Dense star polymer conjugates as dyes

• US 6,312,679 B1
• Filed: 03/24/1993
• Issued: 11/06/2001
• Est. Priority Date: 08/18/1986
• Status: Expired due to Fees

• Current Assignee: 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): Levy, Neil S.
• Application Number:
  US08/036,644
• Time in Patent Office: 3,149 Days
• Field of Search: 424/78.08, 424/9.3, 424/78.1, 424/78-7-, 424/78.22, 424/78.23, 424/78.26, 424/78.27, 424/78.34, 424/78.37, 424/405, 424/409, 424/452, 424/401, 424/1.53, 424/1.11, 424/1.33, 424/1.65, 424/1.81, 424/9.6, 424/DIG.16, 521/25, 521/28, 528/363, 528/328, 528/332, 525/417, 523/105, 106/400, 106/20.R, 106/22.R, 106/23.R, 106/31.13, 106/31.15
• US Class Current: 424/78.08
• 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 47/6885 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 424/16 Dendrimers and dendritic polymers

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 dense star polymer conjugate which comprises at least one dense star polymer associated with at least one unit of a dye.

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

3. The conjugate of claim 2 wherein the dendrimer is radially symmetrical.

4. The conjugate of claim 1 wherein the dye is a pharmaceutical material.

5. A conjugate of claim 4 for use as a diagnostic agent.

6. A conjugate of claim 4 for use as a therapeutic agent.

7. The conjugate of claim 1 wherein the dendrimer contains discontinuities.

8. The conjugate of claim 1 wherein the dense star polymer is a polyamidoamine.

9. The conjugate of claim 8 wherein the polyamidoamine is ester terminated.

10. The conjugate of claim 1 wherein the dense star polymer is a polyethyleneimine.

11. The conjugate of claim 10 wherein the polyethyleneimine has a methylene carboxylate surface.

12. The conjugate of claim 10 wherein the polyethyleneimine has an acetate surface.

13. The conjugate of claim 10 wherein the polyethyleneimine has a surface of a polyamidoamine.

14. The conjugate of claim 1 wherein the dense star polymer is a polyether.

15. The conjugate of claim 1 wherein the dense star polymer has its surface modified with a functional group.

16. A formulation which comprises a conjugate of claim 4 having at least one pharmaceutically acceptable diluent or carrier present.

17. The formulation of claim 16 which also comprises other active ingredients present.

18. A formulation which comprises a conjugate of claim 1 having at least one agriculturally acceptable diluent or carrier present.

19. The formulation of claim 18 which also comprises other active ingredients present.

20. A method for the delivery of at least one carried pharmaceutical material which comprises administering of at least one conjugate of claim 4 containing said material at or near a targeted locus.

21. A method for the delivery of at least one carried agricultural material which comprises administering of at least one conjugate of claim 1 containing said material at or near a targeted locus.

22. The conjugate of claim 2 wherein the dendrimer is of the formula $\left(\mathrm{Core}\right)$

{(Repeat

 



Unit)NrG-1Nr-1(TerminalMoiety)

NrG}

Nc

wherein;

the (Core) is an initiator core compound;

 

# of terminal groups per dendritic branch=$\frac{N_r^G}{2};<br><br>$

G is the number of generations;

N_r is the repeating unit multiplicity which is at least 2;

N_c is the valency of the core compound;

the terminal moiety is determined by the following;

 

# of terminal moieties per dendrimer=$\left[\frac{N_c<br><br>N_r^G}{2}\right]$

wherein N_r, G and N_c are as defined above; and

the Repeat Unit has a valency or functionality of N_r+1 wherein N_r is as defined above.

23. The conjugate of claim 2 wherein the dendrimer is of the formula $(\underset{}{◯}$

I(Zc)

Nc)

{(Xi

Yi

(Zi)

Ni)

Nc

∏

n

 



is

 



1i-1

 



Nn}

(Xt

Yt

(Zt)

Nt)

Nc

∏

n

 



is

 



1t-1

 



Nn

Wherein i is 1 to t-1;

the core compound is represented by the formula

 

where

represents the core, Z^c represents the functional groups bonded to

 

and N_c represents the core valency;

the repeat unit is represented by the formula XⁱYⁱ(Zⁱ)_Ni wherein “

i”

is defined as above;

the final or terminal units are represented by X^tY^t(Z^t)_Nt wherein t represents terminal generation and X^t, Y^t, Z^t and N^t may be the same as or different from X^I, Yⁱ, Zⁱ and Nⁱ except that there is no succeeding generation connected to the Z^t groups and N^t may be less than two;

the Π

function is the product of all the values between its defined limits, such as

i=1

Π

Nⁿ=(N¹)(N²)(N³) . . . (N<sup>i−

2</sup>)(N<sup>i−

1</sup>)

n=1

which is the number of repeat units, XⁱYⁱ(Zⁱ)_Nⁱ, comprising the ith generation of one dendritic branch and when i is 1, then

24. A conjugate of claim 1 wherein at least one of the carried materials is a dye suitable for printing and reprography.

25. A dense star polymer conjugate of the formula:

26. The conjugate of claim 25 wherein x=1 and y=2 or more.

27. The conjugate of claim 25 wherein the molar ratio of any ionic M to P is 0.1-1,000:

1.

