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1.
J Liposome Res ; 30(2): 126-135, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935273

RESUMO

Triaryl-(Z)-olefin (TZO) was synthesized as a Tamoxifen (TMX) analogue for breast cancer treatment to avoid developing the resistance and toxicity of TMX. TZO was synthesized using McMurry olefination reaction and has anti-cancer activity better than TMX by two folds. In this paper, in situ pH-sensitive TZO-loaded noisome hydrogel was prepared for delivering and targeting TZO to its site of activity. Equi-molar of cholesterol and span 60 was used to prepare TZO-loaded niosomes using the Hand Shaking Method. The central composite experimental design was used to prepare differently in situ pH-sensitive TZO-loaded niosomes formulae. The formulae were done by incorporated TZO-loaded niosomes into different concentrations of chitosan and Glyceryl monooleate (GCM). Increasing the chitosan and GCM concentrations resulted in significantly increasing the viscosity and significantly decreasing the release of TZO from different formulae. The formula composed of (0.61% w/v) of chitosan and (0.23% w/v) of GCM was chosen as an optimum formula to evaluate the efficacy of TZO using Ehrlich carcinoma mice model. A significant anti-tumour effect was shown in comparison with TMX. Briefly, in situ pH-sensitive TZO-loaded niosomes could be an effective treatment for breast cancer.


Assuntos
Alcenos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Hidrogéis/farmacologia , Alcenos/síntese química , Alcenos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Hidrogéis/síntese química , Hidrogéis/química , Concentração de Íons de Hidrogênio , Lipossomos/química , Camundongos , Estrutura Molecular , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície , Tomografia Computadorizada por Raios X , Viscosidade
2.
Contrast Media Mol Imaging ; 11(5): 350-361, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27230705

RESUMO

Synthesis of a contrast agent for biomedical imaging is of great interest where magnetic nanoparticles are concerned, because of the strong influence of particle size on transverse relaxivity. In the present study, biocompatible magnetic iron oxide nanoparticles were synthesized by co-precipitation of Fe2+ and Fe3+ salts, followed by surface adsorption with reduced dextran. The synthesized nanoparticles were spherical in shape, and 12 ± 2 nm in size as measured using transmission electron microscopy; this was corroborated with results from X-ray diffraction and dynamic light scattering studies. The nanoparticles exhibited superparamagnetic behavior, superior T2 relaxation rate and high relaxivities (r1 = 18.4 ± 0.3, r2 = 90.5 ± 0.8 s-1 mM-1 , at 7 T). MR image analysis of animals before and after magnetic nanoparticle administration revealed that the signal intensity of tumor imaging, specific organ imaging and whole body imaging can be clearly distinguished, due to the strong relaxation properties of these nanoparticles. Very low concentrations (3.0 mg Fe/kg body weight) of iron oxides are sufficient for early detection of tumors, and also have a clear distinction in pre- and post-enhancement of contrast in organs and body imaging. Many investigators have demonstrated high relaxivities of magnetic nanoparticles at superparamagnetic iron oxide level above 50 nm, but this investigation presents a satisfactory, ultrasmall, superparamagnetic and high transverse relaxivity negative contrast agent for diagnosis in pre-clinical studies. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Meios de Contraste/química , Dextranos , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Nanopartículas/química , Animais , Carcinoma de Ehrlich/diagnóstico por imagem , Meios de Contraste/síntese química , Meios de Contraste/farmacocinética , Dextranos/administração & dosagem , Dextranos/síntese química , Dextranos/farmacocinética , Humanos , Nanopartículas de Magnetita/administração & dosagem , Camundongos , Nanopartículas/administração & dosagem , Neoplasias/diagnóstico por imagem , Especificidade de Órgãos
3.
Appl Radiat Isot ; 105: 40-46, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26232562

RESUMO

The present study describes the optimization of (68)Ga radiolabeling with PAMAM dendrimer-DOTA conjugate. A conjugate (PAMAM-DOTA) concentration of 11.69µM, provided best radiolabeling efficiency of more than 93.0% at pH 4.0, incubation time of 30.0min and reaction temperature ranging between 90 and 100°C. The decay corrected radiochemical yield was found to be 79.4±0.01%. The radiolabeled preparation ([(68)Ga]-DOTA-PAMAM-D) remained stable (radiolabeling efficiency of 96.0%) at room temperature and in serum for up to 4-h. The plasma protein binding was observed to be 21.0%. After intravenous administration, 50.0% of the tracer cleared from the blood circulation by 30-min and less than 1.0% of the injected activity remained in blood by 1.0h. The animal biodistribution studies demonstrated that the tracer excretes through the kidneys and about 0.33% of the %ID/g accumulated in the tumor at 1h post injection. The animal organ's biodistribution data was supported by animal PET imaging showing good 'non-specific' tracer uptake in tumor and excretion is primarily through kidneys. Additionally, DOTA-PAMAM-D conjugation with αVß3 receptors targeting peptides and drug loading on the dendrimers may improve the specificity of the (68)Ga labeled product for imaging and treating angiogenesis respectively.


