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Differential receptor targeting of liver cells using 99mTc-neoglycosylated human serum albumins

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Abstract

Neolactosyl human serum albumin (LSA) targets asialoglycoprotein receptor and shows high liver uptake due to accumulation in hepatocytes. Although neomannosyl human serum albumin (MSA) also shows high liver uptake, it has been reported to be taken up by Kupffer cells and endothelial cells. We compared the biological properties of LSA and MSA. 99mTc-LSA and 99mTc-MSA biodistribution in mice were investigated after intravenous injection. In vivo localization of rhodaminisothiocyanate (RITC)-LSA and fluoresceineisothiocyanate (FITC)-MSA were investigated in mouse liver. Excretion routes of 99mTc-LSA and 99mTc-MSA metabolites were examined. Both 99mTc-LSA and 99mTc-MSA showed high liver uptakes. RITC-LSA was taken up by hepatocytes whereas FITC-MSA was taken up by Kupffer cells and endothelial cells. 99mTc-MSA showed higher spleen and kidney uptakes than 99mTc-LSA. 99mTc-LSA metabolites excreted in urine and feces accounted for 44.4 and 50.0% of 99mTc-LSA injected, respectively, while 99mTc-MSA metabolites accounted for 51.5 and 10.3%, respectively. In conclusion, LSA is specifically taken up by hepatcytes while MSA by Kupffer cells and endothelial cells. After taken up by the liver, LSA is metabolized by the hepatocytes and then excreted through both the hepatobiliary tract and kidney, whereas MSA is metabolized by Kupffer cells and endoghelial cells and then excreted mainly through the kidney.

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References

  • Alazraki, N. P., Eshima, D., Eshima, L.A., Herda, S. C., Murray, D. R., Vansant, J. P., and Taylor, A. T., Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers. Semin. Nucl. Med., 27, 55–67 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Athamna, A., Ofek, Keisari, Y., Markowitz, S., Dutton, G. G., and Sharon, N., Lectinophagocytosis of encapsulated Klebsiella pneumoniae mediated by surface lectins of guinea pig alveolar macrophages and human monocyte-derived macrophages. Infect. Immunol., 59, 1673–1682 (1991).

    CAS  Google Scholar 

  • Bedrosian, I., Scheff, A. M., Mick, R., Callans, L. S., Bucky, L. P., Spitz, F. R., Helsabeck, C., Elder, D. E., Alavi, A., Eraker, D. F., and Czerniecki, B. J., 99mTc-human serum albumin: an effective radiotracer for identifying sentinel lymph nodes in melanoma. J. Nucl. Med., 40, 1143–1148 (1999).

    PubMed  CAS  Google Scholar 

  • Chakraborty, P. and Das, P. K., Role of mannose/N-acetylglucosamine receptors in blood clearance and cellular attachment of Leishmania donovani. Mol. Biochem. Parasitol., 28, 55–62 (1988).

    Article  PubMed  CAS  Google Scholar 

  • Dini, L., Autuori, F., Lentini, A., Oliverio, S., and Piacentini, M., The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor. FEBS Lett., 20, 174–178 (1992).

    Article  Google Scholar 

  • East, L. and Isacke, C. M., The mannose receptor family. Biochim. Biophys. Acta, 1572, 364–386 (2002).

    PubMed  CAS  Google Scholar 

  • Ezekowitz, R. A., Sastry, K., Bailly, P., and Warner, A., Molecular characterization of the human macrophage mannose receptor: demonstrtion of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells. J. Exp. Med., 172, 1785–1794 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Ezekowitz, R. A., Williams, D. J., Koziel, H., Armstrong, M. Y., Warner, A., Richards, F. F., and Rose, R. M., Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature, 351, 155–158 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Ha-Kawa, S. K., Tanaka, Y., Hasebe, S., Kuniyasu, Y., Koizumi, K., Ishii, Y., Yamamoto, K., Kashiwagi, T., Ito, A., Kudo, M., Ikekubo, K., Tsuda, T., and Murase, K., Compartmental analysis of asialoglycoprotein receptor scintigraphy for quantitative measurement of liver function: A multicenter study. Eur. J. Nucl. Med. 24, 130–137 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Hidenbrandt, G. R. and Aronson, N. N. Jr., Uptake of asialoglycoprotein-liposomes by the perfused rat liver. Biochim. Biophys. Acta, 631, 499–502 (1980).

