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Introduction. The currently available dosimetry techniques in computed tomography can be inaccurate which overestimate the absorbed dose. Therefore, we aimed to provide an automated and fast methodology to more accurately calculate the SSDE usingDwobtained by using CNN from thorax and abdominal CT study images.Methods. The SSDE was determined from the 200 records files. For that purpose, patients' size was measured in two ways: (a) by developing an algorithm following the AAPM Report No. 204 methodology; and (b) using a CNN according to AAPM Report No. 220.Results. The patient's size measured by the in-house software in the region of thorax and abdomen was 27.63 ± 3.23 cm and 28.66 ± 3.37 cm, while CNN was 18.90 ± 2.6 cm and 21.77 ± 2.45 cm. The SSDE in thorax according to 204 and 220 reports were 17.26 ± 2.81 mGy and 23.70 ± 2.96 mGy for women and 17.08 ± 2.09 mGy and 23.47 ± 2.34 mGy for men. In abdomen was 18.54 ± 2.25 mGy and 23.40 ± 1.88 mGy in women and 18.37 ± 2.31 mGy and 23.84 ± 2.36 mGy in men.Conclusions. Implementing CNN-based automated methodologies can contribute to fast and accurate dose calculations, thereby improving patient-specific radiation safety in clinical practice.
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Algoritmos , Doses de Radiação , Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Masculino , Feminino , Tamanho Corporal , Redes Neurais de Computação , Software , Automação , Tórax/diagnóstico por imagem , Adulto , Abdome/diagnóstico por imagem , Radiometria/métodos , Radiografia Torácica/métodos , Pessoa de Meia-Idade , Processamento de Imagem Assistida por Computador/métodos , Radiografia Abdominal/métodos , IdosoRESUMO
The development of rHDL-radionuclide theragnostic systems requires evaluation of the absorbed doses that would be produced in healthy tissues and organs at risk. Technetium-99m is the most widely used radionuclide for diagnostic imaging, therefore, the design of theragnostic reconstituted high density-lipoprotein (rHDL) nanosystems labeled with Technetium-99m offers multiple possibilities. OBJECTIVE: To determine the biokinetics, radiopharmacokinetics and estimate the absorbed doses induced in healthy organs by Technetium-99m transported in the core and on the surface of rHDL. METHODS: Biokinetic and radiopharmacokinetic models of rHDL/[99mTc]Tc-HYNIC-DA (Technetium-99m in the core) and [99mTc]Tc-HYNIC-rHDL (Technetium-99m on the surface) were calculated from their ex vivo biodistribution in healthy mice. Absorbed doses were estimated by the MIRD formalism using OLINDA/EXM and LMFIT softwares. RESULTS: rHDL/[99mTc]Tc-HYNIC-DA and [99mTc]Tc-HYNIC-rHDL show instantaneous absorption in kidney, lung, heart and pancreas, with slower absorption in spleen. rHDL/[99mTc]Tc-HYNIC-DA is absorbed more slowly in the intestine, while [99mTc]Tc-HYNIC-rHDL is absorbed more slowly in the liver. The main target organ for rHDL/[99mTc]Tc-HYNIC-DA, which is hydrophobic in nature, is the liver, whereas the kidney is for the more hydrophilic [99mTc]Tc-HYNIC-rHDL. Assuming that 925 MBq (25 mCi) of Technetium-99m, carried in the core or on the surface of rHDL, are administered, the maximum tolerated doses for the organs of greatest accumulation are not exceeded. CONCLUSION: Theragnostic systems based on 99mTc-labeled rHDL are safe from the dosimetric point of view. The dose estimates obtained can be used to adjust the 99mTc-activity to be administered in future clinical trials.
