RESUMEN
Proteins, as a major component of organisms, are considered the preferred biomaterials for drug delivery vehicles. Hemoglobin (Hb) has been recently rediscovered as a potential drug carrier, but its use for biomedical applications still lacks extensive investigation. To further explore the possibility of utilizing Hb as a potential tumor targeting drug carrier, we examined and compared the biodistribution of Hb in healthy and lung tumor-bearing mice, using for the first time 89Zr labelled Hb in a positron emission tomography (PET) measurement. Hb displays a very high conjugation yield in its fast and selective reaction with the maleimide-deferoxamine (DFO) bifunctional chelator. The high-resolution X-ray structure of the Hb-DFO complex demonstrated that cysteine ß93 is the sole attachment moiety to the αß-protomer of Hb. The Hb-DFO complex shows quantitative uptake of 89Zr in solution as determined by radiochromatography. Injection of 0.03 mg of Hb-DFO-89Zr complex in healthy mice indicates very high radioactivity in liver, followed by spleen and lungs, whereas a threefold increased dosage results in intensification of PET signal in kidneys and decreased signal in liver and spleen. No difference in biodistribution pattern is observed between naïve and tumor-bearing mice. Interestingly, the liver Hb uptake did not decrease upon clodronate-mediated macrophage depletion, indicating that other immune cells contribute to Hb clearance. This finding is of particular interest for rapidly developing clinical immunology and projects aiming to target, label or specifically deliver agents to immune cells.
Asunto(s)
Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos , Hemoglobinas/farmacocinética , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Animales , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Deferoxamina/análogos & derivados , Deferoxamina/farmacocinética , Portadores de Fármacos/química , Femenino , Hemoglobinas/química , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos/química , Radioisótopos/farmacocinética , Distribución Tisular , Circonio/química , Circonio/farmacocinéticaRESUMEN
The most widely cited procedures for radiolabeling antibodies with zirconium-89 for immuno-PET require multi-milligram amounts of antibody which can be cost-prohibitive, particularly during the research and development process. We therefore sought to develop a reliable (89)Zr-radiolabeling procedure that provides high radiochemical yields at the microgram scale.