ANDRE LUIS LAPOLLI
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Resumo IPEN-doc 30273 Microfluidic circuit applied to the concentration of 18F for the production of radiopharmaceuticals2023 - GOMES, ANTONIO A.; NARIO, ARIAN P.; LAPOLLI, ANDRE L.; LANDULFO, E.; BERNARDES, EMERSON S.; ROSSI, WAGNER deIntroduction: Microfluidics is becoming a promising technology for synthesizing [18F]-labeled radiopharmaceuticals, reducing costs, reagents, and increasing activity [1]. Conversely, current commercial production of such radiopharmaceuticals for clinical diagnosis by positron emission tomography (PET) imaging requires dedicated and expensive equipment, only available in specialized facilities to produce only one type of 18F radiopharmaceutical [2]. So, as the demand for PET increases, the use of microfluidics becomes essential for this commercial production, and, in this sense, this work presents the results of a developed “micro-cartridge” microfluidic chip applied to the 18F retention and elution process that can improve all the production aspects. Methodology: The micro-cartridge was machined in borosilicate optical glass – BK7 using the ultrashort pulse laser ablation technique. After micromachining, the micro-cartridge is filled with the same resin used in the conventional anionic synthesis cartridge (Waters Accel Plus QMA Light cartridge). Both are later submitted to comparative performance tests to evaluate the radiochemical efficiency in the 18F retention and elution phase between them. Results and discussion: Four comparative tests were performed for both phases (first stage of synthesis of radiopharmaceuticals labeled with 18F), with activities (55.5 ± 11.1 Mbq and 9.2 ± 0.4 Gbq; n = 2). The results showed that the micro-cartridge is equivalent to the conventional cartridge (QMA Plus Light) in the retention phase, presenting a radiochemical efficiency of 99.3% ± 0.7 vs 99.6% ± 0.3, respectively. However, in the 18F elution phase, the micro-cartridge showed a radiochemical efficiency of 93% ± 0.2, and the conventional cartridge had a maximum of 77.4% ± 15.5, showing the great advantage of the micro-cartridge. The hypothesis that supports the superiority of the results of micro-cartridge efficiencies in the elution phase is the high surface-volume ratio, which leads to the prevalence of surface phenomena such as mass transfers and faster reaction syntheses, which occur in microfluidic systems. Although the microfluidic systems studied for radiopharmaceuticals have existed for almost 20 years, the use of the ultrashort pulse laser technique and the type of material used in the micro-cartridge development are not commonly reported. Conclusions: Integrating an anion exchange micro-cartridge on a chip with the ultrashort pulse laser ablation technique opens the door to smaller, and more efficient radiopharmacy chips for producing 18F radiopharmaceuticals. The first unprecedented experimental results in Brazil demonstrate that the initial stages of production of ready-to-use doses for humans (pre-concentration of fluorine) can be carried out with greater efficiency in the elution parameters of 18F compared to synthesis with a conventional cartridge.Resumo IPEN-doc 30026 Microfluídica, uma tecnologia aplicada à concentração de 18F para produção de radiofármacos2023 - GOMES, ANTONIO A.; NARIO, ARIAN P.; LAPOLLI, ANDRE L.; LANDULFO, EDUARDO; BERNARDES, EMERSON S.; ROSSI, WAGNER deIntrodução. O uso de radiofármacos marcados com 18F para o diagnóstico clínico por imagem PET (tomografia por emissão de pósitrons) de diversas doenças tem aumentado consideravelmente. O maior radiofármaco aplicado a diagnósticos com PET é o [18F]-2-desoxi-2-fluoro-D-glicose (FDG) e a sua preparação requer a utilização de equipamentos especializados (e caros) para proteger o farmacêutico que o prepara. Assim, à medida que a demanda de radiofármacos PET aumentar, colocará uma pressão significativa nas instalações