Indium-111-Diethylenetriaminepentaacetic Acid-Octreotide Is Delivered in Vivo to Pancreatic, Tumor Cell, Renal, and Hepatocyte Lysosomes¹

To better understand the factors that govern the target-to-background ratios of ¹¹¹In-diethylenetriaminepentaacetic acid (DTPA) polypeptides, we studied ¹¹¹In-DTPA-octreotide and a model nontargeted compound, ¹¹¹In-DTPA-poly(d)lysine-biotin. We evaluated the fate of ¹¹¹-DTPA-octreotide after it localizes in somatostatin receptor-positive tissues and sought to determine why such a large fraction of these and other ¹¹¹In-DTPA-polypeptides accumulate in the liver and kidneys.

Biodistribution studies in rats with an implanted pancreatic adenocarcinoma demonstrated rapid accumulation of ¹¹¹In-DTPA-octreotide in the pancreas and tumor. Indium-111 also accumulated in the liver and kidneys. Subcellular fractionation of the liver, kidneys, tumor, and pancreas showed that the majority of the radioactivity copurified with lysosomal enzymes. Even at 1 h, little radioactivity was found in the fractions containing a cell surface enzyme. This suggests that in each tissue, the ¹¹¹In-DTPA-octreotide was rapidly shuttled from the cell surface to lysosomes. In the liver, hepatocyte lysosomes were separated from sinusoidal and Kupffer cell lysosomes by administering chloroquine prior to sacrifice. This density shift experiment indicated that ¹¹¹In-DTPA-octreotide accumulated predominantly in hepatocyte lysosomes.

A low molecular weight ¹¹¹In-DTPA-poly(d)lysine-biotin compound was synthesized, and biodistribution studies showed substantial renal accumulation. The poly(d)lysine backbone conferred resistance to degradation, and this fact allowed determination of the distribution of this compound at the cellular level using an antibiotin antibody and immuno-histochemical techniques. These experiments, as well as subcellular fractionation studies, demonstrated that the ¹¹¹In-DTPA-poly(d)lysine-biotin compound accumulated in the lysosomes of proximal renal tubular cells.

These results indicate that lysosomes play a critical role in the cellular physiology of radiolabeled polypeptides. Using these data, we propose a comprehensive model that summarizes the factors that govern the target to background ratios of radiolabeled polypeptides.