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Nanopartículas , Tecnécio , Camundongos , Animais , Lipoproteínas HDL , Distribuição Tecidual , Radiometria/métodosRESUMO
Although liposomal doxorubicin (LPD) is widely used for cancer treatment, knowledge concerning the toxicity induced by this drug in healthy organs and tissues is limited. LPD-induced toxicity studies relative to free doxorubicin (DOX) have focused on cardiotoxicity in tumor-bearing animals. On the other hand, the results on DOX-induced cardiotoxicity depending on gender are controversial. One of the manifestations of toxicity is tissue inflammation. 67Ga-citrate has been used for decades to assess inflammation in various pathologies. In this work, the ex vivo biodistribution of 67Ga-citrate is used to evaluate induced multi-organ toxicity in healthy 10-week-old male and female CD1 mice treated for 5 weeks with LPD. Toxicity in males, determined by 67Ga-citrate, was evident only in the target organs of liposomes (spleen, liver, kidneys, and lungs); the average weight loss was 11% and mortality was 14%. In female mice, 67Ga-citrate revealed a cytotoxic effect in practically all organs, the average weight loss was 37%, and the mortality after the last dose of LPD was 66%. These results confirm the usefulness of 67Ga-citrate and the importance of stratifying by sex in the toxicological evaluation of drugs.
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Antibióticos Antineoplásicos , Cardiotoxicidade , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/tratamento farmacológico , Ácido Cítrico/toxicidade , Doxorrubicina/análogos & derivados , Doxorrubicina/toxicidade , Feminino , Inflamação , Lipossomos/farmacologia , Masculino , Camundongos , Polietilenoglicóis , Distribuição Tecidual , Redução de PesoRESUMO
Reconstituted high-density lipoprotein (rHDL) nanoparticles are excellent transporters of molecules and very useful for targeted therapy as they specifically recognize the scavenger receptor, class B1 (SR-B1) that is present on the surface of a wide range of tumor cells. However, they have rarely been employed to transport photosensitizers (PS) for photodynamic therapy (PDT). Rhodamine (R) compounds have been dismissed as useful PSs for PDT due to their low 1O2 production, excitation wavelengths with little tissue penetration, and poor selectivity for tumor cells. It was recently demonstrated that when irradiating at 532 nm or with Cerenkov radiation (CR) from a ß-emitting radionuclide, R123, R6G, and RB undergo electron transfer reactions (type I reaction) with folic acid. R6G also produces type I reactions with O2. In this work, the photodynamic effects of the rHDL-R system were evaluated in vitro. rHDL nanoparticles loaded with R123, R6G, and RB were synthesized, and the PS was internalized into T47D tumor cells. When cells were irradiated with a 532-nm laser in the presence of an rHDL-R systems, a cytotoxic photodynamic effect was obtained in the order R6G > R123 > RB. In the presence of CR from a 177Lu source, cytotoxicity showed the order R6G > RB > R123. The higher cytotoxicity induced by R6G in both cases corresponds to higher cellular internalization and larger production of type I and II reactions. Thus, in this work, it is proposed that rHDL-R/177Lu system can be applied in theragnostics as a multimodal radiotherapy-PDT-imaging system (imaging by SPECT or Cerenkov) and in hypoxic solid tumors in which external radiation is not effective and 177Lu-CR acts as light source.
