Matrices for drug delivery and methods for making and using the same

• US 6,395,299 B1
• Filed: 02/14/2000
• Issued: 05/28/2002
• Est. Priority Date: 02/12/1999
• Status: Expired due to Fees

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Biostream, Inc.
• Inventors: Babich, John W., Bonavia, Grant, Zubieta, Jon
• Primary Examiner(s): Patterson, Jr., Charles L.
• Application Number:
  US09/503,438
• Time in Patent Office: 834 Days
• Field of Search: 424/484 435/925
• US Class Current: 424/484
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• CPC Class Codes: A61K 38/51 Lyases (4)
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: C12Q 1/00 Measuring or testing processes involving enzymes, nucleic acids or microorganisms measuring or testing apparatus with condition measuring or sensing means, e.g. colony counters, C12M1/34; Compositions therefor; Processes of preparing such compositions
• CPC Class Codes: C12Y 401/01028 Aromatic-L-amino-acid decarboxylase (4.1.1.28), i.e. tryptophane-decarboxylase
• CPC Class Codes: G01N 33/5436 with ligand physically entrapped within the solid phase liposomes G01N33/5432; immunological test elements G01N33/54386
• CPC Class Codes: G01N 33/552 Glass or silica

Abstract

In one aspect, biocompatible matrices such as sol-gels encapsulating a reaction center may be administered to a subject for conversion of prodrugs into biologically active agents. In certain embodiments, the biocompatible matrices of the present invention are sol-gels. In one embodiment, the enzyme L-amino acid decarboxylase is encapsulated and implanted in the brain to convert L-dopa to dopamine for treatment of Parkinson'"'"'s disease.

Claims

1. A method for producing a biologically active agent from a prodrug, comprising:

a. encapsulating a first cell-free reaction center in a biocompatible matrix; and

b. administering said biocompatible matrix to a subject;

wherein said biocompatible matrix comprises an inorganic-based sol-gel matrix and wherein said first reaction center converts a first prodrug into a first biologically active agent in said subject.

2. The method of claim 1, wherein said biocompatible matrix comprises a silica-based sol-gel matrix.

3. The method of claim 2, wherein said first reaction center comprises one of the following:

an enzyme, an antibody or a catalytic antibody.

4. The method of claim 2, wherein said biocompatible matrix encapsulates at least one additive.

5. The method of claim 2, wherein said first reaction center comprises L-amino acid decarboxylase.

6. The method of claim 5, wherein said first prodrug comprises L-dopa and said first biologically active agent comprises dopamine.

7. The method of claim 2, wherein said first reaction center comprises L-tyrosine decarboxylase.

8. The method of claim 7, wherein said first prodrug comprises L-dopa and said first biologically active agent comprises dopamine.

9. The method of claim 2, further comprising encapsulating a second reaction center in said biocompatible matrix before administering said biocompatible matrix to said subject.

10. The method of claim 9, wherein said first biologically active agent produced by said first reaction center from said first prodrug is a second prodrug for said second reaction center, and wherein said second reaction center produces a second biologically active agent that differs from said first biologically active agent.

11. The method of claim 10, wherein said first reaction center comprises tyrosine monooxygenase, and said second reaction center is one of the following:

L-amino acid decarboxylase or L-tyrosine decarboxylase.

12. The method of claim 11, wherein said first prodrug comprises tyrosine, and both said first biologically active agent and said second prodrug comprise L-dopa, and said second biologically active agent comprises dopamine.

13. The method of claims 4, 5, 6, 7, 8, 11 or 12, wherein administering said biocompatible matrix comprises administering said biocompatible matrix to a region of the brain of said subject.

14. The method of claim 13, wherein said region of said brain of said subject is one of the following:

basal ganglia, substantia nigra or striatum.

15. The method of claim 2, wherein said biocompatible matrix is prepared from at least one type of oxysilane.

16. The method of claim 15, wherein said biocompatible matrix is prepared from more than one type of oxysilane.

17. The method of claim 15, wherein said biocompatible matrix is prepared from at least one type of inorganic oxide and at least one type of oxysilane.

