TATIANA SANTANA BALOGH

TATIANA SANTANA BALOGH

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Comparative study of different methodologies for synthesis of nanogels as potential drug carriers
2023 - BALOGH, TATIANA S.
Nanogels are defined as nanometer-scale polymeric gels, considered innovative and promising nanomaterials for drug delivery systems. This joint Polish-Brazilian work aimed to contribute to the development of the area of production of nanogels by means of ionizing radiation, investigating different synthesis methodologies, namely gamma and electron beam-induced irradiation. Original and innovative method of nanogel synthesis via ultraviolet-induced radiation has been proposed in an unprecedented manner and successfully developed. Additionally, the possibility of conjugation of selected nanogels with technetium-99m (99mTc) has been investigated as a possible theranostic agent. In case of ionizing radiation-supported techniques influence of solution concentration, type of gas saturation and dose on physicochemical properties of irradiation products have been analysed. In the UV methodology different ratios of the number of OH radicals available in the system per number of monomeric units were evaluated with and without argon saturation. All samples were characterized in relation to weight-average molecular weight (Mw), Z-average radius of gyration (Rg), hydrodynamic radius (Rh) and second virial coefficient using DLS and SLS techniques. The ratio of the radius of gyration to the hydrodynamic radius (Rg/Rh), the polymer coil density (ρcoil), morphology by SEM and TEM, and topography by AFM were determined. Radiolabelling with technetium-99m was carried out both via direct and indirect methodology, in addition to purification and radiochemical stability tests. PVP K-90-based nanogels of different crosslink densities were successfully obtained in all proposed methods. It has been found that the use of nitrous oxide promoted higher number of hydroxyl radicals, favouring the formation of intramolecular crosslinking. The increase in the amount of OH radicals available in the medium (both by increase of the ionizing radiation dose and concentration of OH radical precursor (H2O2)) provided higher influence of intramolecular crosslinking. It was possible to radiolabel and purify PVP K-90 nanogels produced by e-beam and gamma irradiation with technetium-99m through [99mTc(CO)3(H2O)3]+.
Direct radiolabeling of PVP-nanogel from 99mTcO4
2023 - BALOGH, TATIANA S.; MARQUES, FABIO N.; KADLUBOWSKI, SLAWOMIR; LUGAO, ADEMAR B.
Nanogels are considered promising drug delivery systems for different pathologies, mainly associated with neurological disease, by intranasal administration since drug transport occurs via the olfactory nerve, causing rapid delivery to the brain. The present work aimed to evaluate a protocol for 99mTc labeling of poly(N-vinylpyrrolidone) (PVP) nanogel synthesized by an electron beam for future in vivo biodistribution assays. 10 mM PVP K-90 solution saturated with N2O was irradiated by e-beam using a dose of 7 kGy and a dose rate of 5.35 kGy/s. Nanoparticles characteristic was evaluated by DLS technique to determine the Rh and SLS to determine the Mw and Rg. Rg/Rh and ρcoil were calculated. The sample was morphologically characterized using AFM. The same analyzes were performed with a non-irradiated PVP solution. Radiolabeling was performed by mixing 0.55 mg of SnCl2.2H2O in 50 μL of HCl 0.1 M with (A) 450 μL 0.2 M NaOAc buffer, pH 4.1; (B) 200 μL 0.2 M NaOAc buffer, pH 4.1 and 0.5 M NaHCO3 buffer, pH 7.26; (C) filtered solution B in a 0.22 μm syringe filter. To the solutions (A), (B), and (C) were added 200 μL of nanogel (8.9 mg of PVP K-90), 100 μL of 99mTcO4- (860-980 μCi), and the samples were stirred at 500 rpm for 90 minutes at room temperature. The reaction was assessed by W3MM paper/acetone chromatography at the end of the process. All solutions were filtered through