28. The conjugate of claim 25 wherein the dense star polymer is polyamidoamine.

29. The conjugate of claim 28 wherein the polyamidoamine is ester terminated.

30. The conjugate of claim 25 wherein the dense star polymer is polyethyleneimine.

31. The conjugate of claim 30 wherein the polyethyleneimine has a methylene carboxylate surface.

32. The conjugate of claim 30 wherein the polyethyleneimine has an acetate surface.

33. The conjugate of claim 30 wherein the polyethyleneimine has a surface of a polyamidoamine.

34. The conjugate of claim 25 wherein the dense star polymer is a polyether.

35. The conjugate of claim 25 wherein the dense star polymer has its surface modified with a functional group.

36. A solution of a dendrimer colored with a dye covalently attached thereto.

37. An aqueous ink composition comprising a solution of a dendrimer colored with a dye covalently attached thereto.

38. An ink in accordance with claim 37 wherein the dendrimer is a first, second or third generation dendrimer.

41. An ink in accordance with claim 37 wherein the dendrimer is microparticle of the first generation with an average diameter of about 10.4 Angstroms, and with 3 terminal amino groups.

42. An ink in accordance with claim 37 wherein the dendrimer is microparticle of the third generation with an average diameter of about 22 Angstroms, and with 12 terminal amino groups.

39. An ink composition comprised of a solution of water and a dendrimer colored with a dye attached thereto.

40. An aqueous ink composition comprised of a solution comprised of a dendrimer and a dye.

43. 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) 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 unit of at least one dye moiety, with the proviso that the dye moiety maintains its effectiveness in the conjugate.

44. The conjugate of claim 43 wherein the polymer is a dendrimer.

45. A conjugate of claim 43 wherein at least one of the carried materials is a dye suitable for printing and reprography.

46. The conjugate of claim 43 wherein the dendrimer is polyamidoamine.

47. The conjugate of claim 46 wherein the polyamidoamine is a sodium propionate terminated sixth generation polyamidoamine complexed with Fe⁺³ ions.

48. The conjugate of claim 46 wherein the polyamidoamine is an ester terminated 2.5 generation polyamidoamine complexed with Rh⁺³ ions.

49. The conjugate of claim 46 wherein the polyamidoamine is an ester terminated 3.5 generation polyamidoamine complexed with Pd⁺² ions.

50. The conjugate of claim 46 wherein the polyamidoamine is an amine terminated 9.0 generation polyamidoamine with fluorescein encapsulated.

51. The conjugate of claim 46 wherein the polyamidoamine is an amine terminated 4.0 generation polyamidoamine covalently bonded to dansyl groups.

52. The conjugate of claim 43 wherein the dendrimer is polyethyleneimine.

53. The conjugate of claim 52 wherein the polyethyleneimine is an amine terminated 2.0 generation polyethyleneimine ionically bonded to fluorescein.

54. The conjugate of claim 52 wherein the polyethyleneimine is an amine terminated 2.0 generation polyethyleneimine covalently bonded to fluorescein.

55. The conjugate of claim 52 wherein the polyethyleneimine is an amine terminated 3.0 generation polyethyleneimine covalently bonded to dansyl groups via aminoethyl linkages derived from an aziridine moiety.

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

57. A conjugate of claim 56 wherein at least one of the carried materials is a dye suitable for printing and reprography.

58. The conjugate of claim 56 wherein the dendrimer is polyamidoamine.

59. The conjugate of claim 58 wherein the polyamidoamine is a sodium propionate terminated sixth generation polyamidoamine complexed with Fe⁺³ ions.

60. The conjugate of claim 58 wherein the polyamidoamine is an ester terminated 2.5 generation polyamidoamine complexed with Rh⁺³ ions.

61. The conjugate of claim 58 wherein the polyamidoamine is an ester terminated 3.5 generation polyamidoamine complexed with Pd⁺² ions.

62. The conjugate of claim 58 wherein the polyamidoamine is an amine terminated 9.0 generation polyamidoamine with fluorescein encapsulated.

63. The conjugate of claim 58 wherein the polyamidoamine is an amine terminated 4.0 generation polyamidoamine covalently bonded to dansyl groups.

64. The conjugate of claim 56 wherein the dendrimer is polyethyleneimine.

65. The conjugate of claim 64 wherein the polyethyleneimine is an amine terminated 2.0 generation polyethyleneimine ionically bonded to fluorescein.

66. The conjugate of claim 64 wherein the polyethyleneimine is an amine terminated 2.0 generation polyethyleneimine covalently bonded to fluorescein.

67. The conjugate of claim 64 wherein the polyethyleneimine is an amine terminated 3.0 generation polyethyleneimine covalently bonded to dansyl groups via aminoethyl linkages derived from an aziridine moiety.

68. A solvent soluble dense star polymer conjugate which comprises at least one dense star polymer and at least one dye moiety which 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 dye moiety maintains its effectiveness in the conjugate.

69. The conjugate of claim 68 wherein the dense star polymer is radially symmetrical.

70. The conjugate of claim 68 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.