Assuntos
Dendrímeros/farmacocinética , Radioisótopos de Gálio/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Carcinoma de Ehrlich/diagnóstico por imagem , Humanos , Técnicas In Vitro , Rim/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tomografia por Emissão de Pósitrons , Distribuição Tecidual , Tomografia Computadorizada por Raios X
4.
Nucl Med Commun ; 36(10): 1042-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26147941

RESUMO

OBJECTIVE: Once administered intravenously, technetium-99m (99mTc)-labeled phytate binds to calcium in the serum and behaves as a nanoparticle. On the basis of the high permeability of the tumor vasculature, 99mTc-phytate is expected to leak and accumulate specifically in inflammatory cells. The aim of this study was to evaluate the potential of 99mTc-phytate in assessing the degree of inflammation in Ehrlich solid tumors in mice. MATERIALS AND METHODS: 99mTc-phytate was prepared by adding pertechnetate to a solution containing phytic acid and stannous chloride. The blood half-life of this particle following intravenous injection was determined using blood samples from healthy animals, whereas its size was measured by photon correlation spectroscopy. Scintigraphic imaging and biodistribution studies were carried out in tumor-bearing mice at 30 min and 2 h after injection. RESULTS: The average size of the particles was in the range of 200 nm, suggesting that they are capable of passively passing through fenestrations in tumor vessels, which are 200-2000 nm in size. The blood half-life for 99mTc-phytate was found to be 2.1 min, a result that is in agreement with previous studies. Data from tumor-bearing mice showed high tumor uptake at 2 h after 99mTc-phytate administration. As a result, a high tumor-to-muscle ratio was achieved (T/M = 25.9 ± 7.54). CONCLUSION: These findings indicate that 99mTc-sodium phytate has promising properties for identifying the type of tumor. This approach will have significant implications for characterizing tumor biology and treatment of malignant lesions.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Ácido Fítico/química , Tecnécio/química , Animais , Carcinoma de Ehrlich/complicações , Inflamação/complicações , Inflamação/diagnóstico por imagem , Camundongos , Tamanho da Partícula , Ácido Fítico/farmacocinética , Radioquímica , Cintilografia , Distribuição Tecidual
5.
PLoS One ; 10(7): e0134281, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26221728

RESUMO

Gamma Glutamyl Transferase (GGT) is an important biomarker in malignant cancers. The redox processes ensuing from GGT-mediated metabolism of extracellular GSH are implicated in critical aspects of tumor cell biology. Reportedly, Glutathione monoethyl ester (GSHMe) is a substrate of GGT, which has been used for its rapid transport over glutathione. Exploring GGT to be an important target, a homobivalent peptide system, DT(GSHMe)2 was designed to target GGT-over expressing tumors for diagnostic purposes. DT(GSHMe)2 was synthesized, characterized and preclinically evaluated in vitro using toxicity, cell binding assays and time dependent experiments. Stable and defined radiochemistry with 99mTc and 68Ga was optimized for high radiochemical yield. In vivo biodistribution studies were conducted for different time points along with scintigraphic studies of radiolabeled DT(GSHMe)2 on xenografted tumor models. For further validation, in silico docking studies were performed on GGT (hGGT1, P19440). Preclinical in vitro evaluations on cell lines suggested minimal toxicity of DT(GSHMe)2 at 100 µM concentration. Kinetic analysis revealed transport of 99mTc-DT(GSHMe)2 occurs via a saturable high-affinity carrier with Michaelis constant (Km) of 2.25 µM and maximal transport rate velocity (Vmax) of 0.478 µM/min. Quantitative estimation of GGT expression from western blot experiments showed substantial expression with 41.6 ± 7.07 % IDV for tumor. Small animal micro PET (Positron Emission Tomography)/CT(Computed Tomography) coregistered images depicted significantly high uptake of DT(GSHMe)2 at the BMG-1 tumor site. ROI analysis showed high tumor to contra lateral muscle ratio of 9.33 in PET imaging studies. Avid accumulation of radiotracer was observed at tumor versus inflammation site at 2 h post i.v. injection in an Ehrlich Ascites tumor (EAT) mice model, showing evident specificity for tumor. We propose DT(GSHMe)2 to be an excellent candidate for prognostication and tumor imaging using PET/SPECT.