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Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Lipoproteínas HDL , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , RodaminasRESUMO
Recently, it was demonstrated that doxorubicin (Dox.HCl), a chemotherapeutic agent, could be photoactivated by Cerenkov radiation (CR). The objective of the present work was to develop a multimodal chemotherapy-radiotherapy-photodynamic therapeutic system based on reconstituted high-density lipoprotein (rHDL) loaded with Dox.HCl and 177Lu-DOTA. 177Lu acts as a therapeutic radionuclide and CR source. The system can be visualized by nuclear imaging. Fluorescence microscopy showed that rHDL-Dox specifically recognized cancer cells (T47D) that are positive for SR-B1 receptors. Encapsulated Dox.HCl was released into the cells and produced reactive oxygen species when irradiated with a 450-nm laser (photodynamic effect). The same effect occurred when Dox.HCl was irradiated by 177Lu CR. Through in vitro experiments, it was confirmed that the addition of 177Lu-DOTA to the rHDL-Dox nanosystem did not affect the specific recognition of SR-B1 receptors expressed in cells, or the cellular internalization of 177Lu-DOTA. The toxicity induced by the rHDL-Dox/177Lu nanosystem in cell lines with high (T47D and PC3), poor (H9C2) and almost-zero (human fibroblasts (FB)) expression of SR-B1 was evaluated in vitro and confirmed the synergy of the combined chemotherapy-radiotherapy-photodynamic therapeutic effect; this induced toxicity was proportional to the expression of the SR-B1 receptor on the surface of the cells used. The HDL-Dox/177Lu nanosystem experienced uptake by tumor cells and the liver-both tissues with high expression of SR-B1 receptors-but not by the heart. 177Lu CR offered the possibility of imparting photodynamic therapy where laser light could not reach.
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Antineoplásicos , Portadores de Fármacos , Fotoquimioterapia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Lipoproteínas HDL , Lutécio/farmacologia , Medicina de Precisão , Radioisótopos/farmacologiaRESUMO
The search for methods that identify early toxicity, induced by chemotherapy, is urgent. Changes in the biodistribution of radiopharmaceuticals could give information on early toxicity. Ten-week-old CD1 male mice were divided into four groups. Two groups were administered a weekly dose of 5 mg/kg of doxorubicin hydrochloride (DOX) for 5 weeks and the control groups were administered saline solution. One week after the end of treatment, the biodistribution of 18F-FDG and 67Ga-citrate were carried out, as was the quantification of plasma enzymes CK, CK-MB, LDH and AST. All enzymes were higher in the treated animals, but only significant (p < 0.05) in the case of CK-MB. 18F-FDG uptake increased in all organs of treated animals except retroperitoneal fat, being significant in spleen, brain, heart, liver, lung, kidney, and inguinal fat. 67Ga-citrate had a more complex pattern. The uptake in the DOX group was higher in spleen, lung, kidney, testes, and gonadal fat, it did not change in brain, heart, and liver, and it was lower in the rest of the organs. It only showed significant differences in lung and pancreas. A thorough discussion of the possible causes that produced the change in biodistributions of both radiopharmaceuticals is included. The pilot study showed that both radiopharmaceuticals could identify early multi-organ toxicity induced by DOX. Although 18F-FDG seems to be better, 67Ga-citrato should not be ruled out a priori. The detection of early toxicity would serve to adopt treatments that prevent its progression, thus improving patient's quality of life.
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Distribuição Tecidual , Animais , Ácido Cítrico , Doxorrubicina/toxicidade , Fluordesoxiglucose F18 , Masculino , Camundongos , Projetos Piloto , Qualidade de VidaRESUMO
AIM: The aim of the present work was to determine if both ovariectomy (OVX) and type 2 diabetes mellitus (T2DM) can change X-ray absorptiometry until reach the osteoporosis condition. RESULTS: The segmentation allowed us to quantitatively determine the X-ray absorption in the femurs of mice subjected to OVX, T2DM and both pathologies together. CONCLUSIONS: The test subjects suffering from the mentioned pathologies separately or together, did not reach the osteoporosis condition when they were 30 weeks old.
