Indium-111-diethylenetriaminepentaacetic acid-octreotide is delivered in vivo to pancreatic, tumor cell, renal, and hepatocyte lysosomes.

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 111In-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 immunohistochemical 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.

[1]  Wendy S. Becker,et al.  Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  M. Welch,et al.  In vitro and in vivo evaluation of copper-64-octreotide conjugates. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  T. Visser,et al.  Effect of dose and specific activity on tissue distribution of indium-111-pentetreotide in rats. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[4]  A. Chiti,et al.  Indium-111-DTPA-octreotide Scintigraphy Modulation by Treatment with Unlabelled Somatostatin Analogue in Smali-Cell Lung Cancer , 1995, Tumori.

[5]  M. Brechbiel,et al.  Effect of metabolism on retention of indium-111-labeled monoclonal antibody in liver and blood. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[6]  D. Rauh.  Progress and promise. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[7]  T. Visser,et al.  Radiotherapy with a Radiolabeled Somatostatin Analogue, [111In‐DTPA‐d‐Phe1]‐Octreotide , 1994 .

[8]  G. Griffiths,et al.  The processing and fate of antibodies and their radiolabels bound to the surface of tumor cells in vitro: a comparison of nine radiolabels. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[9]  A. Yokoyama,et al.  A biological method to evaluate bifunctional chelating agents to label antibodies with metallic radionuclides. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[10]  A. Fischman,et al.  A ticket to ride: peptide radiopharmaceuticals. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[11]  M. Welch,et al.  Intracellular metabolism of indium-111-DTPA-labeled receptor targeted proteins. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[12]  D. Miller,et al.  Mechanisms mediating renal secretion of organic anions and cations. , 1993, Physiological reviews.

[13]  T. Yokota,et al.  Microautoradiographic analysis of the normal organ distribution of radioiodinated single-chain Fv and other immunoglobulin forms. , 1993, Cancer research.

[14]  Min Li,et al.  Synthesis, metal chelate stability studies, and enzyme digestion of a peptide-linked DOTA derivative and its corresponding radiolabeled immunoconjugates. , 1993, Bioconjugate chemistry.

[15]  R. Wattiaux,et al.  Chloroquine allows to distinguish between hepatocyte lysosomes and sinusoidal cell lysosomes. , 1993, Biochemical and biophysical research communications.

[16]  T. Yokota,et al.  Differential metabolic patterns of iodinated versus radiometal chelated anticarcinoma single-chain Fv molecules. , 1992, Cancer research.

[17]  J. Weinstein,et al.  Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. , 1992, Cancer research.

[18]  E P Krenning,et al.  Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[19]  K. Fujimori,et al.  Barrier ' ' Microscopic Tumor Nodules : Consequences of a ' ' Binding Site An Analysis of Monoclonal Antibody Distribution in Updated , 2006 .

[20]  J. Konishi,et al.  A novel bifunctional metabolizable linker for the conjugation of antibodies with radionuclides. , 1991, Bioconjugate chemistry.

[21]  C. Dence,et al.  Antibody fragments labeled with fluorine-18 and gallium-68: in vivo comparison with indium-111 and iodine-125-labeled fragments. , 1991, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[22]  T. Visser,et al.  In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats. , 1991, Life sciences.

[23]  L. Kvols,et al.  Distribution of somatostatin receptors in normal and tumor tissue. , 1990, Metabolism: clinical and experimental.

[24]  R K Jain,et al.  Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. , 1990, Cancer research.

[25]  A. Fischman,et al.  Quo vadis radioimmune imaging. , 1989, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[26]  L. Orci,et al.  Binding and internalization of somatostatin, insulin, and glucagon by cultured rat islet cells. , 1989, The Journal of clinical investigation.

[27]  G. Denardo,et al.  Effect of different linkages between chelates and monoclonal antibodies on levels of radioactivity in the liver. , 1989, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[28]  K. D. Hardman,et al.  Single-chain antigen-binding proteins. , 1988, Science.

[29]  J. Klijn,et al.  Absence of somatostatin receptors in human exocrine pancreatic adenocarcinomas. , 1988, Gastroenterology.

