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

James R. Duncan, Mary T. Stephenson, Herman P. Wu and Carolyn J. Anderson
James R. Duncan
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Mary T. Stephenson
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Herman P. Wu
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Carolyn J. Anderson
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DOI:  Published February 1997
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Abstract

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.

Footnotes

  • ↵1 This work was funded by NIH Grant R29CA64475 and by grants from Mallinckrodt Medical Inc.

  • ↵2 To whom requests for reprints should be addressed, at Mallinckrodt Institute of Radiology, 510 South Kingshighway Boulevard, St. Louis, MO 63110.

  • Received June 21, 1996.
  • Accepted December 19, 1996.
  • ©1997 American Association for Cancer Research.
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February 1997
Volume 57, Issue 4
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Indium-111-Diethylenetriaminepentaacetic Acid-Octreotide Is Delivered in Vivo to Pancreatic, Tumor Cell, Renal, and Hepatocyte Lysosomes
James R. Duncan, Mary T. Stephenson, Herman P. Wu and Carolyn J. Anderson
Cancer Res February 15 1997 (57) (4) 659-671;

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Indium-111-Diethylenetriaminepentaacetic Acid-Octreotide Is Delivered in Vivo to Pancreatic, Tumor Cell, Renal, and Hepatocyte Lysosomes
James R. Duncan, Mary T. Stephenson, Herman P. Wu and Carolyn J. Anderson
Cancer Res February 15 1997 (57) (4) 659-671;
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