Assuntos
Glutationa/análogos & derivados , Neoplasias Experimentais/diagnóstico por imagem , Compostos Radiofarmacêuticos , gama-Glutamiltransferase/metabolismo , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/metabolismo , Linhagem Celular Tumoral , Radioisótopos de Gálio , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glutationa/química , Glutationa/farmacocinética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio , Tomografia Computadorizada de Emissão de Fóton Único
6.
Eur J Pharm Sci ; 76: 102-9, 2015 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25956074

RESUMO

Lactoperoxidase (LPO) inhibitors are very selective for solid tumor due to their high binding affinity to the LPO enzyme. A computational study was used to select top-ranked LPO inhibitor (alone and in complex with (99m)Tc) with high in silico affinity. The novel prepared (99m)Tc-amitrole complex demonstrated both in silico and in vivo high affinity toward solid tumors.(99m)Tc-amitrole was radio-synthesized with a high radiochemical yield (89.7±3.25). It showed in vitro stability for up to 6h. Its preclinical evaluation in solid tumor-bearing mice showed high retention and biological accumulation in solid tumor cells with a high Target/Non-Target (T/NT) ratio equal to 4.9 at 60min post-injection. The data described previously could recommend (99m)Tc-amitrole as potential targeting scintigraphic probe for solid tumor imaging.


Assuntos
Amitrol (Herbicida)/farmacocinética , Antineoplásicos/farmacocinética , Carcinoma de Ehrlich/diagnóstico por imagem , Desenho Assistido por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Lactoperoxidase/antagonistas & inibidores , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Amitrol (Herbicida)/administração & dosagem , Amitrol (Herbicida)/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/enzimologia , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Concentração de Íons de Hidrogênio , Lactoperoxidase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Cintilografia , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Relação Estrutura-Atividade , Tecnécio/administração & dosagem , Tecnécio/química , Distribuição Tecidual
7.
Appl Radiat Isot ; 99: 41-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25702887

RESUMO

In the present study, we successfully radiolabeled gefitinib with (99m)Tc by direct labeling method. The radio-ligand had radiolabeling efficiency of >95.0% and in vitro stability of >80.0% at 24h. The radiotracer cleared from blood bi-exponentially. Animal organ biodistribution data indicated hepato-renal excretion of the radiotracer. Scintigraphy carried out in tumor bearing mice (induced by EGFR expressing EAT cell lines) demonstrated that the radiotracer accumulated in the tumor site with T/NT ratio of 3.3±0.2 at 1h.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Quinazolinas/farmacocinética , Tecnécio/farmacocinética , Animais , Linhagem Celular Tumoral , Meios de Contraste/farmacocinética , Gefitinibe , Humanos , Marcação por Isótopo/métodos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Técnicas de Sonda Molecular , Sondas Moleculares , Coelhos , Cintilografia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
8.
J Biomed Nanotechnol ; 9(9): 1636-43, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23980511

RESUMO

Bombesin (BBN) is a tetradecapeptide that binds specifically to gastrin-releasing peptide receptors in humans. Several forms of cancer, including lung, prostate, breast, and colon over-express receptors for bombesin-like peptides. Therefore, radiolabeled bombesin analogs might be useful for tumor identification. Nevertheless, it is well known that higher tumor uptake can yield images in higher quality. Hence, drug delivery systems, such as liposomes, can be used to achieve a higher concentration of radiotracer in tumor site, and also improve the radiotracer stability, since peptides can suffer easily degradation in vivo by natural plasma and tissue peptides. In this paper, we prepared long-circulating, pH-sensitive liposomes and long-circulation, non-pH sensitive liposomes. Both formulations were able to encapsulate the radiolabeled bombesin derivative (99mTc-BBN(7_14)), and also showing high in vitro stability. Biodistribution studies were performed in Ehrlich tumor bearing-mice to compare the ability of pH-sensitive and non-pH sensitive liposomes to deliver 99mTc-BBN(7_14) to tumor site. Results showed higher tumor uptake (2-fold) when pH-sensitive liposomes were used, suggesting that these vesicles can facilitate the access to the tumor by releasing the diagnostic agent into the ideal area. As a result, tumor-to-muscle ratio achieved with pH-sensitive liposomes was higher than that obtained with non-pH-sensitive formulation. In addition, scintigraphic images for pH-sensitive liposomes showed evident tumor uptake, corroborating with biodistribution data. Therefore, the results presented in this paper suggest that pH-sensitive liposomes are able to deliver more efficiently the radiolabeled bombesin analog. This finding poses a new possibility to improve images quality, since the tumor-to-muscle ratio was strongly enhanced.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/metabolismo , Lipossomos/química , Nanocápsulas/química , Compostos de Organotecnécio/farmacocinética , Fragmentos de Peptídeos/farmacocinética , Animais , Linhagem Celular Tumoral , Preparações de Ação Retardada , Concentração de Íons de Hidrogênio , Masculino , Teste de Materiais , Taxa de Depuração Metabólica , Camundongos , Especificidade de Órgãos , Compostos de Organotecnécio/química , Fragmentos de Peptídeos/química , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Sensibilidade e Especificidade , Distribuição Tecidual
9.
Cancer Biother Radiopharm ; 27(3): 221-5, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22432523