a 0.22 μm filter to remove 99mTcO2, as a previously validated process, and the radioactivity in the filter and the solution was measured. Finally, the solutions were concentred in the Amicon® (10 kD), and the radioactivity of the filtered and retained solution were measured too. The solution remaining on the filter was diluted with 300 μl of purified water and the concentration process was repeated twice. Filter content and the sum of filtered solutions 1 and 2 had the radioactivity measured to check labeling efficiency. Nanogel was obtained with an average for Rh of 12.49 nm, Rg of 6.8 nm, Mw of 1.32 x 106 g/mol, ρcoil of 786.98, and Rg/Rh of 0.620. High relief spherical structures were observed in the AFM images instead of the low roughness film observed in the non-irradiated PVP solution. Chromatographic analysis of the sample prepared only with NaOAc buffer (final pH 3.8) and of the sample with the mixture of buffers without previous filtration (final pH 6.8) indicated, respectively, 99.89 and 99.68% associated with the formation of 99mTc-PVP nanogel or 9mTc-colloid. In contrast, the sample prepared with the mixture of buffers and previously filtered (final pH 6.8) showed 80.10% of nonreduced 99mTcO4. Filtration results at 0.22 μm showed that the 9mTccolloid remains 100% retained in the filter, while free 99mTcO4 and 99mTc-PVP nanogel are filtered. Amicon® filtration confirmed 95.75% and 92% of 99mTc-PVP nanogel formation in the samples with NaOAc buffer and a mixture of buffers without previous filtration, respectively. It was possible to synthesize nanogel by electron beam, obtaining an average Rh of 12.49 nm. The labeling process with 99mTcO4- showed a high radiochemical yield in samples prepared with NaOAc buffer and a mixture of buffers without previous filtration.
Fabrication of green nanomaterials
2023 - THIPE, VELAPHI C.; FREITAS, LUCAS F.; LIMA, CAROLINE S.A.; BATISTA, JORGE G.S.; FERREIRA, ARYEL H.; OLIVEIRA, JUSTINE P.R. de; BALOGH, TATIANA S.; KADLUBOWSKI, SLAWOMIR; LUGAO, ADEMAR B.; KATTI, KATTESH V.
The purpose of this chapter is to discuss the production of biocompatible green nanomaterials for biomedical applications using green nanotechnology. To enhance drug loading and delivery, these nanomaterials are engineered with immunomodulatory ligands such as phytochemicals (Epigallocatechin gallate, Mangiferin, Resveratrol), proteins (albumin and papain), crosslinked hydrogels, and nanogels. The nanomaterials described herein are synthesized via redox potential of electron-dense phytochemicals that reduce metallic precursors to their stable corresponding nanoparticles and via water radiolysis with ionizing radiation as a green approach (due to the absence of any reducing agent) for use as radiosensitizers (albumin and papain nanoparticles) in nuclear medicine – theranostics applications. The phytochemicals facilitate the delivery of nanoparticles through receptor mediated endocytosis, while the proteins such as papain, due to their proteolytic action enhances the permeation of nanoparticles into tumor tissue, and albumin increase the pharmacokinetic efficiency of these nanoparticles. The nanoparticles developed have shown effectiveness against a variety of human cancers while posing no toxicity to normal tissue. Additionally, a pilot human clinical combing Ayurvedic medicine with green nanomedicine is given as a novel approach for treating breast cancer and other related illnesses. Finally, the importance of ecotoxicology for nanomaterials is discussed in order to provide safety data in relevant multiple species (fish, daphnia, algae, rodents, etc.) with paratope/epitope distributions for evaluating tissue cross-reactivity profiles in human tissues and to provide critical information on in vivo toxicity in order to predict the possible adverse effects of nanomaterials on human and environmental health as an effort to establish regulatory limits and ISO standards for nanomaterials.
