Bioactive and/or targeted dendrimer conjugates

• US 5,714,166 A
• Filed: 03/07/1995
• Issued: 02/03/1998
• Est. Priority Date: 08/18/1986
• Status: Expired due to Term

• Current Assignee: AVC Holdings Inc., Donald A. Tomalia, Dendritic NanoTechnologies, Inc. (Loveland Products, Inc.), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Dendritech Inc., The Dow Chemical Company (Dow, Inc.), Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Baker, James R., Klakamp, Scott L., Yin, Rui, Bielinska, Anna U., Maxon, Bartley D., Johnson, Jennifer A., Kukowska-Latallo, Jolanta, Piehler, Lars T., Kaplan, deceased, Donald A., Kruper, William J. Jr., Fazio, Michael J., Tomlinson, Ian A., Tomalia, Donald A., Wilson, Larry R., Brothers, Herbert M. II, Hedstrand, David M., Cheng, Roberta C.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/400,203
• Time in Patent Office: 1,064 Days
• Field of Search: 424/1.29, 424/1.33, 424/1.37, 424/1.41, 424/1.49, 424/9.3, 424/9.322, 424/9.32, 424/9.36, 424/9.4, 424/9.42, 424/9.6, 424/78.08, 424/78.16, 424/78.18, 424/78.19, 424/78.22, 424/280, 424/93.1, 424/178.1, 424/193.1, 424/204.1, 424/234.1, 424/DIG. 16, 424/405, 424/417, 424/486, 424/78.23 , 424/78.26, 424/78.27, 424/78.34, 424/78.37, 514/772, 514/772.1, 514/772.3, 514/772.4-772.8, 523/105, 525/417, 935/52, 935/54
• US Class Current: 424/486
• 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 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6949 inclusion complexes, e.g. clathrates, cavitates or fullerenes
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• 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 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

Dendritic polymer conjugates which are composed of at least one dendrimer in association with at least one unit of a carried material, where the carrier material can be a biological response modifier, have been prepared. The conjugate can also have a target director present, and when it is present then the carried material may be a bioactive agent. Preferred dendritic polymers are dense star polymers, which have been complexed with biological response modifiers. These conjugates and complexes have particularly advantageous properties due to their unique characteristics.

Claims

1. A dense star polymer conjugate which comprises at least one dense star polymer associated with at least one unit of at least one bioactive agent, selected from the group consisting of a therapeutic agent, a diagnostic agent, and a therapeutic/diagnostic agent.

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 in configuration.

4. The conjugate of claim 2 wherein the dendrimer is generally spherical, ellipsoidal, or rod-shaped in configuration.

5. The conjugate of claim 1 wherein said dense star polymer 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 said branches of the extended conventional star polymer bearing only one terminal group, and

(3) molecular volume that is no more than about 80% 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.

6. The conjugate of claim 1 wherein the bioactive agent is a biological response modifier.

7. The conjugate of claim 6 wherein two or more biological response modifiers are present.

8. The conjugate of claim 6 wherein said biological response modifier is selected from the group consisting of an interleukin, and interferon.

9. The conjugate of claim 6 wherein said biological response modifier is genetic material.

10. The conjugate of claim 9 wherein said dense star polymer comprises predominately amino functional surface groups.

11. The conjugate of claim 9 wherein said genetic material extends between and serves to connect a plurality of dense star polymer particles together.

12. The conjugate of claim 9 wherein said dense star polymer has one cross-sectional dimension of at least about 50 Å

, wherein said dimension is the narrowest dimension of said dense star polymer.

13. The conjugate of claim 9 wherein the dense star polymer is a dendrimer and the charge ratio of genetic material to dendrimer is from about 10:

1 to about 1;

10,000.

14. The conjugate of claim 13 wherein the charge ratio of genetic material to dendrimer is from about 3:

1 to about 1;

1,000.

15. The conjugate of claim 13 wherein the charge ratio of genetic material to dendrimer is from about 1:

1 to about 1;

100.

16. The conjugate of claim 13 wherein the charge ratio of genetic material to dendrimer is from about 1:

1 to about 1;

15.

