Patent EA-000618-B1 (EA)
Title: Compositions and methods utilizing nitroxydes in combination with biocompatible macromolecules
Inventor: HSIA JEN-CHANG
IPC: A61K47/48
Filed: 1996-03-29
Abstract: 1. A method to promote in vivo conversions of a hydroxylamine form of a nitroxide to a paramagnetic form comprising: reacting a first nitroxide in the hydroxylamine form with a second nitroxide providing enzyme-mimic activity as a hydroxylamine oxidase, wherein the enzyme-mimic compound is a nitroxide-containing compound having a nitroxyl group which is less stable than the first nitroxide in its free radical form. 2. The method of Claim 1 wherein the polynitroxide macromolecule is a synthetic nitroxide polymer. 3. The method of Claim 2 wherein the polynitroxide macromolecule is selected from the group of dextran, hydroxylethyl starch, liposome, hemoglobin or albumin. 4. The composition comprising human serum albumin labelled with nitroxide, wherein said nitroxide is covalently labelled to albumin and the average molar ratio is between approximately 17 and 95. 5. The composition of Claim 4 wherein the average molar ratio of nitroxide to human serum albumin is between approximately 30 and 95. 6. The composition of Claim 4 wherein the average molar ratio of nitroxide to human serum-albumin between approximately 52 and 95. 7. The composition of Claim 4-6 wherein the nitroxide is selected from the group consisting of TEMPOL, PROXYL and DOXYL. 8. A biocompatable composition wherein comprises: a membrane permeable first nitroxide; a second nitroxide having a nitroxyl group capable of accepting an electron from the first nitroxide. 9. The composition of Claim 8 wherein the second nitroxide is a substantially membrane impermeable polynitroxide biocompatible macromolecule. 10. The composition of Claim 9 wherein the polynitroxide biocompatible macromolecule is polynitroxide albumin. 11. The composition of Claim 10 wherein the molar ratio of nitroxide to albumin is between approximately 7 and 95. 12. The composition of Claim 10 wherein the first nitroxide is of the group of TEMPOL, DOXYL, or PROXYL. 13. The composition of Claim 12 wherein the nitroxide is the hydroxylamine derivative thereof. 14. The composition of Claim 9 wherein the polynitroxide biocompatible macromolecule is of the group of native hemoglobin, cross-linked hemoglobin, polymerized hemoglobin, conjugated hemoglobin, liposome-encapsulated hemoglobin, hydroxylethyl starch, dextran or cyclodexlyran. 15. A method to enhance the electron paramagnetic resonance or nuclear magnetic resonance image of a biological structure comprising: administering a -membrane permeable first nitroxide, administering a second nitroxide having a -nitroxyl-group capable of accepting an electron from the first niitroxide; and obtaining an image of the biological structure. 16. The method of Claim 15 wherein the membrane permeable nitroxide is of the group of TEMPOL, PROXYL, or DOXYL and the second nitroxide is a biocompatible macromolecule of the group of hemoglobin, albumin, dextran, cyclodextran, hydroxylethyl starch or liposome. 17. The method of Claim 16 wherein the polynitroxide macromolecule is albumin having a molar ratio of nitroxide to albumin of between approximately 7 to 95. 18. The method of Claim 15 wherein administering of the second nitroxide macromolecule is effective to localize the image enhancement at a site proximate to the interaction of the membrane permeable first nitroxide and the second nitroxide. 19. A method to protect an organism from ionizing radiation comprising: administering a membrane permeable first nitroxide and administering a membrane impermeable second nitroxide having a nitroxyl group capable of accepting an electron from the first nitroxide. 20. The method of Claim 19 wherein the second nitroxide is a nitroxide-labelled macromolecule selected from the group consisting of albumin, hemoglobin, dextran, hydroxylethyl starch, liposome or cyclodextran. 21. The method of Claim 19 wherein the polynitroxide macromolecule is albumin labelled with a nitroxide selected from the group consisting of TEMPOL, DOXYL, or PROXYL at a molar ratio of approximately 7 to 95. 22. A method to treat an organism with a physiological condition using a therapeutic dose of ionizing radiation comprising:<:> administering a membrane permeable nitroxide; and administering a second nitroxide having a nitroxyl group capable of accepting an electron from the first nitroxide, and exposing the organism to ionizing radiation. 23. The method of Claim 22 wherein the membrane permeable nitroxide is selected from the group consisting of TEMPOL, DOXYL, or PROXYL and the second nitroxide is a nitroxide-labelled macromolecule selected from the group consisting of hydroxylethyl-starch, albumin, hemoglobin, liposome, dextran or cyclodextran. 24. The method of Claim 23 wherein the nitroxide-labelled mnacromolecule is polynitroxide albumin wherein the molar ratio of nitroxide to albumin is between approximately 7 and 95. 25. The method of Claim 22 wherein a dose of ionizing radiation is delivered to a site coincident to the concentration of the second nitroxide. 26. The method of Claim 26 wherein the polynitroxide albumin is in a carrier suitable for topical application and further comprising the topically applying the polynitroxide at the site of radiation exposure. 27. The method of Claim 27 wherein at least one of the membrane permeable nitroxide or the polynitroxide albumin is administered intravenously prior to the initiation of radiation therapy.