    Google Scholar 

  • Jeong, J. M., Hong, M. K., Lee, J., Son, M., So, Y., Lee, D. S., Chung J. K., and Lee, M. C., 99mTc-neolactosylated human serum albumin for imaging the hepatic asialoglycoprotein receptor. Bioconjugate Chem., 15, 850–855 (2004a).

    Article  CAS  Google Scholar 

  • Jeong, J. M., Hong, M. K., Kim, Y. J., Lee, J., Kang, J. H., Lee, D. S., Chung J. K., and Lee, M. C., Development of 99mTc-neomannosyl human serum albumin (99mTc-MSA) as a novel receptor binding agent for sentinel lymph node imaging. Nucl. Med. Commun., 25, 1211–1217 (2004b).

    Article  PubMed  CAS  Google Scholar 

  • Kaibori, M., Ha-Kawa, S. K., Uchida, Y., Ishizaki, M., Hijikawa, T., Saito, T., Imamura, A., Hirohara, J., Uemura, Y., Tanaka, K., and Kamyama, Y., Recurrent Hepatitis C After Living Donor Liver Transplantation Detected by Tc-99m GSA Liver Scintigraphy. Dig Dis Sci., 51, 2013–2017 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Krishnamurthy, G. T. and Turner, F. E., Pharmacokinetics and clinical application of technetium 99m-labeled hepatobiliary agents. Seminars Nucl. Med., 20, 130–149 (1990).

    Article  CAS  Google Scholar 

  • Krohn, K. A., Vera, D. R., and Stadalnik, R. C., A complementary radiopharmaceutical and mathematical model for quantitating hepatic-binding protein receptors. Receptor-Binding, CRC Press, Boca Raton, FL., (1982).

    Google Scholar 

  • Krohn, K. A., Vera, D. R., and Steffen, S. M., 99mTc-Neogalactosylalbumin: a general model for some bifunctional carbohydrates. J. Label. Compd. Radiopharm., 18, 91–93 (1980).

    Google Scholar 

  • Kubota, Y., Kojima, M., Hazama, H., Kawa, S., Nakazawa, M., Nishiyama, Y. et al., A new liver function test using the asialoglycoprotein-receptor system on the liver cell membrane: I. Evaluation of liver imaging using Tc-99m-neoglycoprotein. Kaku Igaku, 23, 899–905 (1986).

    PubMed  CAS  Google Scholar 

  • Magnusson, S. and Berg, T., Extremely rapid endocytosis mediated by the mannose receptor of sinusoidal endothelial rat liver cells. Biochem. J., 257, 651–656 (1989).

    PubMed  CAS  Google Scholar 

  • Miki, K., Kubota, K., Inoue, Y., Vera, D. R., and Makuuchi, M., Receptor measurements via Tc-GSA kinetic modeling are proportional to functional hepatocellular mass. J. Nucl. Med., 42, 733–737 (2001).

    PubMed  CAS  Google Scholar 

  • Monoe, T., Nomura, T., Nakao, H., Sobue, S., Mizuno, Y., Nojiri, S., Kanematsu, T., Senda, K., Ohmi, H., Ohara, H., Ioh, T., Itoh, K., and Itoh, M., Prognostic indicators estimated by 99mTc-GSA in acute liver damage. Hepatol. Res., 31, 153–159 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Mu, J. Z., Tang, L. H., and Alpers, D. H., Asialoglycoprotein receptor mRNAs are expressed in most extrahepatic rat tissues during development. Am. J. Physiol., 264, G752–G762 (1993).

    PubMed  CAS  Google Scholar 

  • Ogawara, K.-I., Hasegawa, S., Nishikawa, M., Takakura, Y., and Hashida, M., Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier: quantitative comparison with other hepatotropic ligands. J. Drug Target., 6, 349–360 (1999)

    Article  PubMed  CAS  Google Scholar 

  • Onodera, Y., Takahashi, K., Sugai, Y., Tamaki, N., and Miyasaka, K., Evaluation of the liver uptake rate measured by 99mTc-GSA SPECT to assess liver function]. Kaku Igaku, 36, 37–44 (1999).