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

17. A dense star polymer conjugate of the formula:

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

wherein;

each P represents a dense star polymer;

x represents an integer of 1 or greater;

each M represents at least one unit of a bioactive agent, selected from the group consisting of a therapeutic agent, a diagnostic agent, and a therapeutic/diagnostic agent, said bioactive agent can be the same bioactive agent or a different bioactive agent;

y represents an integer of 1 or greater;

each T represents one or more target directors;

e represents an integer of 1 or greater; and

* indicates that the bioactive agent is associated with the dense star polymer;

with the proviso that the bioactive agent maintains its effectiveness.

19. The conjugate of claim 17 or 18 wherein the dense star polymer, P, is a dendrimer.

20. The conjugate of claim 19 wherein the dendrimer is polyamidoamine or a polyalkyleneimine.

21. The conjugate of claim 17 or 18 wherein the target director, T, is a polyclonal or monoclonal antibody or fragment thereof.

22. The conjugate of claim 17 or 18 wherein M is selected from the group consisting of a drug, pesticide, radionuclide, chelator, chelated metal, toxin, antibody, antibody fragment, antigen, signal generator, signal reflector, signal absorber and fragrance.

23. The conjugate of claim 22 wherein the signal absorber is a contrast agent.

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

25. The conjugate of claim 22 wherein the signal generator is a fluorescing entity or radionuclide.

26. The conjugate of claim 22 wherein the signal reflector is a metal ion selected from Fe, Rh, Pd and Y.

27. The conjugate of claim 17 wherein at least one of the carried materials is an electron beam opacifier.

28. The conjugate of claim 17 or 18 wherein M is an aromatic ultraviolet absorber.

32. The conjugate of claim 17, 18, 19 or 20 for use as a reagent in positron emission tomography, computer aided tomography, or magnetic resonance imaging.

33. The conjugate of claim 17, 18, 19 or 20 for use as a diagnostic agent.

84. A formulation which comprises a conjugate of claim 17 having at least one pharmaceutically acceptable diluent or carrier present.

18. A dense star polymer conjugate of the formula

View Dependent Claims (29, 30, 31, 85)

29. The conjugate of claim 18 wherein said bioactive agent is a biological response modifier.

30. The conjugate of claim 29 wherein said biological response modifier is selected from the group consisting of an interleukin, interferon, tumor necrosis factor, and granulocyte colony stimulating factor.

31. The conjugate of claim 30 wherein said biological response modifier is genetic material.

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

34. A composition comprising a dendritic polymer complexed with at least one unit of biological response modifier, selected from the group consisting of an interleukin, interferon, tumor necrosis factor, and granulocyte colony stimulating factor.

86. A formulation which comprises a conjugate of claim 34 having at least one pharmaceuticalIy acceptable diluent or carrier present.

35. A composition comprising a dendritic polymer complexed with at least one unit of biological response modifier, wherein said biological response modifier is genetic material.

36. The composition of claim 35 wherein said dendritic polymer comprises a dendritic polymer having positive surface functionality over a substantial portion of the polymer surface.

37. The composition of claim 36 wherein said positive surface functionality is created by amino groups at the dendritic polymer surface.

38. The composition of claim 36 wherein said dendritic polymer comprises a dendrimer having positive surface functionality over at least 75% of its dendrimer surface.

39. The composition of claim 36 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 10:

1 to about 1;

10,000.

40. The composition of claim 36 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 3:

1 to about 1;

10,000.

41. The composition of claim 36 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

1 to about 1;

1,000.

42. The composition of claim 36 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

1 to about 1;

15.

43. The composition of claim 36 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

10 to about 1;

10,000.

44. A composition of claim 36 which comprises a complex of dendritic polymer with genetic material, in solution with either DEAE-dextran or glycerol.

45. The composition of claim 44 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

1 to about 1;

15.

46. The composition of claim 44 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

5 to about 1;

10.

47. The composition of claim 45 wherein the complex is in solution with DEAE-dextran at a concentration from about 0.125 to about 2 μ

M.

48. The composition of claim 47 wherein the concentration of DEAE-dextran in said composition is from about 0.25 to about 1 μ

M.

