Hemoglobin-haptoglobin complexes

Abstract

Construct-complexes of a hemoglobin, a hepatocyte modifying substance bound to the hemoglobin, and a haptoglobin bound to the hemoglobin, are provided, for administration to mammalian patients. The construct-complex may be formed ex vivo, or a hemoglobin-hepatocyte modifying substance combination may be administered to the patient so that haptoglobin in the mammalian body bonds thereto to form the construct-complex in vivo. Disorders of the liver may be diagnosed and treated using construct-complexes described herein.

We claim:  
     
         1 . A hemoglobin construct-complex comprising a hemoglobin and a hepatocyte modifying substance bound thereto, said construct-complex being capable of binding to haptoglobin in vivo in a mammalian patient to effect delivery of the hepatocyte modifying substance to hepatocytes of the patient.  
     
     
         2 . The construct-complex of  claim 1  wherein the hepatocyte modifying substance is bound to the hemoglobin through the intermediary of a chemical linker.  
     
     
         3 . The construct-complex of  claim 1  wherein the hepatocyte modifying substance is an agent capable of interacting with hepatocytes and consequently capable of acting in vivo at the liver of a mammalian patient, and selected from therapeutic agents, diagnostic agents and markers.  
     
     
         4 . The construct-complex of  claim 3  wherein the hepatocyte modifying substance is a therapeutic agent selected from antineoplastic substances, antiviral substances, anti-inflammatory substances, anti-parasitic substances, anti-microbial substances, antioxidant substances, hepatoprotective agents, nucleic acids, lipid metabolism agents, anti-toxicants, proteins and enzymes.  
     
     
         5 . The construct-complex of  claim 4  wherein the hepatocyte modifying substance is a nucleic acid.  
     
     
         6 . The construct-complex of  claim 5  wherein the hepatocyte modifying substance is a gene coding for a protein of interest.  
     
     
         7 . The construct-complex of  claim 4  wherein the hepatocyte modifying substance is putrescine.  
     
     
         8 . The construct-complex of  claim 4  wherein the hepatocyte modifying substance is primaquine.  
     
     
         9 . The construct-complex of  claim 3  wherein the hepatocyte modifying substance is a diagnostic agent.  
     
     
         10 . The construct-complex of  claim 9  wherein the diagnostic compound is a radiolabelled compound or a fluorescent compound.  
     
     
         11 . The construct-complex of  claim 1  wherein the hemoglobin is an intramolecularly cross-linked human hemoglobin.  
     
     
         12 . The construct-complex of  claim 11  wherein the hemoglobin is intramolecularly cross-linked with a cross-linking reagent which leaves residual chemical groups available for subsequent reaction with the hepatocyte modifying agent, either directly or through the intermediary of a chemical linker group.  
     
     
         13 . The construct-complex of  claim 12  wherein the cross-linking reagent is a trifunctional reagent which utilizes two of its functional groups for intramolecular cross-linking of hemoglobin and leaves its third functional group available for reaction with a nucleophile.  
     
     
         14 . The construct complex of  claim 13  wherein the cross-linking reagent is trimesoyl tris(3,5-dibromosalicylate).  
     
     
         15 . A hemoglobin construct-complex comprising a hemoglobin, a hepatocyte modifying substance bound to the hemoglobin, and a haptoglobin bound to the hemoglobin.  
     
     
         16 . The construct-complex of  claim 15  formed in vivo by administering to a mammalian patient a construct-complex as defined in  claim 1 .  
     
     
         17 . The construct-complex of  claim 15  wherein the hepatocyte modifying substance is bound to the hemoglobin through the intermediary of a chemical linker.  
     
     
         18 . The construct-complex of  claim 15  wherein the hepatocyte modifying substance is an agent capable of interacting with hepatocytes and consequently capable of acting in vivo at the liver of a mammalian patient, and selected from therapeutic agents, diagnostic agents and markers.  
     
     
         19 . The construct-complex of  claim 18  wherein the hepatocyte modifying substance is a therapeutic agent selected from antineoplastic substances, antiviral substances, anti-inflammatory substances, anti-parasitic substances, anti-microbial substances, antioxidant substances, hepatoprotective agents, nucleic acids, lipid metabolism agents, anti-toxicants, proteins and enzymes.  
     
     
         20 . The construct-complex of  claim 19  wherein the hepatocyte modifying substance is a nucleic acid.  
     
     
         21 . The construct-complex of  claim 18  wherein the hepatocyte modifying substance is a diagnostic agent.  
     
     
         22 . The construct-complex of  claim 21  wherein the diagnostic compound is a radiolabelled compound or a fluorescent compound.  
     
     
         23 . The construct-complex of  claim 15  wherein the hemoglobin is an intramolecularly cross-linked human hemoglobin.  
     
     
         24 . The construct-complex of  claim 23  wherein the hemoglobin is intramolecularly cross-linked with a cross-linking reagent which leaves residual chemical groups available for subsequent reaction with the hepatocyte modifying agent, either directly or through the intermediary of a chemical linker group.  
     
     
         25 . The construct-complex of  claim 24  wherein the cross-linking reagent is a trifunctional reagent which utilizes two of its functional groups for intramolecular cross-linking of hemoglobin and leaves its third functional group available for reaction with a nucleophile.  
     
     
         26 . The construct complex of  claim 25  wherein the cross-linking reagent is trimesoyl tris(3,5-dibromosalicylate).  
     
     
         27 . A process for treating or diagnosing hepatocytic disorders in a mammalian patient which comprises administering to the patient an effective amount of a construct-complex, as defined in  claim 1 .  
     
     
         28 . A process for treating or diagnosing hepatocytic disorders in a mammalian patient which comprises administering to the patient an effective amount of a construct-complex.  
     
     
         29 . A process for treating metastatic cells carrying haptoglobin receptors, in a mammalian patient, which comprises administering to the patient an effective amount of a construct-complex as defined in  claim 1 .  
     
     
         30 . A process for treating metastatic cells carrying haptoglobin receptors, in a mammalian patient, which comprises administering to the patient an effective amount of a construct-complex as defined in claim  15 .