RESUMO

BACKGROUND: The currently available radiopharmaceuticals are not specific for tumor imaging. PURPOSE: The present study was conducted to radiolabel doxorubicin with Technetium-99m ([99m]Tc) as a scintigraphic marker of high DNA turnover/intercalation in malignant cells. METHODS: Labeling was done by direct method and the developed radiotracer was subjected to quality control tests. The blood kinetics, scintigraphy of tumor-bearing mice, and biodistribution were studied after intravenous injection of about 7.4 MBq of [99m]Tc-doxorubicin. The isotime (5 minutes) anterior images were acquired at different time intervals of 1.5, 3, and 4 hours. RESULTS: The labeling efficiency of [99m]Tc-doxorubicin was estimated to be more than 95%. The protein-binding efficiency was greater than 88% and in vitro stability was up to 24 hours. The biodistribution data support the clearance of the radioligand by dual (renal and hepatic) pathways. A semiquantitative data analysis of the anterior images indicated that a focal concentration of the radiotracer was seen in the tumor at 1.5 hours, which persisted in 3-hour and 4-hour images, respectively. CONCLUSIONS: This scintigraphic approach, therefore, could be a powerful tool for cancer detection at early stage. The technique, however, needs further validation through animal experimentation and clinical studies.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/tratamento farmacológico , Doxorrubicina/uso terapêutico , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Tecnécio , Animais , Carcinoma de Ehrlich/patologia , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Cintilografia , Distribuição Tecidual , Células Tumorais Cultivadas
10.
Eur J Pharm Sci ; 43(4): 290-6, 2011 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-21605669

RESUMO

PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the Gd-DTPA-BMA complex were prepared and radiolabeled by neutron activation. The radiolabeled liposomes presented significant in vitro cytotoxic activity against Ehrlich tumor cells when compared with controls. The biodistribution profile of these liposomes and free (159)Gd-DTPA-BMA were studied in mice bearing a previously-developed solid Ehrlich tumor. The results demonstrated an important uptake of the formulations by the tumor tissue, with a tissue/blood partition coefficient (Kp) 3.88 and 14.16 times higher than that of the free complex for pH-sensitive PEG-coated and PEG-folate-coated liposomes containing the (159)Gd-DTPA-BMA complex, respectively. Both formulations accumulated in the liver and spleen, thereby revealing some difficulty in escaping the action of the MPS cells. The formulation without folate presented a lower renal uptake, which is desirable in patients with chronic renal failure due to the potential risk of nephrogenic systemic fibrosis (NFS). The scintigraphic study revealed that the target/non-target ratio is always greater than three for pH-sensitive PEG-coated liposome formulations and above nine for pH-sensitive PEG-folate-coated liposome formulations. The results obtained in this study demonstrated that the formulations employed can be considered to be a potential alternative for the treatment of cancer, including patients with chronic renal failure.


Assuntos
Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/metabolismo , Gadolínio DTPA/administração & dosagem , Gadolínio DTPA/farmacocinética , Lipossomos/química , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/diagnóstico por imagem , Química Farmacêutica/métodos , Portadores de Fármacos/química , Ácido Fólico/química , Gadolínio/administração & dosagem , Gadolínio/química , Humanos , Concentração de Íons de Hidrogênio , Marcação por Isótopo/métodos , Lipossomos/administração & dosagem , Camundongos , Dermopatia Fibrosante Nefrogênica/tratamento farmacológico , Dermopatia Fibrosante Nefrogênica/metabolismo , Polietilenoglicóis/química , Radioisótopos/administração & dosagem , Radioisótopos/química , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Distribuição Tecidual
11.
Bioorg Med Chem Lett ; 20(21): 6182-4, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20850312
12.
Cancer Biother Radiopharm ; 25(6): 645-55, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21204758