18. The method of claim 15 or 16, wherein said type of oxysilane has at least one non-hydrolizable substituent.

19. The method of claim 2, wherein said biocompatible matrix consists essentially of siloxane.

20. The method of claim 2, wherein said biocompatible matrix comprises siloxane.

21. The method of claim 2, wherein administering said biocompatible matrix comprises surgical implantation.

22. The method of claim 2, further comprising administering said first prodrug to said subject.

23. The method of claim 2, wherein said first prodrug comprises an exogenous prodrug.

24. The method of claim 2, wherein said first prodrug comprises an endogenous prodrug.

25. The method of claim 2, wherein said first reaction center comprises an enzyme or antibody that is xenogeneic to said subject.

26. The method of claim 3, wherein the ratio of Km (nonencapsulated) to Km (encapsulated) for said first reaction center is greater than or equal to one.

27. The method of claim 3, wherein the ratio of Km (nonencapsulated) to Km (encapsulated) for said first reaction center is less than or equal to one.

28. The method of claim 2, wherein said first reaction center comprises more than one weight percent of said biocompatible matrix.

29. The method of claim 2, wherein said first reaction center comprises less than one weight percent of said biocompatible matrix.

30. The method of claim 29, wherein said first reaction center comprises more than five weight percent of said biocompatible matrix.

31. The method of claim 2, wherein said first reaction center comprises more than ten weight percent of said biocompatible matrix.

32. The method of claim 2, wherein said first reaction center is attached to said biocompatible matrix.

33. The method of claim 2, wherein said biocompatible matrix is immunoisolatory.

34. The method of claim 2, wherein administering said biocompatible matrix comprises parenteral administration.

35. The method of claim 2, wherein administering said biocompatible matrix comprises systemic administration.

36. The method of claim 2, wherein treatment of said subject by said method results in long-term, stable production of said first biologically active agent in said subject.

37. The method of claim 22, wherein said first prodrug is administered to said subject on at least more than one occasion.

38. The method of claim 2, wherein said first biologically active agent is cytotoxic.

39. The method of claim 38, wherein said biocompatible matrix is implanted in proximity to a neoplasm.

40. The method of claim 2, wherein said first reaction center does not leach significantly from said biocompatible matrix.

41. The method of claim 2, wherein said biocompatible matrix comprises a xero-gel.

42. The method of claim 15, wherein said oxysilane is one of the following:

tetramethyl orthosilicate or tetraethyl orthosilicate.

43. The method of claim 3, wherein said biocompatible matrix causes prodrug activation.

44. The method of claim 2, wherein said first prodrug is a deleterious agent to said subject and said first biologically active agent is less deleterious to said subject than said first prodrug.

45. The method of claim 44, wherein said first prodrug is an agent to which said subject is capable of becoming addicted, and wherein said subject is less capable of becoming addicted to said first biologically active agent.

46. The method of claim 45, wherein said first prodrug is one of the following:

ethanol or cocaine.

47. The method of claim 2, wherein said first prodrug is one of the following:

L-phenylalanine, noradrenalin, norepinephrine, histadine, histamine, 1-methylhistamine, glutumate, GABA or serine.

48. The method of claim 2, wherein said subject is human.

49. The method of claim 2, wherein said subject receives a therapeutically effective amount of said biocompatible matrix and said first prodrug.

50. The method of claim 23, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is about five or more.

51. The method of claim 50, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is about ten or more.

52. The method of claim 51, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is at least about one hundred.

53. The method of claim 37, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using the biologically active agent of said first prodrug alone is at about five or more.

54. The method of claim 53, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using the biologically active agent of said first prodrug alone is at about ten or more.

55. The method of claim 51, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using the biologically active agent of said first prodrug alone is at least about one hundred.

