Compositions for oxygen transport comprising a high oxygen affinity modified hemoglobin

Abstract

The present invention relates to blood products, and more particularly to compositions comprising a modified oxygenated hemoglobin having a high affinity for oxygen and methods for making such compositions. Such compositions according to the present invention have better stability to auto oxidation and superior oxygen carrying characteristics.

What is claimed is: 
     
         1 . A method of treating a human patient in need of treatment, the method comprising administering to the patient a hemoglobin composition comprising polyalkylene oxide (PAO) surface-modified hemoglobin having a P 50  less than 15 torr as measured at a pH of 7.4 and a temperature of 37° C. and an aqueous diluent,
 wherein the patient is suffering from trauma, acute blood loss, ischemia, heart attack, stroke, sepsis, septic shock, anemia, or hypoxia, the patient is having hemodilution as part of a surgical procedure, the patient is having cardioplegia during cardiac surgery, the patient is suffering from cancer and the hemoglobin is used to increase the sensitivity of a tumor to radiation or chemotherapy treatment, or the patient is treated to stimulate hemoglobin synthesis during hematopoiesis; and 
 the PAO surface-modified hemoglobin is prepared by a process comprising the steps of: 
 thiolating an oxygenated hemoglobin to form thiolated oxygenated hemoglobin; and 
 reacting the thiolated oxygenated hemoglobin with at least one PAO polymer, the PAO polymer comprising a thiol reactive moiety and polyalkylene oxide linked by a linker consisting of alkylene or phenylene. 
 
     
     
         2 . The method of  claim 1  wherein the patient is suffering from trauma. 
     
     
         3 . The method of  claim 2  wherein the trauma is cerebrovascular trauma. 
     
     
         4 . The method of  claim 1  wherein the patient is suffering from acute blood loss. 
     
     
         5 . The method of  claim 1  wherein the patient is suffering from ischemia. 
     
     
         6 . The method of  claim 1  wherein the patient suffered a heart attack. 
     
     
         7 . The method of  claim 1  wherein the patient suffered a stroke. 
     
     
         8 . The method of  claim 1  wherein the patient is suffering from sepsis. 
     
     
         9 . The method of  claim 1  wherein the patient is suffering from septic shock. 
     
     
         10 . The method of  claim 1  wherein the patient is suffering from anemia. 
     
     
         11 . The method of  claim 10  wherein the patient is suffering from chronic anemia. 
     
     
         12 . The method of  claim 10  wherein the patient is suffering from sickle cell anemia. 
     
     
         13 . The method of  claim 1  wherein the patient is suffering from hypoxia. 
     
     
         14 . The method of  claim 1  wherein the patient is having hemodilution as part of a surgical procedure. 
     
     
         15 . The method of  claim 1  wherein the patient is having cardioplegia during cardiac surgery. 
     
     
         16 . The method of  claim 1  wherein the patient is suffering from cancer and the hemoglobin is used to increase the sensitivity of a tumor to radiation or chemotherapy treatment. 
     
     
         17 . The method of  claim 1  wherein the patient is treated to stimulate hemoglobin synthesis during hematopoiesis. 
     
     
         18 . The method of  claim 1  wherein the linker consists of alkylene. 
     
     
         19 . The method of  claim 18  wherein the thiol reactive moiety is maleimidyl. 
     
     
         20 . The method of  claim 19  wherein the oxygenated hemoglobin is human, cow, pig or horse oxygenated hemoglobin. 
     
     
         21 . The method of  claim 20  wherein each maleimidyl moiety is attached to an added thiol group on the surface of the hemoglobin or is attached to a native beta93Cys thiol group in the hemoglobin. 
     
     
         22 . The method of  claim 21  wherein two maleimidyl moieties are each attached to a native beta93Cys thiol group in the hemoglobin and other maleimidyl moieties are each attached to an added thiol group on the surface of the hemoglobin. 
     
     
         23 . The method of  claim 21  wherein the PAO of the PAO polymer has the formula —(OCH 2 CH 2 ) n OCH 3  where n is greater than or equal to 4. 
     
     
         24 . The method of  claim 21  wherein the the PAO surface-modified hemoglobin is administered intravenously. 
     
     
         25 . The method of  claim 21  wherein the PAO surface-modified hemoglobin has a P 50  of less than 10 torr. 
     
     
         26 . The method of  claim 25  wherein the PAO surface-modified hemoglobin has a P 50  of less than 7 torr. 
     
     
         27 . The method of  claim 25  wherein the PAO surface-modified hemoglobin has a P 50  of 6±2 torr. 
     
     
         28 . The method of  claim 21  wherein the oxygenated hemoglobin is thiolated with 2-iminothiolane. 
     
     
         29 . The method of  claim 21  wherein the patient is suffering from trauma. 
     
     
         30 . The method of  claim 21  wherein the trauma is cerebrovascular trauma. 
     
     
         31 . The method of  claim 21  wherein the patient is suffering from acute blood loss. 
     
     
         32 . The method of  claim 21  wherein the patient is suffering from ischemia. 
     
     
         33 . The method of  claim 21  wherein the patient suffered a heart attack. 
     
     
         34 . The method of  claim 21  wherein the patient suffered a stroke. 
     
     
         35 . The method of  claim 21  wherein the patient is suffering from sepsis. 
     
     
         36 . The method of  claim 21  wherein the patient is suffering from septic shock. 
     
     
         37 . The method of  claim 21  wherein the patient is suffering from anemia. 
     
     
         38 . The method of  claim 37  wherein the patient is suffering from chronic anemia. 
     
     
         39 . The method of  claim 37  wherein the patient is suffering from sickle cell anemia. 
     
     
         40 . The method of  claim 21  wherein the patient is suffering from hypoxia. 
     
     
         41 . The method of  claim 21  wherein the patient is having hemodilution as part of a surgical procedure. 
     
     
         42 . The method of  claim 21  wherein the patient is having cardioplegia during cardiac surgery. 
     
     
         43 . The method of  claim 21  wherein the patient is suffering from cancer and the hemoglobin is used to increase the sensitivity of a tumor to radiation or chemotherapy treatment. 
     
     
         44 . The method of  claim 21  wherein the patient is treated to stimulate hemoglobin synthesis during hematopoiesis. 
     
     
         45 . A method of preserving an organ ex vivo, the method comprising administering a hemoglobin composition to the organ, the composition comprising polyalkylene oxide (PAO) surface-modified hemoglobin having a P 50  less than 15 torr as measured at a pH of 7.4 and a temperature of 37° C. and an aqueous diluent,
 wherein the PAO surface-modified hemoglobin is prepared by a process comprising the steps of: 
 thiolating an oxygenated hemoglobin to form thiolated oxygenated hemoglobin; and 
 reacting the thiolated oxygenated hemoglobin with at least one PAO polymer, the PAO polymer comprising a thiol reactive moiety and polyalkylene oxide linked by a linker consisting of an alkylene or phenylene. 
 
     
     
         46 . A method of preserving cells in vitro, the method comprising culturing the cells in a hemoglobin composition comprising polyalkylene oxide (PAO) surface-modified hemoglobin having a P 50  less than 15 torr as measured at a pH of 7.4 and a temperature of 37° C. and an aqueous diluent,
 wherein the PAO surface-modified hemoglobin is prepared by a process comprising the steps of: 
 thiolating an oxygenated hemoglobin to form thiolated oxygenated hemoglobin; and 
 reacting the thiolated oxygenated hemoglobin with at least one PAO polymer, the PAO polymer comprising a thiol reactive moiety and polyalkylene oxide linked by a linker consisting of an alkylene or phenylene.