49. The composition of claim 44 wherein said complex is in solution with glycerol at a concentration from about 2.0 to about 10.0% by volume.

50. The composition of claim 49 wherein said complex is in solution with glycerol at a concentration from about 2.0 to about 5.0% by weight.

51. The composition of claim 44, 47 or 50 wherein said composition further comprises DMSO.

52. The composition of claim 44 or 45 wherein said composition further comprises chloroquine.

53. The composition of claim 36 wherein a target director is associated with said dendritic polymer.

54. The composition of claim 53 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 10:

1 to about 1;

10,000.

55. The composition of claim 53 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 1:

1 to about 1;

15.

56. The composition of claim 53 wherein said genetic material and said dendritic polymer are complexed in a charge ratio from about 3:

1 to about 1;

10.

57. The composition of claim 53 or 55 which comprises a complex of dendritic polymer with genetic material, in solution with either DEAE-dextran or glycerol.

58. The composition of claim 53 or 55 wherein the target director is a polyclonal or monoclonal antibody or fragment thereof.

59. The composition of claim 53 or 55 wherein said target director is galactose trisaccharide, biotin, pyruvic acid, insulin or avidin.

60. The composition of claim 36, 39, 44, 45, 53 or 55 wherein said dendritic polymer comprises particles whose dimensions are from about 20 Å

at their narrowest dimensions to about 1,000 Å

at their largest dimensions.

61. The composition of claim 60 wherein the dendritic polymer is a dense star polymer.

62. The composition of claim 61 wherein the dense star polymer is a dendrimer.

63. The composition of claim 61 wherein said dense star polymer comprises dense star dendrimer which is generally spherical, eilipsoidal, or rod-shaped in configuration.

64. The composition of claim 61 wherein said dendritic polymer comprises aggregates of dendrimers having positive surface functionality and dendrimers having negative surface functionality at a positive:

negative charge ratio from about 25;

1 to about 100;

1.

65. The composition of claim 61 wherein said dendritic polymer comprises a dense star polymer having amino acids over a substantial portion of its surface, and substantially only on its surface.

66. The composition of claim 65 wherein said amino acid is lysine or arginine.

67. The composition of claim 61 wherein the dense star polymer comprises a collection of bridged dense star dendrimers.

68. The composition of claim 67 wherein said genetic material extends between and serves to connect a plurality of dense star polymer particles.

69. The composition of claim 61 wherein said dendritic polymer is comprised of a dispersion of different sized dendrimer particles, ranging from particles having a diameter as small as about 20 Å

at their smallest dimension to particles having a diameter of about 110 Å

, there being other particles of intermediate diameters in said dispersion.

70. A composition of claim 36, 39, 44, 45, 53, 55 or 57 wherein a genetic material is complexed with a first dendritic polymer which has been placed in a solution containing a second dendritic polymer, said second dendritic polymer being larger than said first dendritic polymer.

71. The composition of claim 70 wherein said dendritic polymer is a dense star polymer.

72. The composition of claim 70 or 71 wherein said first dendritic polymer has a diameter at its narrowest dimension from about 22 to about 50 Å

, and said second dendritic polymer has at its narrowest dimension a diameter from about 50 to about 1,000 Å

.

73. The composition of claim 70, 71 or 72 wherein one or both of said first and second dendritic polymers are comprised of spherically shaped dendrimers.

74. The composition of claim 70 wherein both of said first and second dendritic polymers are comprised of spherically shaped dendrimers.

75. The composition of claim 36, 39, 44, 45, 53 or 55 wherein said dendritic polymer comprises an unsymmetrically branched dendritic polymer.

76. The composition of claim 75 wherein the monomeric building block of said unsymmetrically branched dendritic polymer is an amino acid.

77. The composition of claim 76 wherein the said amino acid is lysine.

78. The composition of claim 36, 39, 44, 45, 53 or 55 wherein said dendritic polymer comprises aggregates of dendrimers having positive surface functionality and dendrimers having negative surface functionality at a positive:

negative charge ratio from about 25;

1 to about 100;

1.