56. The method of claim 2, wherein said first biologically active agent comprises a neutrophic factor.

57. The method of claim 2, wherein said first biologically active agent comprises a type selected from the group consisting of anti-angiogenesis factors;

antiinfectives;

antibiotics agents;

antiviral agents;

analgesics;

anorexics;

antihelmintics;

antiarthritics;

antiasthmatic agents;

anticonvulsants;

antidepressants;

antidiuretic agents;

antidiarrheals;

antihistamines;

antiinflammatory agents;

antimigraine preparations;

antinauseants;

antineoplastics;

antiparkinsonism drugs;

antipruritics;

antipsychotics;

antipyretics, antispasmodics;

anticholinergics;

sympathomimetics;

xanthine derivatives;

cardiovascular preparations;

calcium channel blockers;

beta-blockers;

antiarrhythmics;

antihypertensives;

catecholamines;

diuretics;

vasodilators;

central nervous system stimulants;

cough preparations;

cold preparations;

decongestants;

growth factors;

hormones;

steroids;

corticosteroids;

hypnotics;

inmunosuppressives;

muscle relaxants;

parasympatholytics;

psychostimulants;

sedatives;

tranquilizers;

proteins;

polysaccharides;

glycoproteins;

lipoproteins;

interferons;

cytokines;

chemotherapeutic agents;

anti-neoplastics;

antibiotics;

anti-virals;

anti-fungals;

anti-inflammatories;

anticoagulants;

lymphokines; and

antigenic materials.

58. The method of claim 3, wherein said first reaction center comprises an enzyme that is a member of a class selected from the group consisting of oxidoreductases;

transferases;

hydrolases;

isomerases; and

ligases.

59. The method of claim 2, wherein said first reaction center replaces, augments or supplements some endogenous biological activity in said subject.

60. The method of claim 59, wherein said first reaction center comprises an enzyme in which said subject is deficient.

61. The method of claim 60, wherein said first reaction center is one of the following:

glucocerebrosidase;

α

-1,4-glucosidase;

α

-galactosidase;

α

-L-iduronidase;

β

-glucuronidase;

aminolaevulinate dehydratase;

bilirubin oxidase;

catalase;

fibrinolysin;

glutaminase;

hemoglobin;

heparinase;

L-arginine ureahydrolase (A1);

arginase;

liver microsomal enzymes;

phenylalanine ammonia lyase;

streptokinase;

superoxide dismutase;

terrilythin;

tyrosinase;

UDP glucuronyl transferase;

urea cycle enzymes;

urease;

uricase;

or urokinase.

62. The method of claim 1, wherein said first reaction center comprises one of the following:

an enzyme, an antibody or a catalytic antibody.

63. The method of claim 1, wherein said first prodrug comprises L-dopa and said first biologically active agent comprises dopamine.

64. The method of claim 1, wherein administering said biocompatible matrix comprises administering said biocompatible matrix to a region of the brain of said subject.

65. The method of claim 1, wherein administering said biocompatible matrix comprises surgical implantation.

66. The method of claim 1, wherein the ratio of Km (nonencapsulated) to Km (encapsulated) for said first reaction center is greater than or equal to one.

67. The method of claim 1, wherein said biocompatible matrix causes prodrug activation.

68. The method of claim 1, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is about five or more.

69. The method of claim 1, wherein said first reaction center replaces, augments or supplements some endogenous biological activity in said subject.

70. A biocompatible matrix for treatment, comprising:

a. a inorganic-based sol-gel matrix that is biocompatible; and

,

b. a first cell-free reaction center encapsulated in said matrix, wherein said first reaction center, after administration of said matrix to a subject, produces a therapeutically effective amount of a first biologically active agent from a first prodrug in said subject.

71. The biocompatible matrix of claim 70, wherein said biocompatible matrix comprises a silica-based sol-gel matrix.

72. The biocompatible matrix of claim 70, wherein said first reaction center comprises one of the following:

an enzyme, an antibody or a catalytic antibody.