Synthesis of poly(N-vinyl pyrrolidone) (PVP) nanogels by gamma irradiation using different saturation atmospheres
2022 - BALOGH, TATIANA S.; BONTURIM, EVERTON; VIEIRA, LUCAS D.; LUGAO, ADEMAR B.; KADLUBOWSKI, SLAWOMIR
Nanogels are internally crosslinked particles of nanometric size used in various fields e.g. as such as carriers in drug delivery systems. They can be produced using ionizing radiation in dilute aqueous solutions. This method is carried out in a pure polymer-solvent system, avoiding the addition of any additives such as monomers, surfactants, catalysts and crosslinking agents and no further purification step is necessary. Poly(N-vinyl pyrrolidone) (PVP K-90) nanogels were prepared by gamma irradiation in an aqueous solution. The samples were prepared in triplicate in multipurpose cobalt-60 gamma irradiator using 1, 10, 25 and 100 mM PVP solutions. Samples were irradiated in argon and nitrous oxide conditions with doses from 1 kGy up to 25 kGy with 10 kGy/h dose rate. The mean particle size (Rh) was determined by Dynamic Light Scattering (DLS) and radius of gyration (Rg) and weight-average molecular weight (Mw) by Static Light Scattering (SLS). These samples were morphologically characterized using Atomic Force Microscopy (AFM) and Transmission Electron Microscopy (TEM). Samples prepared with 100 mM PVP K-90 solution formed macroscopic gels, in the samples obtained with 25 mM PVP K-90 solution there was a prevalence of intermolecular crosslinking. On the other hand, in the samples generated with 10 mM PVP K-90 solution, there was a predominance of intramolecular crosslinking demonstrated in the tendency to: decrease in the radius of gyration (Rg), in the constancy of the weight-average molecular weight (Mw), in the increase in polymer coil density (ρcoil), in the Rg/Rh ratio (shape factor) around 1.0 indicating homogenous, internally cross-linked spheres, in the high relief spherical structures observed in the AFM images and in the spherical particles with high contrast observed in the TEM images. The saturation of the samples with nitrous oxide doubled formation of hydroxyl radicals, favoring the generation of polymeric radicals. Higher average number of radicals in each macromolecule contributed to the higher number of intramolecular crosslinks.
Influence of argon and nitrous oxide on the synthesis of PVP nanogels prepared by gamma radiation
2020 - BALOGH, T.S.; KADLUBOWSKI, S.; BONTURIM, E.; LUGAO, A.B.; VARCA, G.H.
Nanogels are innovative systems with great potential for use in chemotherapy, disease diagnosis, release of bioactive substances, vaccines, cell culture systems, biocatalysis, in the generation of bioactive scaffolds in regenerative medicine among other applications. The definition of this material can be directly derived from the definition of polymeric gel, that is, a two-component system consisting of a permanent three-dimensional network of linked polymer chains and solvent molecules filling the pores of this network. Its internal structure is similar to that of hydrogels however presents particle size range varying from 0 to 100 nm leading to several advantages. Nanogel production methods involve intramolecular crosslinking that can be achieved using ionizing radiation. This method avoids the addition of any additives allowing the reaction to be carried out in a pure polymer-solvent system and the production of nanogels for biomedical applications free from monomer and crosslinking agents or surfactants. In this work influence of argon and nitrous oxide on the formation of nanogels by gamma irradiation has been evaluated. The samples were prepared in duplicate in multipurpose cobalt-60 gamma irradiator using a 25 mM PVP solution. Samples were irradiated in argon and nitrous oxide conditions with doses from 1 kGy up to 25 kGy with 10 kGy/h dose rate. These samples were morphologically characterized using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) as well as the pristine PVP solution. The mean particle size of the samples and the polydispersity index was performed in equipment Zetasizer Nano ZS - Malvern® and the determination of radius of gyration and molecular weight was performed in equipment Heleos - Wyatt®. It was observed in the conditions evaluated that saturation with argon or nitrous oxide promoted similar results except for 25 kGy dose. At this dose larger mean particle size and radius of gyration were observed in the sample saturated with nitrous oxide.
An updated review of macro, micro, and nanostructured hydrogels for biomedical and pharmaceutical applications
2020 - LIMA, CAROLINE S.A. de; BALOGH, TATIANA S.; VARCA, JUSTINE P.R.O.; VARCA, GUSTAVO H.C.; LUGAO, ADEMAR B.; CAMACHO-CRUZ, LUIS A.; BUCIO, EMILIO; KADLUBOWSKI, SLAWOMIR S.
