de Nucleotídeos/uso terapêutico , Neoplasias Hematológicas/terapia , Radioquímica/métodos , Animais , Feminino , Humanos , CamundongosRESUMO
BACKGROUND: There is increasing interest in the development of newborn screening tests to identify children at risk of fetal alcohol spectrum disorder (FASD) in order to provide these children with early intervention. Phosphatidylethanol (PEth) has emerged as a potential universal newborn screening candidate. METHODS: The aim of this report was to present the results of a study designed to compare PEth levels in 1,140 postpartum women and their newborn infants in Montevideo, Uruguay, and Sao Paulo, Brazil. Self-report alcohol use during pregnancy data was collected, along with both maternal and newborn dried blood spot samples for PEth analysis. RESULTS: The average age and parity of the women in the sample were 26 years of age and 2.3 pregnancies. For the Uruguay sample (n = 611), 45.8% of postpartum women had PEth levels ≥ 8 ng/ml with a mean positive PEth of 43.6 ng/ml. In contrast, 86.8% of the newborns had PEth levels ≥ 8 ng/ml, with a mean positive PEth of 77.4 ng/ml. For the Brazil sample (n = 529), 33.2% of women had PEth levels ≥ 8 ng/ml with a mean positive PEth of 31 ng/ml. In contrast, 76.9% of the Brazil newborns had PEth levels ≥ 8 ng/ml and 43.9% with a mean positive PEth of 61.1 ng/ml. PEth levels were significantly higher in newborns compared with their postpartum mothers in both the Uruguay and Brazil samples. Self-reported third-trimester alcohol was 6% in the Uruguay sample and 9.1% in the Brazil sample compared with positive maternal PEth levels in 45.8% and 33.2%, respectively. CONCLUSIONS: Clinicians may want to consider newborn PEth screening in high-risk populations where prenatal alcohol use is common. The mechanism underlying significantly higher PEth levels in newborns compared with their mothers is not known.
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Consumo de Bebidas Alcoólicas/sangue , Transtornos do Espectro Alcoólico Fetal/sangue , Glicerofosfolipídeos/sangue , Complicações na Gravidez/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Adulto , Brasil , Teste em Amostras de Sangue Seco , Intervenção Educacional Precoce , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Período Pós-Parto/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Autorrelato , UruguaiRESUMO
BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract. A rare site of localization of these tumors is the esophagus. Evidence-based consensus regarding the type of surgery for patients with esophageal GIST remains unclear. CLINICAL CASE: A female without history of diseases experienced dysphagia, weight loss (6 kg) and malaise. Computed tomography revealed thickening of the esophagus. During the endoscopic ultrasonography a localized lesion was observed in the esophagus that depended on the muscularis propria. We opted to treat with an esophagectomy with replacement by transmediastinal transposition of the stomach. Patient recovered well from the surgery and she was discharged home in stable condition in post-operative day seven. At 6 months she has no symptoms. CONCLUSION: This case illustrates the clinical presentation of an esophageal GIST which represents only 1% of all sites where GISTs have been reported; open surgery was successfully performed with minimal morbidity, complete resolution of symptoms and improvement of the patient's quality of life. Esophagectomy with replacement by transmediastinal transposition of the stomach should be performed when the center has experience to do so with minimal morbidity and mortality.
ANTECEDENTES: Los tumores del estroma gastrointestinal (GIST) son las lesiones malignas mesenquimales más comunes del tracto digestivo. Un sitio raro de localización de estos tumores es el esófago. A la fecha actual no hay un consenso claro basado en evidencia científica con respecto al tipo de cirugía a realizar en pacientes con GIST en esta localización inusual. CASO CLÍNICO: Una mujer previamente sana presentó disfagia, pérdida de peso (6 kg) y malestar general. La tomografía computarizada reveló un engrosamiento del esófago y en la ultrasonografía endoscópica se observó una lesión localizada en el esófago dependiente de la muscular propia. Se optó por realizar esofagectomía con reemplazo mediante transposición transmediastinal del estómago. La paciente se recuperó bien de la cirugía y fue dada de alta en condición estable en el séptimo día del posoperatorio. A los 6 meses, se encuentra asintomática. CONCLUSIÓN: Este caso ilustra la presentación clínica de un GIST esofágico que representa solo el 1% de todos los sitios reportados. La cirugía se realizó con éxito, con morbilidad mínima, resolución completa de los síntomas y mejoría de la calidad de vida de la paciente. La esofagectomía con reemplazo mediante transposición transmediastinal del estómago (comúnmente llamado ascenso gástrico) debe realizarse cuando el centro tiene experiencia para hacerlo con morbilidad y mortalidad mínimas.
