Hemoglobin-haptoglobin complexes
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 .