Hydrogels are materials with wide applications in several fields, including the biomedical and pharmaceutical industries. Their properties such as the capacity of absorbing great amounts of aqueous solutions without losing shape and mechanical properties, as well as loading drugs of different nature, including hydrophobic ones and biomolecules, give an idea of their versatility and promising demand. As they have been explored in a great number of studies for years, many routes of synthesis have been developed, especially for chemical/permanent hydrogels. In the same way, stimuli-responsive hydrogels, also known as intelligent materials, have been explored too, enhancing the regulation of properties such as targeting and drug release. By controlling the particle size, hydrogel on the micro- and nanoscale have been studied likewise and have increased, even more, the possibilities for applications of the so-called XXI century materials. In this paper, we aimed to produce an overview of the recent studies concerning methods of synthesis, biomedical, and pharmaceutical applications of macro-, micro, and nanogels.
Synthesis and characterization of PVP nanogels prepared by gamma radiation using 60Co source
2019 - BALOGH, T.S.; KADLUBOWSKI, S.; BONTURIM, E.; VARCA, G.; LUGAO, A.B.
Nanogels are promising and innovative systems in nanometer scale, with particle size range varying from 0 to 100 nm, of great potential in nanomedicine, pharmaceutics and bionanotechnology. They present several advantages such as capacity of injection into the circulation reaching target tissues and ability to deliver their payloads locally and intracellularly. Nanogels are defined as two-component system on nanometer scale consisting of a permanent three-dimensional network of linked polymer chains, and molecules of a solvent filling the pores of this network. They are formed by intramolecular crosslinking that can be achieved by the use of ionizing radiation, this method allows the formation of nanogels free of additives, rendering them non-toxic, a fundamental requirement for biomedical application. In this work, five samples of nanogels were developed using a 25 mM PVP solution. The samples were saturated with argon and prepared in multipurpose cobalt-60 gamma irradiator using doses of 1, 2, 5, 10 and 25 kGy at a dose rate of 10 kGy/hour corresponding, respectively, to samples A, B, C, D and E. These samples were morphologically characterized using atomic force microscopy (AFM) as well as the pristine PVP solution. The mean particle size of the samples as well as the determination of polydispersity index was performed in equipment Zetasizer Nano ZS - Malvern® and the determination of radius of gyration and molecular weight was realized in equipment Heleos - Wyatt®. The mean particle size of the samples A, B, C, D and E, were, respectively, 41.89, 46.85, 61.04, 62.79 and 62.11 nm and the mean particle size of the pristine PVP solution was 43.28 nm. The AFM results revealed the presence of spherical nanostructures in the samples prepared with dose equal to or more than 5 kGy (samples C, D and E). Under the conditions evaluated in the study the morphological characterization of the nanogels revealed that the doses of 5 kGy, 10 and 25 kGy are the most suitable doses for the nanogel formation as it led to spherical structures when compared to the other conditions assayed.
Estudo de purificação de Mo-99 por sublimação em forno tubular
2017 - DAMASCENO, MARCOS O.; LIMA, VINICIUS S.; BALOGH, TATIANA S.; FORBICINI, CHRISTINA A.L.G. de O.
