Starburst conjugates

• US 5,338,532 A
• Filed: 02/13/1991
• Issued: 08/16/1994
• Est. Priority Date: 08/18/1986
• Status: Expired due to Term

• Current Assignee: Donald A. Tomalia, AVC Holdings Inc. (Dow, Inc.), Dendritic NanoTechnologies, Inc. (Loveland Products, Inc.)
• Original Assignee: The Dow Chemical Company (Dow, Inc.)
• Inventors: Kruper, William J. Jr., Fazio, Michael J., Tomlinson, Ian A., Tomalia, Donald A., Wilson, Larry R., Hedstrand, David M., Cheng, Roberta C., Kaplan, Donald A.
• Primary Examiner(s): Page, Thurman K.
• Application Number:
  US07/654,851
• Time in Patent Office: 1,280 Days
• Field of Search: 424/9.83, 424/78.08, 424/78.1, 424/78.17, 424/78.37, 424/9, 424/639, 424/617, 424/646, 424/647, 424/648, 424/1.1, 424/4, 521/28, 521/25, 436/173, 436/806, 514/772.1, 514/772.3
• US Class Current: 424/1.49
• CPC Class Codes: A01N 25/10 Macromolecular compounds
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61K 47/6885 the conjugate or the polymer being a starburst, a dendrimer, a cascade
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07C 211/29 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C08G 73/02 Polyamines
• CPC Class Codes: C08G 83/003 Dendrimers
• CPC Class Codes: C08L 101/005 Dendritic macromolecules
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: Y10S 436/806 Electrical property or magnetic property
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

Starburst conjugates which are composed of at least one dendrimer in association with at least one unit of a carried agricultural, pharmaceutical, or other material have been prepared. These conjugates have particularly advantageous properties due to the unique characteristics of the dendrimer.

Claims

1. A solvent soluble, radially symmetrical dense star polymer conjugate which comprises

at least one solvent soluble, radially symmetrical dense star polymer wherein the dense star polymer has at least one core branch emanating from a core, said branch having at least one terminal group provided that

(1) the ratio of terminal groups to the core branches is two or greater,

(2) the density of terminal groups per unit volume in the polymer is at least 1.5 times that of an extended conventional star polymer having similar core and monomeric moieties and a comparable molecular weight and number of core branches, each of such branches of the extended conventional star polymer bearing only one terminal group, and

(3) the dense star polymer has a molecular volume that is no more than about 80 percent of the molecular volume of said extended conventional star polymer as determined by dimensional studies using scaled Corey-Pauling molecular models, and

has regular dendritic branching;

attached to or linked to the surface of the dense star polymer or encapsulated within the interior of the dense star polymer by means of covalent bonding, hydrogen bonding, adsorption, absorption, metallic bonding, van der Waals forces, ionic bonding, coulombic forces, hydrophobic or hydrophilic forces, or any combination thereof, at least one carried material wherein the carried material is a contrast agent, a fluorescing entity, a paramagnetic entity, a radionuclide, or an aromatic ultraviolet absorber, with the proviso that the carried material maintains its effectiveness in the conjugate.

2. The conjugate of claim 1 wherein the dense star polymer is a dendrimer.

3. The conjugate of claim 1 wherein the carried material causes a detectable and measurable perturbation of a system.

4. The conjugate of claim 1 for use as a reagent in positron emission tomography, computer aided tomography, or magnetic resonance imaging.

5. The conjugate of claim 2 wherein the carried material is a contrast agent.

6. The conjugate of claim 5 wherein the contrast agent is prepared by reaction of an α

,β

-unsaturated ester, an α

,β

-unsaturated ketone, an α

,β

-unsaturated nitrile, an α

,β

-unsaturated carboxyl, isothiocyanato or epoxide moiety.