    PubMed  CAS  Google Scholar 

  • Roccatello, D., Picciotto, G., Torchio, M., Ropolo, R., Ferro, M., Franceschini, R., Quattrocchio, G., Cacace, G., Coppo, R., and Sena, L. M., Removal systems of immunoglobulin A and immunoglobulin A containing complexes in IgA nephropathy and cirrhosis patients. The role of asialoglycoprotein receptors. Lab. Invest., 69, 714–723 (1993).

    PubMed  CAS  Google Scholar 

  • Schlesinger, L. S., Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J. Immunol., 150, 2920–2930 (1993).

    PubMed  CAS  Google Scholar 

  • Schwarz, A. and Steinsträsser, A., A novel approach to Tc-99m-labeled monoclonal antibodies. J. Nucl. Med., 28, 721 (1987).

    Google Scholar 

  • Shiomi, S., Evaluation of hepatic functional reserve by scintigraphy with 99mTc-GSA. Hepatol. Res., 31, 124–126 (2005).

    Article  PubMed  Google Scholar 

  • Stockert, R. J., The asialoglycoprotein receptor: Relationships between structure, function, and expression. Physiol. Rev., 75, 591–600 (1995).

    PubMed  CAS  Google Scholar 

  • Takagi, K., Uehara, T., Kaneko, E., Nakayama, M., Koizumi, M., Endo, K., and Arano, Y., 99mTc-labeled mannosyl-neoglycoalbumin for sentinel lymph node identification. Nucl. Med. Biol., 31, 893–900 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Vera, D. R., Stadalnik, R. C., and Krohn, K. A., Technetium-99m galactosyl-neoglycoalbumin: preparation and preclinical studies. J. Nucl. Med., 26, 1157–1167 (1985).

    PubMed  CAS  Google Scholar 

  • Vera, D. R., Wallace, A. M., Hoh, C. K., and Mattrey, R. F., A synthetic macromolecule for sentinel node detection: 99mTc-DTPA-mannosyl-dextran. J. Nucl. Med., 42, 951–959 (2001a).

    PubMed  CAS  Google Scholar 

  • Vera, D. R., Wallace, A. M., and Hoh, C. K., [99mTc]MAG3-mannosyl-dextran: a receptor-binding radiopharmaceutical for sentinel node detection. Nucl. Med. Biol., 28, 493–498 (2001b).

    Article  PubMed  CAS  Google Scholar 

  • Weigel, P. H., Galactosyl and N-acetylgalactosaminyl homeostasis: a function for mammalian asialoglycoprotein receptors. Bioessays, 16, 519–524 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Wileman, T. E., Lennartz, M. R., and Stahl, P. D., Identification of the macrophage mannose receptor as a 175 kDa membrane protein. Proc Natl Acad Sci U.S.A., 83, 2501–2505 (1986).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Jae Min Jeong, Mee Kyung Hong, Dong Soo Lee, June-Key Chung & Myung Chul Lee

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Jae Min Jeong & June-Key Chung

  3. Institute of Radiation Medicine, Medical Research Center, Seoul, Korea

    Jae Min Jeong, Dong Soo Lee, June-Key Chung & Myung Chul Lee

  4. Department of Pathology, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Ja-June Jang

  5. Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Korea

    Jaetae Lee

  6. Department of Nuclear Medicine, Seoul National University Hospital, 28 Yungun-dong Chongro-ku, Seoul, 110-744, Korea

    Sungeun Kim

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  1. Sungeun Kim
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Correspondence to Jae Min Jeong.

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Kim, S., Jeong, J.M., Hong, M.K. et al. Differential receptor targeting of liver cells using 99mTc-neoglycosylated human serum albumins. Arch. Pharm. Res. 31, 60–66 (2008). https://doi.org/10.1007/s12272-008-1121-x

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  • DOI: https://doi.org/10.1007/s12272-008-1121-x

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