RESUMO

Single-photon emission computed tomography has become a significant imaging modality with huge potential to visualize and provide information of anatomic dysfunctions that are predictive of future diseases. This imaging tool is complimented by radiopharmaceuticals/radiosubstrates that help in imaging specific physiological aspects of the human body. The present study was undertaken to explore the utility of technetium-99m (99(m)Tc)-labeled glutamate conjugates for tumor scintigraphy. As part of our efforts to further utilize the application of chelating agents, glutamic acid was conjugated with a multidentate ligand, diethylenetriaminepentaacetic acid (DTPA). The DTPA-glutamate conjugate [DTPA-bis(Glu)] was well characterized by IR, NMR, and mass spectroscopy. The biological activity of glutamic acid was compared with its DTPA conjugate by radiocomplexation with 99(m)Tc (labeling efficiency ≥98%). In vivo studies of both the radiolabeled complexes 99(m)Tc-Glu and 99(m)Tc-DTPA-bis(Glu) were then carried out, followed by gamma scintigraphy in New Zealand albino rabbits. Improved serum stability of 99(m)Tc-labeled DTPA conjugate indicated that 99(m)Tc remained bound to the conjugate up to 24 hours. Blood clearance showed a relatively slow washout of the DTPA conjugate when compared with the labeled glutamate. Biodistribution characteristics of the conjugate in Balb/c mice revealed that DTPA conjugation of glutamic acid favors less accumulation in the liver and bone and rapid renal clearance. Tumor scintigraphy in mice showed increasing tumor accumulation, stable up to 4 hours. These preliminary studies show that 99(m)Tc-DTPA-bis(Glu) can be a useful radiopharmaceutical for diagnostic applications in single-photon emission computed tomography imaging.


Assuntos
Ácido Glutâmico/análogos & derivados , Neoplasias/diagnóstico por imagem , Ácido Pentético/análogos & derivados , Compostos Radiofarmacêuticos , Tecnécio/química , Estruturas Animais/metabolismo , Animais , Carcinoma de Ehrlich/diagnóstico por imagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Estabilidade de Medicamentos , Ácido Glutâmico/síntese química , Ácido Glutâmico/farmacocinética , Ácido Glutâmico/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ácido Pentético/síntese química , Ácido Pentético/farmacocinética , Ácido Pentético/farmacologia , Coelhos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Imagem Corporal Total
13.
Chem Biol Drug Des ; 74(2): 159-64, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19614681

RESUMO

(99m)Tc-Diethylene triamine pentaacetic acid-bis (amide) conjugates have been synthesized and evaluated as a potential radiopharmaceutical for tumor imaging. The compounds were synthesized by the condensation reaction of DTPA bis(anhydride) with different l-amino acids (methyl tryptophan, and 5-hydroxy tryptophan) and were characterized on the basis of IR, NMR, and Mass spectroscopy. (99m)Tc-labeled compounds were found stable for about 24 h under physiological conditions with more than 95% radiolabeling yield. Blood kinetic studies of all these complexes showed a bi-exponential pattern as well as quick wash out from the blood circulation. The biological t(1/2)(F) and t(1/2)(S) were found to be 20 +/- 0.001 min for DTPA-(Me-Trp)(2) and 18 +/- 0.001 min for DTPA-(5HT)(2) and t(1/2) (slow) 5 h 45 min +/- 0.001, 5 h 30 +/- 0.001 min for DTPA-(Me-Trp)(2), and DTPA-(5HT)(2), respectively. Imaging and biodistribution studies were performed in mice bearing Ehrlich ascites tumor (EAT) tumors in right thigh. Radioconjugate derived from l-5-hydroxytryptophan exhibited remarkable localization at tumor site; whereas radiotracer derived from l-methyl tryptophan shows relatively less accumulation at the tumor site. Tumor-to-muscles ratios were 5.07 +/- 0.001, and 4.2 +/- 0.001 at 1 and 4 h for (99m)Tc-DTPA-(Me trp)(2) and 4.97 +/- 0.001 and 5.8 +/- 0.001 at 1 and 4 h after postinjection for (99m)Tc-DTPA-(5HT)(2), respectively. The preliminary results with these amino acid based ligands are encouraging to carrying out further in vivo experiments for targeted tumor imaging.


