RESUMEN
Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. Inâ vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.
Asunto(s)
Adenina/análogos & derivados , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carbocianinas/farmacología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adenina/química , Adenina/farmacología , Animales , Anticuerpos Monoclonales/química , Antineoplásicos/química , Carbocianinas/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Linfoma de Células B Grandes Difuso/patología , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Piperidinas/química , Ingeniería de Proteínas , Inhibidores de Proteínas Quinasas/química , Electricidad EstáticaRESUMEN
For specific imaging of bacterial infections we aimed at targeting the exclusive bacterial iron transport system via siderophore-based radiotracers. De novo synthesis and radiolabeling yielded the salmochelin-based PET radiotracer [68Ga]Ga-RMA693, which showed a favourable biodistribution and a bacteria-specific uptake in an animal model of Escherichia coli infection.