Synthesis, purification, and tumor cell uptake of 67Ga-deferoxamine--folate, a potential radiopharmaceutical for tumor imaging.
The vitamin folic acid was covalently linked to the chelating agent deferoxamine (DF) via an amide bond using a simple carbodiimide coupling reaction. A mixture of two isomers, DF--folate(alpha) and DF--folate(gamma), was produced involving the alpha- and gamma-carboxyl group of folic acid, respectively. These two isomers were separated by anion-exchange chromatography using a NH4HCO3 gradient. Competitive binding studies revealed that only the DF-folate(gamma) is recognized by the folate receptor on KB cells, interacting with an affinity comparable to unconjugated folic acid. The DF--folate conjugates were radiolabeled with the gamma-emitting radionuclide 67Ga3+ and tested for uptake by cultured KB cells overexpressing the folate receptor. The cellular accumulation of 67Ga-DF-folate(gamma) tracer exhibited rapid uptake kinetics in cell culture with a t1/2 of approximately 3 min. The KB cell association of 67Ga-DF--folate(gamma) was competitively blocked by free folic acid, indicating that uptake of the 67Ga-DF--folate(gamma) was specifically mediated by the folate receptor. Since the folate receptor is overexpressed on the surfaces of many neoplastic cells, these results suggest that 67Ga-DF--folate(gamma) complex might be useful as a diagnostic agent for noninvasive imaging of folate receptor-positing tumors.
Wang
S
S
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Lee
R J
RJ
Mathias
C J
CJ
Green
M A
MA
Low
P S
PS
D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002852:Chromatography, Ion Exchange; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism; D005710:Gallium Radioisotopes; D006801:Humans; D007624:KB Cells; D007700:Kinetics; D008168:Lung; D009369:Neoplasms / Q000000981:diagnostic imaging; D016719:Radioimmunodetection; D011956:Receptors, Cell Surface; D016339:Spectrometry, Mass, Fast Atom Bombardment
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005710:Gallium Radioisotopes; D011956:Receptors, Cell Surface; C099574:deferoxamine-gamma-folate conjugate; D005492:Folic Acid; D003676:Deferoxamine