de produção de traçadores PET, a qual necessitará de investimento em novas tecnologias de produção de radiofármacos. Uma tecnologia chave desenvolvida nos últimos tempos tem sido o uso de sistemas microfluídicos. Os dispositivos microfluídicos oferecem muitas vantagens para a síntese de radiofármacos de curta duração (por exemplo, 18F)tais como: reações mais rápidas, transferência de calor eficiente, alta relação superfície – volume e rendimentos mais elevados. Embora os sistemas microfluídicos estudados para radiofármacos existam há quase 20 anos, no Brasil, até onde sabemos, esta tecnologia e estudo é inédita. Objetivos. Apresentar os primeiros resultados no desenvolvimento de um chip microfluídico para uma “microcoluna” destinada ao processo de retenção e eluição de 18F. Metodologia. A microcoluna foi usinada em vidro óptico de borosilicato – BK7 utilizando a técnica de ablação com laser de pulsos ultracurtos. Após a microusinagem, a microcoluna é preenchida com a mesma resina utilizada no cartucho convencional de síntese “Sep-Pak Accell Plus QMA Plus Light” da fabricante Waters™. Ambas são posteriormente submetidas a testes de desempenho comparativos de eficiência na fase de retenção e eluição de 18F. Resultados. Foram realizados 4 testes comparativos para ambas as fases (primeira etapa da síntese de 18F-FDG), com atividades (1,5 ± 0,3 mCi e 248 ± 11 mCi; “n = 2”). Os resultados demostraram que a eficiência da microcoluna é equivalente à da coluna convencional (QMA Plus Light) na fase de retenção (99,3% ± 0,67 vs99,6% ± 0,32). No entanto, na fase de eluição de 18F, houve uma diferença significativa entre ambas (99,93% ±0,18 vs 77,38% ± 15,54), destacando a grande vantagem da microcoluna. Conclusão. A integração do cartucho de troca iônica em um chip, com a técnica de ablação com laser de pulso ultracurto, abre as portas para chips de radiofarmácia menores e mais eficientes para a produção de 18F-FDG e outros compostos. Os resultados experimentais inéditos no Brasil demonstram que as etapas iniciais da produção de doses prontas para humanos (pré-concentração de flúor) podem ser realizadas com uma eficiência superior nos parâmetros de eluição do 18Fem comparação a síntese com cartucho convencional.Artigo IPEN-doc 28825 Synthesis of a 2‑nitroimidazole derivative N‑(4‑[18F]fluorobenzyl)‑2‑(2‑nitro‑1H‑imidazol‑1‑yl)‑acetamide ([18F]FBNA) as PET radiotracer for imaging tumor hypoxia2022 - NARIO, ARIAN P.; WOODFIELD, JENILEE; SANTOS, SOFIA N. dos; BERGMAN, CODY; WUEST, MELINDA; ARAUJO, YASNIEL B.; LAPOLLI, ANDRE L.; WEST, FREDERICK G.; WUEST, FRANK; BERNARDES, EMERSON S.Background: Tissue hypoxia is a pathological condition characterized by reducing oxygen supply. Hypoxia is a hallmark of tumor environment and is commonly observed in many solid tumors. Non-invasive imaging techniques like positron emission tomography (PET) are at the forefront of detecting and monitoring tissue hypoxia changes in vivo. Results: We have developed a novel 18F-labeled radiotracer for hypoxia PET imaging based on cytotoxic agent benznidazole. Radiotracer N-(4-[18F]fluorobenzyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide ([18F]FBNA) was synthesized through acylation chemistry with readily available 4-[18F]fluorobenzyl amine. Radiotracer [18F]FBNA was obtained in good radiochemical yields (47.4 ± 5.3%) and high radiochemical purity (> 95%). The total synthesis time was 100 min, including HPLC purification and the molar activity was greater than 40 GBq/µmol. Radiotracer [18F]FBNA was stable in saline and mouse serum for 6 h. [18F]FBNA partition coefficient (logP = 1.05) was found to be more lipophilic than [18F]EF-5 (logP = 0.75), [18F]FMISO (logP = 0.4) and [18F]FAZA (logP = − 0.4). In vitro studies showed that [18F]FBNA accumulates in gastric cancer cell lines AGS and MKN45 under hypoxic conditions. Conclusions: Hence, [18F]FBNA represents a novel and easy-to-prepare PET radioligand for imaging hypoxia.