Assuntos
5-Hidroxitriptofano/análogos & derivados , Carcinoma de Ehrlich/diagnóstico por imagem , Ácido Pentético/análogos & derivados , Compostos Radiofarmacêuticos/farmacocinética , Triptofano/farmacocinética , 5-Hidroxitriptofano/química , 5-Hidroxitriptofano/farmacocinética , Aminoácidos/química , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pentético/química , Ácido Pentético/farmacocinética , Coelhos , Compostos Radiofarmacêuticos/química , Pentetato de Tecnécio Tc 99m/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Triptofano/análogos & derivados , Triptofano/química
14.
Cancer Biother Radiopharm ; 24(1): 41-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19243247

RESUMO

PURPOSE: The biologic effects and the underlying mechanisms of Ehrlich ascitic tumor (EAT) cells induced by ultrasound were investigated in this study. METHODS: Cells were subjected to ultrasonic irradiation with a frequency of 2.17 MHz and an intensity of 3 W/cm(2) for variable periods of time. Trypan blue exclusion was used to detect the integrity of cellular membrane; the membrane permeability was investigated by the incorporation of fluorescein isothiocyanate dextran during ultrasound exposure; and the cell membrane ultrastructure changes were observed under a scanning electron microscope. The potential mechanism was estimated from the generation of hydroxyl radicals, the lipid peroxidation levels, and intracellular reactive oxygen radicals production. RESULTS: The cell membrane damage effects induced by ultrasound increased with a prolonged exposure time; the fluorescent rates of the cells irradiated with ultrasound for 30 and 60 seconds were 11.46% and 18.50%, respectively; the amount of hydroxyl radicals in 30 (26.10 U/mL) and 60 seconds (28.47 U/mL) were significantly enhanced, compared with the control group (24.44 U/mL); then, the level of lipid peroxidation was also changed from 0.27 to 0.54 (30 seconds) and 1.21 nmol/mL (60 seconds). CONCLUSIONS: Shear forces and free radicals produced by acoustic cavitation may play important roles in these actions.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/terapia , Membrana Celular/diagnóstico por imagem , Terapia por Ultrassom/métodos , Animais , Permeabilidade da Membrana Celular , Sobrevivência Celular , Fluoresceína-5-Isotiocianato/farmacologia , Radical Hidroxila , Peroxidação de Lipídeos , Camundongos , Microscopia Eletrônica de Varredura , Espécies Reativas de Oxigênio , Sonicação , Resultado do Tratamento , Azul Tripano/farmacologia , Ultrassonografia
15.
Hell J Nucl Med ; 11(2): 91-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18815662

RESUMO

UNLABELLED: 5-fluorouracil (5-FU) has been used for cancer chemotherapy since more than four decades. There are reports of use of (18)F and (19)F analogues of 5-FU for tumor studies using PET and NMR respectively. However, study pertaining to its use in g-scintigraphy is still lacking. In the present study, we have optimized the methodology to radiolabel it with technetium-99m ((99m)Tc) efficiently and evaluated its physicochemical and biological properties. METHODS: 5-FU was radiolabeled with (99m)Tc and evaluated for physicochemical properties. Blood kinetics were studied in rabbits and biodistribution was carried out in normal as well as tumor bearing mice. In vivo and in vitro tumor uptake of the radiocomplex was evaluated in Ehrlich Ascites Tumor (EAT) bearing mice and human breast cancer cell line (MDA-MB-468). RESULTS: The resultant radiopharmaceutical ((99m)Tc-5-FU) has been found to be stable up to 24 h in both in vitro normal and physiological conditions. The blood clearance of the (99m)Tc-5-FU showed a bi-phasic pattern. High extraction of (99m)Tc-5-FU by the liver (36.41+/-2.79% of injected dose/g tissue) has been observed in mice, along with time dependent increase in the solid tumor to muscle ratio (2:1) measured at 4 h. Incubation of the radiocomplex with human breast cancer cells lines also showed time dependent increase in the uptake of the tracer. CONCLUSION: It can be concluded that the (99m)Tc-5-FU possesses selectivity towards solid tumor tissue.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/metabolismo , Fluoruracila/análogos & derivados , Compostos de Organotecnécio/farmacocinética , Animais , Linhagem Celular Tumoral , Fluoruracila/química , Fluoruracila/farmacocinética , Marcação por Isótopo/métodos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , Compostos de Organotecnécio/química , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
16.
Zhonghua Zhong Liu Za Zhi ; 30(10): 737-40, 2008 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-19173800

