RESUMO
BACKGROUND: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. METHODS: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. RESULTS: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. CONCLUSIONS: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.
Assuntos
Endopeptidases , Radioisótopos de Gálio , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Lutécio/química , Humanos , Animais , Camundongos , Distribuição Tecidual , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Gálio/química , Linhagem Celular Tumoral , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Gelatinases/antagonistas & inibidores , Gelatinases/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Feminino , Masculino , Nanomedicina TeranósticaRESUMO
PURPOSE: The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. METHODS: [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. RESULTS: [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. CONCLUSION: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging.
Assuntos
Glioblastoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Masculino , Animais , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Glioblastoma/diagnóstico por imagem , Radioisótopos de Gálio , Distribuição Tecidual , TemperaturaRESUMO
Las conductas autolesivas en niños y jóvenes con Trastorno del Espectro Autista (TEA) entrañan riesgos para su integridad física, afectan a sucalidad de vida, la de sus familias y dificultan su integración en el ámbito escolar y social, integración ya de por sí limitada por las característicaspropias de este tipo de trastornos. Aunque hay pocos estudios sobre autolesiones en esta población, en general se ha visto que, a mayor afectacióny menor nivel cognitivo, las conductas autolesivas son más frecuentes que en casos más leves. El objetivo de este trabajo fue revisar la eficaciade las intervenciones de tipo cognitivo-conductual para la reducción de conductas autolesivas en niños y jóvenes con TEA. Para ello se realizaronbúsquedas en PsycINFO, Scopus y Google Scholar. La revisión incluyó estudios en lengua inglesa o española sobre intervenciones de tipo cognitivo-conductual para reducir conductas autolesivas en niños y jóvenes con TEA; con muestras formadas por personas TEA entre 1 y 30 años quepresentaban conductas autolesivas; y realizados entre 1970 y 2022. De los 228 estudios identificados, solo 7 cumplieron los criterios de inclusión.Los estudios incluidos en la presente revisión incluyeron participantes entre los 3 y los 26 años diagnosticados con TEA y fueron publicados entre1974 y 2015, evidenciando la eficacia de las intervenciones cognitivo-conductuales. Aunque dichos estudios muestran resultados positivos tras lasintervenciones, su número es escaso, por lo que es necesario seguir investigando sobre la eficacia de las intervenciones de carácter cognitivo-conductual para reducir conductas autolesivas en niños y jóvenes con TEA. (AU)
Self-injurious behaviours in children and young people with Autism Spectrum Disorder (ASD) imply risks to their physical integrity and affect their quality of lifeand that of their families. In addition, they hinder their integration into the school and social environments, this being limited by the characteristics ofthis type of disorder. Although there is little information about self-harm in this population, in general it has been seen that the greater the affectationand the lower the cognitive level, the more prevalent self-injurious behaviours are. The aim of this study was to review the efficacy of cognitive-behavioral interventions for the reduction of self-injurious behaviors in children and youth with ASD. For it, we searched PsycINFO, Scopus and GoogleScholar. The review included studies in English or Spanish languages on cognitive-behavioral interventions to reduce self-injurious behaviors inchildren and youth with ASD; with samples consisting of individuals with ASD between 1 and 30 years of age presenting self-injurious behaviors;and conducted between 1970 and 2022. Of the 228 studies identified, only 7 met the inclusion criteria. The included studies included participantsbetween the ages of 3 and 26 years diagnosed with ASD and were published between 1974 and 2015, evidencing the efficacy of cognitive-behavioral interventions. Although these studies show positive post-intervention results, they are scarce in number. Further research is therefore neededon the effectiveness of behavioural and cognitive interventions to reduce self-injurious behaviours in children and young people with ASD. (AU)
Assuntos
Humanos , Criança , Adolescente , Transtorno do Espectro Autista/prevenção & controle , Comportamento AutodestrutivoRESUMO
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