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Diabetes Mellitus Experimental/diagnóstico por imagem , Fêmur/diagnóstico por imagem , Ovariectomia , Absorciometria de Fóton , Animais , Densidade Óssea , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Feminino , Camundongos , Osteoporose/complicações , Osteoporose/diagnóstico por imagemRESUMO
Doxorubicin (DOX), an effective chemotherapeutic agent, has a wide excitation band centred at 480 nm. Cerenkov radiation (CR) is considered an internal light source in photodynamic therapy (PDT). DOX could be photoactivated by CR and thus, enhancing its cytotoxicity. In this work, 18F-FDG was used to evaluate the effect of Cerenkov radiation on DOX, in comparison to irradiation with a 450-nm laser beam, in terms of ROS production. The production of 1O2 and O2â- reactive species during DOX irradiation was detected indirectly by ABMA and DCPIP bleaching, respectively. The cytotoxic effect of the DOX / 18F-FDG CR system was evaluated in the T47D breast cancer cell line. The irradiation of DOX produced 1O2 and O2â- species using both 18F-FDG CR and a 450-nm laser beam. The majority reactive species produced in both cases was 1O2; a favourable result, given the greater cytotoxicity of this species. The viability of T47D cells in presence of DOX (5 nM), 18F-FDG (37.5 µCi) and DOX (5 nM)/18F-FDG (37.5 µCi) was (86 ± 9)%, (84 ± 8)% and (64 ± 5)%, respectively; these results suggest a synergistic cytotoxic effect derived from the cytotoxic activity of DOX and its photoactivation by 18F-FDG CR. It is worth noting that the system could be optimized in terms of DOX concentration and 18F-FDG activity for better results. Due to the fact that 18F-FDG is widely used in nuclear imaging, the DOX/18F-FDG system also possesses theragnostic characteristics. Thus, in this work, it is demonstrated that DOX can be used in a dual therapy system based on chemotherapy-PDT when 18F-FDG CR is used as a DOX excitation source.
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Doxorrubicina/química , Fluordesoxiglucose F18/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/efeitos da radiação , Humanos , Cinética , Lasers , Fotodegradação , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo , Superóxidos/química , Superóxidos/metabolismoRESUMO
Cerenkov radiation (CR) is the emission of UV-vis light generated by the de-excitation of the molecules in the medium, after being polarized by an excited particle traveling faster than the speed of light. When ß particles travel through tissue with energies greater than 219 keV, CR occurs. Tissues possess a spectral optical window of 600 to 1100 nm. The CR within this range can be useful for quantitative preclinical studies using optical imaging and for the in-vivo evaluation of Lu177-radiopharmaceuticals (ß-particle emitters). The objective of our research was to determine the experimental emission light spectrum of Lu177-CR and evaluate its transmission properties in tissue as well as the feasibility to applying CR imaging in the preclinical studies of Lu177-radiopharmaceuticals. The theoretical and experimental characterizations of the emission and transmission spectra of Lu177-CR in tissue, in the vis-NIR region (350 to 900 nm), were performed using Monte Carlo simulation and UV-vis spectroscopy. Mice Lu177-CR images were acquired using a charge-coupled detector camera and were quantitatively analyzed. The results demonstrated good agreement between the theoretical and the experimental Lu177-CR emission spectra. Preclinical CR imaging demonstrated that the biokinetics of Lu177-radiopharmaceuticals in the main organs of mice can be acquired.
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Lutécio , Imagem Óptica/métodos , Radioisótopos , Compostos Radiofarmacêuticos , Animais , Partículas beta , Linhagem Celular Tumoral , Radiação Eletromagnética , Estudos de Viabilidade , Humanos , Lutécio/química , Lutécio/farmacocinética , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
The therapeutic potential of 177Lu-iPSMA on hypoxic cancer cells has not been yet demonstrated. The aim of this work was to evaluate the radiation dose effect of 177Lu-iPSMA on viability and DNA damage in U87MG human glioma cells subjected to hypoxia-mimetic conditions. U87MG cells treated with 177Lu-iPSMA were incubated with CoCl2 in order to induce hypoxia-mimetic conditions. The cytotoxic and genotoxic effect was evaluated with an in vitro viability test and a neutral comet assay. 177Lu-iPSMA decreased the cell viability and induced DNA double strand breaks in U87MG human glioma cells under hypoxia-mimetic conditions. 177Lu-iPSMA produced the maximum effect at 48â¯h, suggesting that this radiopharmaceutical could be used as a strategy for the treatment of human glioma hypoxic cells.