7. The conjugate of claim 6 wherein the contrast agent is hydrophobic.

8. The conjugate of claim 6 wherein the contrast agent is hydrophilic.

9. The conjugate of claim 5 wherein the contrast agent comprises a metal ion selected from Gd, Mn and Fe.

10. The conjugate of claim 5 wherein the contrast agent is a chelated metal ion selected from Gd, Mn and Fe.

11. The conjugate of claim 9 wherein the contrast agent is derived from 1,4,7,10-tetraazacyclododecane-N,N'"'"',N"-triacetic acid.

12. The conjugate of claim 11 wherein the dendrimer portion of the conjugate is polyamidoamine.

13. The conjugate of claim 11 wherein the dendrimer portion of the conjugate is polyethyleneimine.

14. The conjugate of claim 9 wherein the contrast agent is derived from diethylenetriaminepentaacetic acid.

15. The conjugate of claim 9 wherein the dendrimer portion of the conjugate is polyamidoamine.

16. The conjugate of claim 9 wherein the contrast agent is derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

17. The conjugate of claim 15 for use as a diagnostic agent.

18. The conjugate of claim 17 wherein the diagnostic agent is hydroxyethyl-1,4,7-tris(carbomethoxymethyl)-1,4,7,10-tetraazacyclododecane PAMAM conjugated with a metal ion selected from Gd, Mn and Fe.

19. The conjugate of claim 17 wherein the diagnostic agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid PAMAM conjugated with a metal ion selected from Gd, Mn and Fe.

20. The conjugate of claim 1 wherein the carried material is a fluorescing entity.

21. The conjugate of claim 20 wherein the dense star polymer is a polyethyleneimine.

22. The conjugate of claim 21 wherein the fluorescing entity is fluorescein and the dense star polymer is a polyethyleneimine.

23. The conjugate of claim 1 wherein the carried material is a paramagnetic entity.

24. The conjugate of claim 23 wherein the paramagnetic entity is a metal ion selected from Gd, Mn, and Fe.

25. The conjugate of claim 23 wherein the paramagnetic entity is a chelated metal ion selected from Gd, Mn, and Fe.

26. The conjugate of claim 1 wherein the carried material is a radionuclide.

27. The conjugate of claim 26 wherein the radionuclide is selected from ⁹⁰ Y and ¹¹¹ In.

28. The conjugate of claim 1 wherein the carried material is an aromatic ultraviolet absorber.

29. The conjugate of claim 28 wherein the aromatic ultraviolet absorber is salicyclic acid.

30. A solvent soluble, radially symmetrical dense star polymer conjugate of the formula:

space="preserve" listing-type="equation">(P).sub.x *(M).sub.y (I)

wherein each P represents a dendrimer of a dense star polymer wherein the dense star polymer has at least one core branch emanating from a core, said branch having at least one terminal group provided that

(1) the ratio of terminal groups to the core branches is two or greater,

(2) the density of terminal groups per unit volume in the polymer is at least 1.5 times that of an extended conventional star polymer having similar core and monomeric moieties and a comparable molecular weight and number of core branches, each of such branches of the extended conventional star polymer bearing only one terminal group, and

(3) the dense star polymer has a molecular volume that is no more than about 80 percent of the molecular volume of said extended conventional star polymer as determined by dimensional studies using scaled Corey-Pauling molecular models, and

has regular dendritic branching;

x represents an integer of 1 or greater;

each M represents a carried material, or a different carried material and is a contrast agent, fluorescing entity, paramagnetic entity, radionuclide, or aromatic ultraviolet absorber;

y represents an integer of 1 or greater; and

* indicates that the carried material is attached to or linked to the surface of the dense star polymer or encapsulated within the interior of the dense star polymer by means of covalent bonding, hydrogen bonding, adsorption, absorption, metallic bonding, van der Waals forces, ionic bonding, coulombic forces, hydrophobic or hydrophilic forces, or any combination thereof;

with the proviso that the carried material maintains its effectiveness in the conjugate.

31. The conjugate of claim 30 wherein the contrast agent is hydrophobic.

32. The conjugate of claim 30 wherein the contrast gent is hydrophilic.

33. The conjugate of claim 30 wherein the M is encapsulated and the weight ratio of M to P is 10:

1.