79. The composition of claim 36, 39, 44, 45, 53 or 55 wherein said dendritic polymer comprises a dense star polymer having amino acids over a substantial portion of its surface, and substantially only on its surface.

80. The composition of claim 79 wherein said amino acid is lysine or arginine.

81. The composition of claim 36, 39, 44, 45, 53 or 55 wherein said dendritic polymer is comprised of a dispersion of different sized dendrimer particles, ranging from particles having a diameter as small as about 20 Å

at their smallest dimension to particles having a diameter of about 110 Å

, there being other particles of intermediate diameters in said dispersion.

82. The composition of claim 36, 39, 53 or 55 wherein said composition further includes chloroquine.

87. A formulation which comprises a conjugate of claim 53 having at least one pharmaceutically acceptable diluent or carrier present.

88. A process for preparing a conjugate of dendritic polymer and biological response modifier, selected from the group consisting of an interleukin, interferon, tumor necrosis factor, and granulocyte colony stimulating factor, comprising reacting the dendritic polymer with the biological response modifier in a suitable solvent at a temperature which facilitates the association of the biological response modifier and the dendritic polymer.

89. A process for preparing a conjugate of dendritic polymer and biological response modifier, wherein said biological response modifier comprises genetic material and said dendritic polymer has a predominantly cationic surface character, comprising reacting the dendritic polymer with the biological response modifier in a suitable solvent at a temperature which facilitates the association of the biological response modifier and the dendritic polymer, said process comprising electrostatically attaching said genetic material to said dendritic polymer to create said conjugate.

90. A process for preparing a complex of dendritic polymer and genetic material comprising:

reacting said dendritic polymer with said genetic material in a suitable solvent at a temperature which facilitates the complexing of said genetic material with said dendritic polymer, said process

comprising placing said complex in a solution with DEAE-dextran or glycerol.

91. The process of claim 90 which includes attaching a target director to said dendritic polymer before complexing it with genetic material.

92. The process of claim 90 wherein said dendritic polymer has a predominantly cationic surface, said process comprising electrostatically attaching genetic material to said dendritic polymer to create said complex.

93. A process for forming a dendritic polymer-genetic material complex comprising:

complexing genetic material with a first dendritic polymer by reacting the polymer with the genetic material in a suitable solvent at a temperature which facilitates association of the genetic material with the polymer; and

placing said complex in a solution containing a second dendritic polymer, said second dendritic polymer being larger than said first dendritic polymer.

94. The process of claim 93 which includes attaching a target director to said dendritic polymer before complexing it with genetic material.

95. The process of claim 93 wherein said dendritic polymer has a predominately cationic surface, said process comprising electrostatically attaching said genetic material to said dendritic polymer.

96. A process for forming a genetic material:

dendritic polymer complex comprising;

mixing, in water, sufficient genetic material to yield a final concentration from about 1 to about 10 μ

g per mL, with sufficient dendritic polymer, having positive surface functionality, to yield a genetic material;

dendritic polymer charge ratio from about 3;

1 to about 1;

10,000;

said mixing being done at a pH from about 5 to about 10 and at a temperature from about 20°

to about 40°

C.

97. The process of claim 96 wherein said charge ratio is from about 1:

1 to about 1;

1,000.

98. The process of claim 96 which includes adding sufficient DEAE-dextran to said complex after it is formed, to yield a DEAE-dextran concentration from about 0.125 to about 2 μ

M.

99. The process of claim 98 wherein said charge ratio is from about 1:

1 to about 1;

15.

100. The process of claim 99 wherein said charge ratio is from about 1:

5 to about 1;

10.

101. The process of claim 98 wherein sufficient DEAE-dextran is added to yield a DEAE-dextran concentration from about 0.25 to about 1 μ

M.

102. The process of claim 98 wherein said dendritic polymer has a diameter from about 50 Å

at its narrowest diameter, to a maximum diameter of about 1,000 Å

.

103. The process of claim 96 wherein said dendritic polymer is comprised of a dispersion of different sized dendrimer particles, ranging from particles having a diameter as small as about 20 Å

at their smallest dimension to particles having a diameter of about 110 Å

, there being other particles of intermediate diameters in said dispersion.