RESUMO

OBJECTIVE: To evaluate if 99mTc-HYNIC-annexin V may be used to detect the early chemotherapeutic effect and to determine the best timing for detecting apoptosis in vivo. METHODS: Annexin V was labeled with 99mTc using HYNIC as a bifunctional agent. Normal Kunming mice received inoculation of Ehrlich ascites cells into the right upper limb. After the tumor reached 1 cm in diameter, the mice were randomly divided into saline treatment group as control and cyclophosphamide (150 mg/kg injected intraperitoneally) treatment group. 99mTc-HYNIC-annexin V was injected intravenously at 1 h and 24 h after treatment. Region of interest technique (ROI) from the SPECT images taken at different time was used to get the ratio of tumor/limb in each group. TUNEL staining was used to detect apoptotic cells and the rates of positive stained cells were calculated. RESULTS: After treatment with saline, only little amount of the radiolabeled tracer could be seen in the tumor and showed weak image of the tumor. But after 24 h of treatment with cyclophosphamide, clear image on the tumor could be seen. 24 h after the treatment of cyclophosphamide, the ratio of tumor/limb was (6.27 +/- 0.24) which was much higher than that at 24 h after treatment with saline (2.36 +/- 0.18) and that at 1 h after cyclophosphamide treatment (4.00 +/- 0.38). At 24 h after cyclophosphamide treatment, TUNEL staining showed a significantly higher rate of apoptotic cells in the mice. CONCLUSION: 99mTc-HYNIC-annexin V can be used as an apoptosis-imaging agent to detect and evaluate the early curative effect after chemotherapy. The effective detection of apoptotic response in tumor with 99mTc-HYNIC-annexin V requires a 24 h interval after chemotherapy. SPECT images can be obtained at 60 min after injection of the imaging agent. It suggests that 99mTc-HYNIC-annexin V may become a promising agent for apoptosis-imaging in clinical application.


Assuntos
Anexina A5 , Apoptose , Carcinoma de Ehrlich/diagnóstico por imagem , Ciclofosfamida/uso terapêutico , Compostos de Organotecnécio , Animais , Anexina A5/farmacocinética , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Masculino , Camundongos , Transplante de Neoplasias , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Aleatória , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
17.
J Huazhong Univ Sci Technolog Med Sci ; 27(4): 471-4, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17828515

RESUMO

The validity of (99m)Tc-YIGSR, a novel receptor radio-tracer, in imaging the Ehrlich ascites tumor was evaluated. YIGSR, a pentapeptide of laminin, was labeled with (99m)Tc by using a bifunctional chelator S-Acetly-NH(3)-MAG(3). The MIBI was labeled with (99m)Tc by following the kit instruction. The mice of tumor group were intravenously injected 1-2 mCi of (99m)Tc-YIGSR or (99m)Tc-MIBI via caudal vein, immobilized and imaged under a Gamma camera. The same procedure was performed in mice of blockade group, in which the unlabeled YIGSR was previously injected to block the receptor-recognition sites, and inflammation group serving as control. The reverse-phase Sep-Pak C(18) chromatogram was found to have an essentially complete conjugation between YIGSR and S-Acetly-NH(3)-MAG(3). The conjugated YIGSR could be radio-labeled successfully with (99m)Tc at room temperature and neutral pH, with a radio-labeling yield of 62%. Without the chelator S-Acetly-NH(3)-MAG(3), the YIGSR was labeled with (99m)Tc at an efficiency of 4%. The imagological study revealed obvious tumor accumulation of (99m)Tc-YIGSR 15 min after the injection, and the uptake peaked after 3 h with a tumor-to-muscle ratio (T/M) of 11.36. The radio-tracer was slowly cleared up and resulted in a T/M of 3.01 at the 8th h after the injection. As for blocked group, the tumor uptake of radiotracer was significantly lower, with the highest T/M being 4.61 after 3 h and 0.89 after 8 h. The T/M was 3.72 at the 3rd h and 1.29 at the 8th h after the (99m)Tc-YIGSR injection in the inflammatory group. The T/M was significantly higher in tumor group than in inflammatory group or control group (P<0.001). In the 99mTc-MIBI group, the T/M was 1.40 at the 3rd h and 0.55 at the 8th h after the injection, which showed a significant difference as compared with (99m)Tc-YIGSR (P<0.001). It is concluded that YIGSR can be successfully radiolabelled by using S-Acetly-NH(3)-MAG(3). (99m)Tc-YIGSR has many advantages in tumor imaging, such as quick and clear visualization, high sensitivity and specificity, and satisfactory target/non-target ratio (N/NT). It promises to be tumor radio-tracer.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Compostos Radiofarmacêuticos , Receptores de Laminina/metabolismo , Tecnécio Tc 99m Mertiatida , Tecnécio Tc 99m Sestamibi , Animais , Camundongos , Traçadores Radioativos , Cintilografia
18.
Bull Exp Biol Med ; 143(4): 452-4, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18214298

RESUMO

The use of manganese bacteriopheophorbide characterized by a high relaxation capacity and selectively accumulating in the tumor as a contrast agent for magnetic resonance tomography significantly improves tumor contrasting against the background of normal tissues. The pharmacokinetics and selectivity of accumulation were studied by diffuse reflection spectroscopy.


