Disulfide-containing dendritic polymers

• US 6,020,457 A
• Filed: 09/30/1997
• Issued: 02/01/2000
• Est. Priority Date: 09/30/1996
• Status: Expired due to Term

• Current Assignee: Dendritic NanoTechnologies, Inc. (Loveland Products, Inc.)
• Original Assignee: Dendritech Inc.
• Inventors: Swanson, Douglas R., Spindler, Ralph, Yin, Rui, Klimash, June W., Hsu, Yong, Tomalia, Donald A., Brothers, Herbert M. II, Cheng, Roberta C.
• Primary Examiner(s): HAMPTON HIGHTOWER, PATRICIA
• Application Number:
  US08/941,527
• Time in Patent Office: 854 Days
• Field of Search: 528/397, 528/373, 528/363, 525/410, 525/419, 424/DIG. 16
• US Class Current: 528/373
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: B82Y 40/00 Manufacture or treatment of nanostructures
• CPC Class Codes: C08G 83/003 Dendrimers
• CPC Class Codes: Y10S 424/16 Dendrimers and dendritic polymers

Abstract

Dendritic polymers containing disulfide functional groups which are essentially inert under non-reducing conditions, but which form sulfhydryl groups upon being subjected to a reducing agent are prepared by synthesizing dendritic polymers having a core with a disulfide linkage or by reacting a dendritic polymer with a molecule containing a disulfide linkage and reactive terminal groups. In one aspect of the invention, dendritic polymers having a single disulfide functional group at the core are provided. The single disulfide group at the core can be reduced to form two sulfhydryl groups to which other molecules, such as proteins, oligonucleotides, peptides, hormones, other dendritic polymers, non-dendritic polymers, etc., can be bound. Applications for the disulfide functionalized dendritic polymers include formation of differentiated dendrimers, formation of binding reagents for diagnostics, drug delivery, gene therapy and magnetic resins imaging, and in the preparation of self-assembled dendrimer monolayers on a quartz crystal resonators to provide dendrimer-modified electrodes which are useful for detecting various ions or molecules. In another aspect of the invention, dendritic polymers having sulfhydryl terminals are provided. The sulfhydryl terminated dendritic polymers can be used to prepare stable, curable resins composition which can undergo cross linking when subjected to a reducing agent.

Claims

1. A dendritic polymer having a core containing a disulfide moiety and at least two dendrons emanating from the core, each dendron having at least two terminal groups.

2. The dendritic polymer of claim 1, wherein the core is a polyamine compound containing a disulfide moiety.

3. The dendritic polymer of claim 2, wherein the polyamine compound is a diamine.

4. The dendritic polymer of claim 3, wherein the diamine is cystamine.

5. The dendritic polymer of claim of 1, wherein the dendrons are polyamidoamine dendrons.

6. A dendritic polymer having a core and a plurality of dendrons emanating from the core, each of the dendrons having branch arms which include a disulfide moiety which is essentially inert under non-reducing conditions, but which when subjected to a reducing agent will react with the reducing agent to form a dendritic polymer having sulfhydryl terminal groups.

7. The dendritic polymer of claim 6, wherein the disulfide moieties comprise the terminal groups of the branch arms.

8. A thin film coated substrate comprising a substrate which has been subjected to application of ions or ionizable compounds of the same charge over the surface of the substrate, and one or more layers of organic materials which in each layer contain ions of the same charge, the ions of the layer immediately adjacent the substrate having the opposite charge of the modified substrate and, in the case of further layers, each further layer having a charge opposite that of the previous layer, and at least one of the layers comprising a dendritic polymer.

9. The thin film coated substrate of claim 8, wherein at least one of the layers comprises a dendritic polymer having a core containing a disulfide moiety.

10. A quartz crystal electrode comprising a metal coated quartz crystal electrode subjected to application of a dendritic polymer coating.

11. The quartz crystal electrode of claim 10, wherein the dendritic polymer coating comprises a monolayer of dendritic polymer molecules.

12. The quartz crystal electrode of claim 10, wherein the dendritic polymer has a core with a disulfide moiety.

13. The quartz crystal electrode of claim 10, wherein the dendritic polymer is a polyamidoamine dendrimer having a core with a disulfide moiety.

14. The quartz crystal electrode of claim 10, wherein the dendritic polymer is a polyamidoamine dendrimer having a cystamine core.

15. A differentiated dendritic polymer having a core with a disulfide moiety and at least two dendrons emanating from the core, each of the dendrons having at least two terminal groups, at least one of the dendrons having terminal groups that are different from those of the other dendron.

16. The differentiated dendritic polymer of claim 15, wherein a first dendron is of a different generation than a second dendron.

17. A method of making a dendritic polymer having a core with a disulfide moiety and a plurality of dendrons emanating from the core, comprising:

providing a core molecule having a disulfide moiety and a plurality of reactive terminal groups; and

reacting the terminal groups of the core molecule with a plurality of dendrons, each dendron having a single reactive group which bonds to one of the reactive terminal groups of the core molecule.

18. The method of claim 17, wherein the core is a polyamine compound containing a disulfide moiety.

19. The method of claim 18, wherein the polyamine compound is a diamine.

20. The method of claim 19, wherein the diamine is cystamine.

21. A method of making a dendritic polymer having a core with a disulfide moiety and a plurality of dendrons emanating from the core, comprising:

providing a core molecule having a disulfide moiety and a plurality of reactive terminal groups;

reacting the terminal groups of the core molecule with a first reagent to form a -1/2 generation dendrimer, each molecule of the fit reagent having at least a single reactive site which bonds with one of the reactive terminal groups of the core molecule and at least one reactive moiety which becomes a terminal reactive moiety on the -1/2 generation dendrimer;

reacting each of the terminal reactive moieties on the -1/2 generation dendrimer with a second reagent to form a zero generation dendrimer, each molecule of the second reagent including at least one reactive site which bonds with a terminal reactive moiety on the -1/2 generation dendrimer and at least one reactive site which becomes a terminal reactive moiety on the zero generation dendrimer; and

optionally employing additional reagents to synthesize a dendritic polymer of a desired generation.

