Biodistribution and metabolism of targeted and nontargeted protein-chelate-gadolinium complexes: Evidence for gadolinium dissociation in vitro and in vivo

The intracellular metabolism of receptor-targeted ¹⁵³Gd-DTPA-glycoproteins was studied in vitro and in vivo. These agents bound to cell surface receptors, underwent receptor mediated endocytosis, and were rapidly degraded to a metabolite which co-migrated with a ¹⁵³Gd-DTPA-lysine standard on thin layer chromatography. The rates of dissociation of ¹⁵³Gd and ¹¹¹In from a glycoprotein-chelate conjugate were determined in vitro. Gadolinium readily dissociated, in a pH-sensitive manner, from glycoprotein-DTPA, and to a lesser degree glycoprotein-MX-DTPA. The biodistribution of targeted and blood pool ¹⁵³Gd ¹¹¹In labeled proteins also suggested that gadolinium dissociates from protein-DTPA and protein-MX-DTPA and their metabolites leading to an accumulation of gadolinium in bone. Metal-DTPA-glycoprotein agents targeted to cell surface receptors can still produce very high concentrations of radioactive or paramagnetic metals within the lysosome due to the high rate of accumulation afforded by receptor mediated endocytosis and the low release rate of metabolites such as metal-DTPA-lysine. However, the continued development of gadolinium based macromolecular agents will require improvements in bifunctional chelates.