Assuntos
Bacterioclorofilas/química , Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês/química , Animais , Bacterioclorofilas/farmacocinética , Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Meios de Contraste/farmacocinética , Compostos de Manganês/farmacocinética , Camundongos , Camundongos Nus , Cintilografia
19.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-634886

RESUMO

The validity of (99m)Tc-YIGSR, a novel receptor radio-tracer, in imaging the Ehrlich ascites tumor was evaluated. YIGSR, a pentapeptide of laminin, was labeled with (99m)Tc by using a bifunctional chelator S-Acetly-NH(3)-MAG(3). The MIBI was labeled with (99m)Tc by following the kit instruction. The mice of tumor group were intravenously injected 1-2 mCi of (99m)Tc-YIGSR or (99m)Tc-MIBI via caudal vein, immobilized and imaged under a Gamma camera. The same procedure was performed in mice of blockade group, in which the unlabeled YIGSR was previously injected to block the receptor-recognition sites, and inflammation group serving as control. The reverse-phase Sep-Pak C(18) chromatogram was found to have an essentially complete conjugation between YIGSR and S-Acetly-NH(3)-MAG(3). The conjugated YIGSR could be radio-labeled successfully with (99m)Tc at room temperature and neutral pH, with a radio-labeling yield of 62%. Without the chelator S-Acetly-NH(3)-MAG(3), the YIGSR was labeled with (99m)Tc at an efficiency of 4%. The imagological study revealed obvious tumor accumulation of (99m)Tc-YIGSR 15 min after the injection, and the uptake peaked after 3 h with a tumor-to-muscle ratio (T/M) of 11.36. The radio-tracer was slowly cleared up and resulted in a T/M of 3.01 at the 8th h after the injection. As for blocked group, the tumor uptake of radiotracer was significantly lower, with the highest T/M being 4.61 after 3 h and 0.89 after 8 h. The T/M was 3.72 at the 3rd h and 1.29 at the 8th h after the (99m)Tc-YIGSR injection in the inflammatory group. The T/M was significantly higher in tumor group than in inflammatory group or control group (P<0.001). In the 99mTc-MIBI group, the T/M was 1.40 at the 3rd h and 0.55 at the 8th h after the injection, which showed a significant difference as compared with (99m)Tc-YIGSR (P<0.001). It is concluded that YIGSR can be successfully radiolabelled by using S-Acetly-NH(3)-MAG(3). (99m)Tc-YIGSR has many advantages in tumor imaging, such as quick and clear visualization, high sensitivity and specificity, and satisfactory target/non-target ratio (N/NT). It promises to be tumor radio-tracer.


Assuntos
Carcinoma de Ehrlich/diagnóstico por imagem , Traçadores Radioativos , Compostos Radiofarmacêuticos , Receptores de Laminina/metabolismo , Tecnécio Tc 99m Mertiatida , Tecnécio Tc 99m Sestamibi
20.
Mol Imaging ; 5(3): 148-52, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16954029

RESUMO

Although apoptosis can be readily assessed in vitro with a variety of techniques, the detection of apoptosis in the in vivo setting poses a much more difficult proposition. Apoptosis in an organism is followed almost inevitably by rapid clearance of dying cells via phagocytosis, thus limiting the ability to analyze apoptosis in vivo using classical techniques. To address this issue, we developed a method to enhance in vivo apoptosis detection using pretreatment with chloroquine, an inhibitor of macrophage activity, in Swiss albino mice. This technique resulted in a significant increase in the accumulation of apoptotic cells induced by 5-fluorouracil, as detected by propidium iodide staining in solid and ascitic forms of Ehrlich ascitic tumors and in bone marrow cells. We further validated our technique using DNA fragmentation and endonuclease assays. Our results demonstrated that chloroquine pretreatment can significantly enhance accumulation of apoptotic cells in organisms, and we envision combining this method with modern imaging techniques to optimize in vivo detection of apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Cloroquina/farmacologia , Fluoruracila/farmacologia , Animais , Células da Medula Óssea/diagnóstico por imagem , Células da Medula Óssea/efeitos dos fármacos , Carcinoma de Ehrlich/diagnóstico por imagem , Carcinoma de Ehrlich/tratamento farmacológico , Cloroquina/uso terapêutico , Sinergismo Farmacológico , Masculino , Camundongos , Microscopia de Fluorescência/métodos , Radiografia
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