34. The conjugate of claim 30 wherein the M is encapsulated and the weight ratio of M to P is 8:

1.

35. The conjugate of claim 30 wherein the M is encapsulated and the weight ratio of M to P is 5:

1.

36. The conjugate of claim 30 wherein the M is encapsulated and the weight ratio of M to P is 3:

1.

37. The conjugate of claim 30 wherein the M is encapsulated and the weight ratio of M to P is from 0.5:

1 to 0.1;

1.

38. The conjugate of claim 30 wherein the M is on the surface and the molar ratio of an ionic M to P is 0.1-1,000:

1.

39. The conjugate of claim 30 wherein the M is on the surface and the molar ratio of an ionic M to P is 1-50:

1.

40. The conjugate of claim 30 wherein the M is on the surface and the molar ratio of an ionic M to P is 2-6:

1.

41. A conjugate of claim 30 wherein the carried material is a contrast agent.

42. The conjugate of claim 41 wherein the contrast agent comprises a metal ion selected from Gd, Mn and Fe.

43. The conjugate of claim 42 wherein the contrast agent is a chelated metal ion selected from Gd, Mn and Fe.

44. The conjugate of claim 41 wherein the contrast agent is prepared by reaction of an α

,β

-unsaturated ester, an α

,β

-unsaturated ketone, an α

,β

-unsaturated nitrile, an α

,β

-unsaturated carboxyl, isothiocyanato or epoxide moiety.

45. The conjugate of claim 44 wherein the contrast agent is derived from 1,4,7,10-tetraazacyclododecane-N,N'"'"',N"-triacetic acid.

46. The conjugate of claim 45 wherein the dendrimer portion of the conjugate is polyamidoamine.

47. The conjugate of claim 45 wherein the dendrimer portion of the conjugate is polyethyleneimine.

48. The conjugate of claim 44 wherein the contrast agent is derived from diethylenetriaminepentaacetic acid.

49. The conjugate of claim 44 wherein the contrast agent is derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

50. The conjugate of claim 41 for use as a diagnostic agent.

51. The conjugate of claim 50 wherein the diagnostic agent is hydroxyethyl-1,4,7-tris(carbomethoxymethyl)-1,4,7,10-tetraazacyclododecane PAMAM conjugated with a metal ion selected from Gd, Mn and Fe.

52. The conjugate of claim 50 wherein the diagnostic agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid PAMAM conjugated with a metal ion selected from Gd, Mn and Fe.

53. The conjugate of claim 30 wherein the carried material is a fluorescing entity.

54. The conjugate of claim 53 wherein the fluorescing entity is fluorescein and the dendrimer portion is a polyethyleneimine.

55. The conjugate of claim 53 wherein the fluorescing entity is fluorescein and the dendrimer portion is a polyamidoamine.

56. The conjugate of claim 30 wherein the carried material is paramagnetic entity.

57. The conjugate of claim 56 wherein the paramagnetic entity is a metal ion selected from Gd, Mn, and Fe.

58. The conjugate of claim 56 wherein the paramagnetic entity is a chelated metal ion selected from Gd, Mn and Fe.

59. The conjugate of claim 30 wherein the carried material is a radionuclide.

60. The conjugate of claim 59 wherein the radionuclide is selected from ⁹⁰ Y and ¹¹¹ In.

61. The conjugate of claim 59 wherein the dendrimer is polyethyleneimine and the radionuclide is ⁹⁰ Y.

62. The conjugate of claim 30 wherein the carried material is an aromatic ultraviolet absorber.

63. The conjugate of claim 62 wherein the aromatic ultraviolet absorber is salicyclic acid.

64. The conjugate of claim 30 wherein the carried material causes a detectable and measurable perturbation of a system.

65. The conjugate of claim 30 for use as a reagent in positron emission tomography, computer aided tomography, or magnetic resonance imaging.