22. The method of claim 21, wherein the core is a polyamine compound containing a disulfide moiety.

23. The method of claim 22, wherein the polyamine compound is a diamine.

24. The method of claim 23, wherein the diamine is cystamine.

25. The method of claim 21, wherein the dendrons are polyamidoamine dendrons.

26. The method of claim 25, wherein an iterative excess reagent technique, alternately employing excess amounts of methyl acrylate and ethylene diamine, is employed.

27. A method of making a dendritic polymer having a core and a plurality of dendrons emanating from the core, each of the dendrons having branched arms which include a disulfide moiety, comprising:

providing a dendritic polymer having reactive terminal groups; and

reacting the terminal groups of the dendritic polymer with a monomer having a disulfide moiety, each of the monomer molecules including a reactive site which bonds with one of the reactive terminal groups of the dendritic polymer.

28. The method of claim 27, wherein the disulfide moieties comprise the termninal groups of the branched arms.

29. The method of claim 27, wherein each of the monomer molecules bonded to the dendritic polymer includes additional reactive sites, and the method further comprises subsequently employing divergent dendritic polymer synthesis techniques to form dendritic polymers having internal disulfide branch cells.

30. A method of making a thin film coated substrate, comprising:

providing a substrate which has been modified by application of ions or ionizable compounds of the same charge over the surface of the substrate; and

applying one of more layers made of organic materials, the organic materials in each layer having ions of the same charge, the organic materials being applied from a solution of the organic materials to the substrate which has been modified, the organic material for the first layer having ions of the opposite charge relative to the charge of the ions of the substrate which has been modified and, in the case of further layers, each further layer containing ions of opposite charge relative to the charge of the ions in the previous layer, at least one of the layers comprising a dendritic polymer.

31. The method of claim 30, wherein at least one of the layers comprises a dendritic polymer having a core containing a disulfide moiety.

32. A method of forming a differentiated dendritic polymer, comprising:

providing a first dendritic polymer having a core with a disulfide moiety and at least two dendrons emanating from the core, each of the dendrons having at least two terminal groups;

providing a second dendritic polymer having a core with a disulfide moiety and a plurality of dendrons emanating from the core, each of the dendrons of the second dendritic polymer having at least two terminal groups;

combining and subjecting the first and second dendritic polymers to reducing conditions to form a mixture of two different types of dendritic molecules, each having a single reactive sulfhydryl group; and

subjecting the mixture to aerobic, oxidizing conditions to form a mixture containing the first and second dendritic polymers, and a differentiated dendritic polymer comprised of a part of each of the original first and second dendritic polymers.

33. The method of claim 32, wherein the first and second dendritic polymers are of different generations.

34. A gel comprised of crosslinked dendritic polymers, comprising:

dendritic polymers, each having sulfhydryl terminal groups which react with sulfhydryl terminal groups of another dendritic polymer to form a crosslinked gel.

35. The gel of claim 34, wherein the dendritic polymer is the reaction product of a dendritic polymer having amine terminal groups and iminothiolane.

36. The gel of claim 35, wherein the dendritic polymer is a polyamidoamine dendrimer.

37. The gel of claim 34, wherein the dendritic polymer was prepared by subjecting a dendritic polymer having sulfide moieties to oxidizing conditions.

38. The gel of claim 34, wherein the crosslinked dendritic polymer gel can be resolubilized upon addition of a reducing agent to provide a redox reversible gel.

39. The gel of claim 38, wherein the reducing agent is dithiothreitol.

40. A dendritic polymer conjugate comprising a dendritic polymer having a sulfhydryl group and a first carried material having a sulfhydryl-reactive group, conjugated to the dendritic polymer at the sulfhydryl group.

41. The conjugate of claim 40, wherein the dendritic polymer includes surface functional groups, and the dendritic polymer is conjugated to a second carried material through the surface functional groups.

42. The conjugate of claim 41, wherein at least one of the first and second carried materials is a bioactive agent.

43. The conjugate of claim 42, wherein the bioactive agent is selected from the group consisting of pharmaceutical agents, drugs, pharmaceutical intermediaries, radioprotective agents, toxins, antibodies, antibody fragments, hormones, biological responses modifiers, scavenging agents, immuno-potentiating agents, genetic materials, antigens, polypeptides, proteins and combinations thereof.

44. The conjugate of claim 41, wherein at least one of the first and second carried materials is an oligonucleotide.

45. The conjugate of claim 40, wherein the sulfhydryl group is derived from a disulfide core.

46. The conjugate of claim 40, wherein the dendritic polymer is a polyamidoamine dendrimer.

47. The conjugate of claim 41, wherein the second carried material is a bioactive agent, a signal amplifier, or a combination thereof.

48. The conjugate of claim 41, wherein the second carried material is selected from the group consisting of pharmaceutical agents, drugs, pharmaceutical intermediaries, radioprotective agents, toxins, antibodies, antibody fragments, hormones, biological responses modifiers, scavenging agents, immuno-potentiating agents, genetic materials, antigens, polypeptides, proteins and combinations thereof.

49. The conjugate of claim 41, wherein the second carried material is triethyltinpropanate.