104. The process of claim 96 wherein said dendritic polymer comprises aggregates of dendrimers having positive surface functionality and dendrimers having negative surface functionality at a positive:

negative charge ratio from about 25;

1 to about 100;

1, said aggregates having diameters of no more than about 1,000 Å

.

105. The process of claim 96 wherein said dendritic polymer comprises a dense star polymer having amino acids over a substantial portion of its surface, and substantially only on its surface.

106. The process of claim 105 wherein said amino acid is lysine or arginine.

107. The process of claim 96 wherein said dendritic polymer comprises relatively small dendrimer particles having a diameter of 22 to 50 Å

at their smallest dimension;

said process further including adding dendritic polymers whose particles have diameters from about 50 to about 110 Å

at their smallest dimension, after said complex has formed.

108. The process of claim 96 wherein said dendritic polymer particles include target director moieties attached thereto.

109. The process of claim 96 which includes adding sufficient glycerol to said complex after it is formed, to yield a glycerol concentration from about 2 to about 10 percent by weight.

110. The process of claim 109 wherein said glycerol concentration is from about 2 to about 5 percent by weight.

111. The process of claim 109 wherein said charge ratio is from about 1:

1 to about 1;

15.

112. The process of claim 109 wherein said dendritic polymer has a diameter from about 50 Å

at its narrowest diameter, to a maximum diameter of about 1,000 Å

.

113. A process for forming a concentrated genetic material:

dendritic polymer complex which can be diluted for use comprising;

mixing, in water, sufficient genetic material to yield a concentration from about 1 to about 10 μ

g per 20 μ

L, with sufficient dendritic polymer, having positive surface functionality, to yield a genetic material;

dendritic polymer charge ratio from about 4;

1 to about 1;

10,000;

said mixing being done at a pH from about 5 to about 10 and at a temperature from about 20°

to about 40°

C.

114. The process of claim 113 wherein said charge ratio is from about 1:

1 to about 1;

1,000.

115. The process of claim 113 wherein said charge ratio is from about 1:

1 to about 1;

15.

116. The process of claim 113 wherein said charge ratio is from about 1:

5 to about 1;

10.

117. The process of claim 113 wherein said dendritic polymer has a diameter from about 50 Å

at its narrowest diameter, to a maximum diameter of about 1,000 Å

.

118. The process of claim 113 wherein said dendritic polymer is comprised of a dispersion of different sized dendrimer particles, ranging from particles having a diameter as small as about 20 Å

at their smallest dimension to particles having a diameter of about 110 Å

, there being other particles of intermediate diameters in said dispersion.

119. The process of claim 113 wherein said dendritic polymer comprises aggregates of dendrimers having positive surface functionality and dendrimers having negative surface functionality at a positive:

negative charge ratio from about 25;

1 to about 100;

1, said aggregates having diameters of no more than about 1,000 Å

.

120. The process of claim 113 wherein said dendritic polymer comprises a dense star polymer having amino acids over a substantial portion of its surface, and substantially only on its surface.

121. The process of claim 120 wherein said amino acid is lysine or arginine.

122. The process of claim 113 wherein said dendritic polymer particles include target director moieties attached thereto.

123. The process of claim 123 wherein said dendritic polymer comprises relatively small dendrimer particles having a diameter of about 22 to about 50 Å

at their smallest dimension;

said process further including adding dendritic polymers whose particles have diameters from about 50 to about 110 Å

at their smallest dimension, after said complex is formed.

124. A method of effecting cell transfection and bioavailability of genetic material comprising providing a complex of a dendritic polymer and genetic material, and making said complex available to cells to be transfected.

125. A method for transporting genetic material through a cellular membrane and into a cellular nucleus comprising:

complexing said genetic material with dendritic polymer;

followed by making said complex available to cells to be transfected.

126. A method for protecting genetic material from digestion during transit to and transfection into a cell comprising:

complexing said genetic material with dendritic polymer prior to exposing the said genetic material to digestive enzymes.