Introdução: O 99Mo é um radioisótopo importante devido ao seu produto de decaimento - 99mTc, que atua como marcador molecular em cerca de 80% dos exames diagnósticos (Eur. J. Nucl. Med. Mol. Imag. 36;795,2009). Em muitos países, são empregadas técnicas cromatográficas para a obtenção do 99Mo de fissão de alta pureza, podendo ainda incluir etapas de complexação, precipitação ou sublimação dependendo do processo adotado. O projeto do reator multipróposito brasileiro (RMB) prevê a produção de radioisótopos, como 99Mo via fissão do 235U (Sci. Am. 98;82,2010). O nosso laboratório vem realizando estudos de possíveis etapas de purificação de 99Mo, visando o desenvolvimento de novas rotas de produção. Objetivo: Apresentar resultados preliminares de testes nas principais variáveis da etapa de sublimação do 99Mo como parte do processo de purificação. Os testes incluíram temperatura e tempo de sublimação, taxa de aquecimento e fluxo de gás de arraste, visando redução do tempo de processo e a máxima eficiência de recuperação de 99Mo. Métodos: Os experimentos partiram de uma solução de NH4MoO4 20 g.L-1 contendo uma pequena quantidade de 99Mo como radiotraçador, simulando uma solução em uma dada etapa do processo de purificação. Uma alíquota de 1 mL foi reservada para referência, enquanto outra alíquota de 1 mL foi levada à secura em um cadinho de platina sobre uma placa aquecida. O cadinho foi introduzido em um tubo de quartzo de um forno horizontal e aquecido. Um fluxo de ar para arraste dos vapores foi estabelecido. Após o resfriamento o tubo foi lavado internamente com 10 mL de solução de NaOH 1 M, uma alíquota de 1 mL foi retida desta solução, para contagem da atividade e cálculo de rendimento. As amostras foram analisadas em detector gama Ge hiperpuro em 739 KeV. Resultados: Foram observados depósitos de MoO3 no interior do tubo nas regiões próximas à saída do forno. Os testes com temperaturas já partir de 750°C mostraram excelentes rendimentos de recuperação (98 % ± 0,7). Devido à reduzida massa de óxido presente nas amostras, nos testes com temperatura de 800°C o tempo de sublimação de 5 mim foi suficiente para obter a saída de praticamente todo o material do cadinho. As curvas de aquecimento do forno são determinantes para a celeridade do processo, deste modo taxas de aquecimento de até 30 °C.min-1 foram aplicadas sem prejuízos de recuperação de 99Mo, valores maiores não foram testados por limitações do equipamento. Fluxos de arraste aplicados entre 3 e 9 mL.h-1 possibilitaram a formação de anéis bem definidos de MoO3 depositados a aproximadamente 10 cm do cadinho, facilmente visível dentro do tubo de quartzo, enquanto que sob fluxos acima de 15 mL.h-1 os depósitos apresentam-se mais difusos e com aumento de perdas por arraste. Conclusão: A técnica de sublimação em forno tubular permite a obtenção do 99Mo com elevada pureza e reduzidas perdas. A análise dos resultados permitirá melhor configuração dos parâmetros do forno, contribuindo para a maximização do rendimento de recuperação com redução do tempo total de processo. Os próximos testes incluirão amostras com (NH4)2SO4 ou (NH4)HCO3, simulando outras soluções de extração do molibdênio em um estágio prévio a sublimação.
Recovery of 131I from fission 99Mo production process by distillation method
2017 - DAMASCENO, MARCOS O.; BALOGH, TATIANA S.; FORBICINI, CHRISTINA A.L.G. de O.
The results of one of the recovery stages of 131I as a byproduct of the 99Mo fission production process are presented in this work. A modified wet-distillation apparatus was used for iodide purification and some work parameters were tested. The assays included iodide anion eluent, concentration of H2SO4, H2O2, the catalyst effect of MoO3, temperature and time process. The results of eluting anions demonstrated lower recovery of 131I using nitrate salt. The sulfate solution and its respective acid (H2SO4) at concentration 1.6 M, presented better results. Hydrogen peroxide was used as a main oxidant of the ions iodide, the experiments realized with 6 mL of H2O2 3% showed higher recovery than assays prepared with H2O2 higher and lower amount. Molybdenum oxide was evaluated as catalyst of iodine in solution; however, the results did not demonstrate an advantage in relation to its absence. In addition, the recovery of iodide was delayed at initial periods of the process in presence of the catalyst, leading to an increase on time process. Temperature decrease of distillation solution from 80 to 50 °C showed advantageous since the recovery yields were similar beside a lower wet drag to trap solution. Time distillation was carried out at least four hours with sampling each hour; the best times were between 1 and 2 hours. Shorter periods of distillation avoid dilution of the capture solution on the further recovery process. Several parameters were studied and it was possible to set up system that provided 131I recovery around 50% yield.