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Neoplasias Esofágicas/cirurgia , Esofagectomia , Tumores do Estroma Gastrointestinal/cirurgia , Estômago/transplante , Adulto , Feminino , HumanosRESUMO
Background: Carboranylanilinoquinazoline-hybrids, developed for boron neutron capture therapy, have demonstrated cytotoxicity against murine-glioma cells with EGFR-inhibition ability. In addition, their adequate aqueous/metabolic stabilities and ability to cross blood-brain barrier make them good leads as to become antiglioma drugs. Aim: Analyze drug-like properties of representative carboranylanilinoquinazolines. Materials & methods: To expand carboranylanilinoquinazolines therapeutic spectrum, we studied their ability to act against glioma-mammal cells, U-87 MG and other tyrosine kinase-overexpress cells, HT-29. Additionally, we predicted theoretically and studied experimentally drug-like properties, in other words, organization for economic cooperation and development-recommended toxicity-studies and, due to some aqueous-solubility problems, and vehicularization for oral and intravenous administrations. Conclusion: We have identified a promising drug-candidate with broad activity spectrum, appropriate drug-like properties, adequate toxicological behavior and able ability to be loaded in suitable vehicles.
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Compostos de Anilina/química , Antineoplásicos/química , Neoplasias Encefálicas/radioterapia , Receptores ErbB/antagonistas & inibidores , Glioma/radioterapia , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Terapia por Captura de Nêutron de Boro/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Colesterol/química , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Fosfatidilcolinas/química , Poliaminas/química , Polietilenos/química , Polipropilenos/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/farmacologia , Solubilidade , ÁguaRESUMO
Pretargeted imaging, based on the highly reactive process between [1,2,4,5]tetrazines with trans-cyclooctene (TCO), appears as an attractive strategy to overcome disadvantages associated with traditional radioimmunoconjugates. To be successful, the radiolabeled component should react in vivo with the conjugated antibody and the non reactive excess clear fast from the organism. Herein, we explore the in vivo effects of hydrophilic linker incorporation into [1,2,4,5]tetrazine systems bearing a 6-hydrazinonicotinyl (HYNIC) moiety for technetium-99m coordination. Incorporation of a polypeptide chain containing hydrophilic aminoacids, resulted in a derivative with renal clearance. Pretargeted bevacizumab imaging was used as proof of concept.
RESUMO
PURPOSE: To study the rhenium-188 labeling of polyamidoamine (PAMAM) generation 4 (G4) dendrimer and its evaluation on biodistribution and chromosomal aberrations in melanoma cells induced by ionizing radiation as potential treatment agent. MATERIALS AND METHODS: Dendrimers were first conjugated with Suc-HYNIC (succinimidyl 6-hydrazinopyridine-3-carboxylic acid hydrochloride). Dendrimer-HYNIC was then incubated with 188ReO4-. Biodistribution was performed administrating 188Re-dendrimer to normal (NM) or melanoma-bearing mice (MBM). Chromosome aberration test was conducted in order to measure treatment capacity of 188Re-dendrimer in melanoma cells. RESULTS: Radiolabeling yield of dendrimer was approx. 70%. Biodistribution studies in NM showed blood clearance with hepatic and renal depuration. MBM showed a similar pattern of biodistribution with tumor uptake of 6% of injected dose. Aberrant metaphases quantified in control cells were 7%, increasing to 29.5% in cells treated with 15µCi (0.555 MBq) of 188Re-dendrimer for 24 h. CONCLUSIONS: 188Re-dendrimer can produce double-stranded breaks in DNA induced by ionizing radiation in melanoma cells in vitro.