[30]  S. Larson,et al.  Advantages of radioiodine over radioindium labeled monoclonal antibodies for imaging solid tumors. , 1988, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[31]  H. Strauss,et al.  Differences in experimental tumor localization of dual-labeled monoclonal antibody. , 1986, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[32]  J N Weinstein,et al.  Pharmacokinetics of monoclonal immunoglobulin G1, F(ab')2, and Fab' in mice. , 1986, Cancer research.

[33]  S. Sullivan,et al.  The processing of receptor-bound [125I-Tyr11]somatostatin by RINm5F insulinoma cells. , 1986, The Journal of biological chemistry.

[34]  A. Schonbrunn,et al.  Receptor-bound somatostatin and epidermal growth factor are processed differently in GH4C1 rat pituitary cells , 1986, The Journal of cell biology.

[35]  M. Welch,et al.  Comparative studies using 125I- and 111In-labeled monoclonal antibodies. , 1986, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.

[36]  B. Draznin,et al.  Internalization and cellular processing of somatostatin in primary culture of rat anterior pituitary cells. , 1985, Endocrinology.

[37]  P. Leroux,et al.  Ultrastructural autoradiographic localization of somatostatin-28 in the rat pituitary gland. , 1985, Endocrinology.

[38]  D. Russell,et al.  Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. , 1985, Annual review of cell biology.

[39]  E R Weibel,et al.  Distribution of Organelles and Membranes between Hepatocytes and Nonhepatocytes in a Stereological Study , 2022 .

[40]  R. Estensen,et al.  ENDOCYTOSIS IN CHANG LIVER CELLS , 1971, The Journal of cell biology.

[41]  Hans Rudolf Gnägi,et al.  CORRELATED MORPHOMETRIC AND BIOCHEMICAL STUDIES ON THE LIVER CELL , 1969, The Journal of cell biology.

[42]  E. E. Snell,et al.  A. Rev. Biochem. , 1969 .

[43]  H. Ryser.  Uptake of Protein by Mammalian Cells: An Underdeveloped Area , 1968, Science.

[44]  H. Ryser.  A Membrane Effect of Basic Polymers dependent on Molecular Size , 1967, Nature.

[45]  A. B. Maunsbach.  Absorption of I-125-labeled homologous albumin by rat kidney proximal tubule cells. A study of microperfused single proximal tubules by electron microscopic autoradiography and histochemistry. , 1966, Journal of ultrastructure research.

[46]  W. Straus.  OCCURRENCE OF PHAGOSOMES AND PHAGO-LYSOSOMES IN DIFFERENT SEGMENTS OF THE NEPHRON IN RELATION TO THE REABSORPTION, TRANSPORT, DIGESTION, AND EXTRUSION OF INTRAVENOUSLY INJECTED HORSERADISH PEROXIDASE , 1964, The Journal of cell biology.

[47]  W. Straus.  CYTOCHEMICAL OBSERVATIONS ON THE RELATIONSHIP BETWEEN LYSOSOMES AND PHAGOSOMES IN KIDNEY AND LIVER BY COMBINED STAINING FOR ACID PHOSPHATASE AND INTRAVENOUSLY INJECTED HORSERADISH PEROXIDASE , 1964, The Journal of cell biology.

[48]  W. Straus.  Cytochemical investigation of phagosomes and related structures in cryostat sections of the kidney and liver of rats after intravenous administration of horseradish peroxidase. , 1962, Experimental cell research.

[49]  Werner Straus,et al.  CONCENTRATION OF ACID PHOSPHATASE, RIBONUCLEASE, DESOXYRIBONUCLEASE, β-GLUCURONIDASE, AND CATHEPSIN IN "DROPLETS" ISOLATED FROM THE KIDNEY CELLS OF NORMAL RATS , 1956, The Journal of biophysical and biochemical cytology.

[50]  Carolyn C Johnstone,et al.  The urinary system. , 2014, Nursing standard (Royal College of Nursing (Great Britain) : 1987).