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Details for Patent: 5,262,176

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Details for Patent: 5,262,176

Title: Synthesis of polysaccharide covered superparamagnetic oxide colloids
Abstract:In a method for the synthesis of a colloid including a superparamagnetic metal oxide coated with a polymer, an acidic solution of a metal salt and a polymer may be cooled, and then neutralized by the controlled addition of a cool solution of a base, and may then be converted, by the application of heat, to a homogenous superparamagnetic metal oxide colloid. According to a preferred embodiment, the polymer may be a polysaccharide. In a further embodiment of the invention, the polysaccharide may be dextran and the metal salt may be ferrous and ferric salts, which produces, according to the methods of the invention, a superparamagnetic iron oxide colloid with an extended plasma half-life.
Inventor(s): Palmacci; Stephen (Walpole, MA), Josephson; Lee (Arlington, MA)
Assignee: Advanced Magnetics, Inc. (Cambridge, MA)
Filing Date:May 02, 1991
Application Number:07/694,636
Claims:1. An improved method for obtaining an in vivo MR image of an organ or tissue of a human or animal subject, of the type including administering to such subject as a contrast agent to enhance such MR image an effective amount of a colloid including homogeneous superparamagnetic metal oxide particles dispersed in a physiologically acceptable carrier, wherein the colloid is synthesized by associating superparamagnetic metal oxide particles with a polymer in such a way that the polymer covers the superparamagnetic metal oxide particles and the polymer covering blocks opsominzation.

2. A method according to claim 1, wherein the polymer is a polysaccharide.

3. A method according to claim 1, further comprising crosslinking the polymer.

4. A method according to claim 2, further comprising crosslinking the polysaccharide.

5. A method according to claim 4, wherein the polysaccharide is dextran; and

wherein the dextran is crosslinked with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.

6. A method according to claim 2, wherein the polysaccharide is dextran.

7. A method according to claim 6, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.

8. A method according to claim 1, wherein the synthesis of the colloid includes:

(i) providing an acidic solution including a metal salt and the polymer;

(ii) cooling the solution, obtained in step (i);

(iii) neutralizing the solution, obtained in step (ii), by the controlled addition of a cool solution of a base; and

(iv) heating the solution, obtained in step (iii), to obtain the homogenous superparamagnetic metal oxide colloid.

9. A method according to claim 8, wherein the polymer is a polysaccharide.

10. A method according to claim 9, wherein the polysaccharide is dextran.

11. A method according to claim 10, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of

(a) ferric salts;

(b) ferrous salts; and

(c) ferrous and ferric salts;

wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 10:1 by weight; and

wherein the colloid, obtained in step (iv), is a superparamagnetic iron oxide colloid that includes a core consisting substantially of a single crystal of iron oxide.

12. A method according to claim 10, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of

(a) ferric salts;

(b) ferrous salts; and

(c) ferrous and ferric salts;

wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 4:1 by weight; and

wherein the colloid, obtained in step (iv), is a superparamagnetic iron oxide colloid that includes a core consisting substantially of a range of 1-4 crystals of iron oxide.

13. A method according to claim 10, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.

14. A method according to claim 8, further comprising, after step (iv):

(v) crosslinking the polymer.

15. A method according to claim 9, further comprising, after step (iv):

(v) crosslinking the polysaccharide.

16. A method according to claim 15, wherein the polysaccharide is dextran; and

wherein the step of crosslinking the dextran is performed with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.

17. A superparamagnetic metal oxide colloid comprising: a superparamagnetic metal oxide associated with a polymer in such a way that the polymer covers the superparamagnetic metal oxide and the polymer covering blocks opsominzation.

18. A colloid according to claim 17, wherein the polymer is a polysaccharide.

19. A colloid according to claim 17, wherein the polymer is crosslinked.

20. A colloid according to claim 18, wherein the polysaccharide is crosslinked.

21. A colloid according to claim 20, wherein the polysaccharide is dextran; and

wherein the dextran is crosslinked with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide,, ethylchloroformate and divinyl sulfone.

22. A colloid according to claim 17, wherein the colloid is synthesized by:

(i) providing an acidic solution including a metal salt and the polymer;

(ii) cooling the solution, obtained in step (i);

(iii) neutralizing the solution, obtained in step (ii), by the controlled addition of a cool solution of a base; and

(iv) heating the solution, obtained in step (iii), to obtain the superparamagnetic metal oxide colloid.

23. A colloid according to claim 22, wherein the polymer, is a polysaccharide.

24. A colloid according to claim 23, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan galactan, sulfated dextran and diethylaminodextran.

25. A colloid according to claim 22, wherein step (ii) includes the step of cooling the solution to between approximately 0.degree. C. and approximately 12.degree. C.; and

wherein step (iv) includes the step of heating the solution to between approximately 60.degree. C. and approximately 100.degree. C., for not less than approximately 30 minutes, to obtain the superparamagnetic metal oxide colloid.

26. A colloid according to claim 25, wherein the polymer is a polysaccharide.

27. A colloid according to claim 26, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of

(a) ferric salts;

(b) ferrous salts; and

(c) ferrous and ferric salts; and

wherein, in step (iv), a superparamagnetic iron oxide colloid is obtained.

28. A colloid according to claim 27, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan, galactan, sulfated dextran and diethylaminodextran.

29. A colloid according to claim 26, wherein the colloid is capable of interacting with a cell receptor and undergoing receptor mediated endocytosis into a specific population of cells.

30. A colloid according to claim 29, wherein the polysaccharide is arabinogalactan and wherein the cells are hepatocytes.

31. A colloid according to claim 29, wherein the plasma clearance of the colloid is inhibited by asialoglycoproteins.

32. A colloid according to claim 26, wherein the polysaccharide is dextran.

33. A colloid according to claim 32, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.

34. A colloid according to claim 27,

wherein the polysaccharide is dextran;

wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 10:1 by weight; and

wherein the colloid, obtained in step (iv), includes a core consisting substantially of a single crystal of iron oxide.

35. A colloid according to claim 27,

wherein the polysaccharide is dextran;

wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 4:1 by weight; and

wherein the colloid, obtained in step (iv), includes a core consisting substantially of a range of 1-4 crystals of iron oxide.

36. A colloid according to claim 25, wherein the colloid is an MR contrast agent.

37. A colloid according to claim 36, wherein the polymer is a polysaccharide.

38. A colloid according to claim 37, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan, galactan, sulfated dextran and diethylaminodextran.

39. A colloid according to claim 25, wherein the synthesis of the colloid further comprises, after step (iv):

(v) crosslinking the polymer.

40. A colloid according to claim 26, wherein the synthesis of the colloid further comprises, after step (iv):

(v) crosslinking the polysaccharide

41. A colloid according to claim 40, wherein the polysaccharide is dextran; and

wherein the dextran is crosslinked with a crosslinking agent that is selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.

42. A colloid according to claim 39, wherein the colloid is an MR contrast agent.

43. A colloid according to claim 40, wherein the colloid is an MR contrast agent.

44. A colloid according to claim 41, wherein the colloid is an MR contrast agent.
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