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.

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 intermediatary 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 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 hemoglogin. 
   
   
       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 metatatic 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 .