127. A method for stabilizing and compacting genetic material comprising:

complexing said genetic material with dendritic polymer.

128. A method of effecting cell transfection and bioavailability of genetic material comprising providing a complex of a dendritic polymer and genetic material, in solution with DEAE-dextran or glycerol, and making said complex available to cells to be transfected.

129. The method of claim 128 which includes attaching a target director to said dendritic polymer.

130. A method for effecting cell transfection and bioavailability of genetic material comprising:

forming a complex of a first dendritic polymer and genetic material, followed by placing said complex in a solution containing a second dendritic polymer, wherein said second dendritic polymer is larger than said first dendritic polymer; and

making the resulting complex and second dendritic polymer available to cells to be transfected.

131. The method of claim 130 wherein at least one of said first and second dendritic polymers has attached a target director.

132. A dense star polymer conjugate which comprises at least one dense star polymer associated with at least one unit of at least one bioactive agent, selected from the group consisting of therapeutic agents, diagnostic agents, and therapeutic/diagnostic agents.

133. A dense star polymer conjugate of the formula:

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

wherein;

each P represents a dense star polymer;

x represents an integer of 1 or greater;

each M represents at least one unit of a bioactive agent, said bioactive agent can be the same bioactive agent or a different bioactive agent, said bioactive agent, selected from the group consisting of therapeutic agents, diagnostic agents, and therapeutic/diagnostic agents;

y represents an integer of 1 or greater;

each T represents one or more target directors;

e represents an integer of 1 or greater; and

* indicates that target director and bioactive agent are associated with the dense star polymer;

with the proviso that the bioactive agent maintains its effectiveness.

134. A dense star polymer conjugate of the formula:

space="preserve" listing-type="equation"> (T).sub.e -(C'"'"').sub.f !.sub.g *(P).sub.x * (C").sub.h -(M).sub.y !.sub.k(III)

wherein;

each C'"'"' represents the same or different connecting group;

each C" represents the same or different connecting group;

g and k each individually represent an integer of 1 or greater;

e represents an integer of 1 or greater;

f and h each individually represent an integer of 0 or greater;

- indicates a covalent bond in instances where a connecting group is present;

each P represents a dense star polymer;

x represents an integer of 1 or greater;

each T represents one or more target directors;

each M represents at least one unit of a carried bioactive agent, selected from the group consisting of therapeutic agents, diagnostic agents, and therapeutic/diagnostic agents;

y represents an integer of 1 or greater; and

* indicates that target director and carried bioactive agent are associated with the dense star polymer;

with the proviso that the carried bioactive agent maintains its effectiveness.

135. A dense star polymer conjugate of the formula:

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

wherein;

each P represents a dense star polymer;

x represents an integer of 1 or greater;

each M represents at least one unit of a earned material, said carried material can be the same carried material or a different carried material, said carrier material selected from the group consisting of fragrance moieties, scavenging agents, pheromones, pesticides, agricultural materials, and pollutants;

y represents an integer of 1 or greater;

each T represents one or more target directors;

e represents an integer of 1 or greater; and

* indicates that target director and carried material are associated with the dense star polymer;

with the proviso that the carrier material maintains its effectiveness.

136. A dense star polymer conjugate of the formula:

space="preserve" listing-type="equation"> (T).sub.e -(C'"'"'.sub.f !.sub.g *(P).sub.x * (C").sub.h -(M).sub.y !.sub.k(III)

wherein;

each C'"'"' represents the same or different connecting group;

each C" represents the same or different connecting group;

g and k each individually represent an integer of 1 or greater;

e represents an integer of 1 or greater;

f and h each individually represent an integer of 0 or greater;

- indicates a covalent bond in instances where a connecting group is present;

each P represents a dense star polymer;

x represents an integer of 1 or greater;

each T represents one or more target directors;

each M represents at least one unit of a carried material, selected from the group consisting of fragrance moieties, scavenging agents, pheromones, pesticides, agricultural materials, and pollutants;

y represents an integer of 1 or greater; and

* indicates that target director and carried material are associated with the dense star polymer;

with the proviso that the carried material maintains its effectiveness.