73. The biocompatible matrix of claim 71, wherein said first reaction center comprises one of the following:

L-amino acid decarboxylase or L-tyrosine decarboxylase.

74. The biocompatible matrix of claim 73, wherein said first reaction center comprises L-amino acid decarboxylase, said first prodrug comprises L-dopa, and said first biologically active agent comprises dopamine.

75. The biocompatible matrix of claim 71, wherein said biocompatible matrix further comprises a second reaction center.

76. The biocompatible matrix of claim 75, wherein said first biologically active agent produced by said first reaction center from said first prodrug is a second prodrug for said second reaction center, and wherein said second reaction center produces a second biologically active agent that differs from said first biologically active agent.

77. The biocompatible matrix of claim 76, wherein said first reaction center comprises tyrosine monooxygenase, and said second reaction center is one of the following:

L-amino acid decarboxylase or L-tyrosine decarboxylase.

78. The biocompatible matrix of claims 73, 74 or 77, wherein administering said biocompatible matrix comprises administering said biocompatible matrix to a region of the brain of said subject.

79. The biocompatible matrix of claim 78, wherein said region of said brain of said subject is one of the following:

basal ganglia, substantia nigra or striatum.

80. The biocompatible matrix of claim 71, wherein said biocompatible matrix is prepared from at least one type of oxysilane.

81. The biocompatible matrix of claim 71, wherein said biocompatible matrix is siloxane.

82. The biocompatible matrix of claim 80, wherein said type of oxysilane has at least one non-hydrolizable substituent.

83. The biocompatible matrix of claim 71, wherein said first prodrug is exogenous to said subject.

84. The biocompatible matrix of claim 70, wherein said first prodrug is endogenous to said subject.

85. The biocompatible matrix of claim 71, wherein said first reaction center comprises an enzyme that is xenogeneic to said subject.

86. The biocompatible matrix of claim 72, wherein the ratio of Km (nonencapsulated) to Km (encapsulated) for said first reaction center is greater than or equal to one.

87. The biocompatible matrix of claim 70, wherein said first reaction center comprises more than one weight percent of said biocompatible matrix.

88. The biocompatible matrix of claim 85, wherein said xenogeneic enzyme comprises more than five weight percent of said biocompatible matrix.

89. The biocompatible matrix of claim 71, wherein said first reaction center comprises more than ten weight percent of said biocompatible matrix.

90. The biocompatible matrix of claim 71, wherein said biocompatible matrix is immunoisolatory.

91. The biocompatible matrix of claim 71, wherein said biocompatible matrix is capable of long-term, stable production of said first biologically active agent in said subject.

92. The biocompatible matrix of claim 72, wherein said first biologically active agent is cytotoxic.

93. The biocompatible matrix of claim 70, wherein said first reaction center does not leach significantly from said biocompatible matrix after administration.

94. The biocompatible matrix of claim 71, wherein said biocompatible matrix comprises a xero-gel.

95. The biocompatible matrix of claim 80, wherein said oxysilane is one of the following:

tetramethyl orthosilicate or tetraethyl orthosilicate.

96. The biocompatible matrix of claim 71, wherein said first prodrug is a deleterious agent to said subject and said first biologically active agent is less deleterious to said subject than said first prodrug.

97. The biocompatible matrix of claim 70, wherein said first prodrug is an agent to which said subject is capable of becoming addicted, and wherein said subject is less capable of becoming addicted to said first biologically active agent.

98. The biocompatible matrix of claim 71, wherein said first prodrug is one of the following:

L-phenylalanine, noradrenalin, norepinephrine, histadine, histamine, 1-methylhistamine, glutumate, GABA or serine.

99. The biocompatible matrix of claim 83, wherein the ratio of the therapeutic index of treatment using said first prodrug and said first biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is about five or more.

100. The biocompatible matrix of claim 91, wherein the ratio of the therapeutic index of treatment using said first prodrug and said first biocompatible matrix over the therapeutic index of treatment using said first prodrug alone is at least about one hundred.

101. The biocompatible matrix of claim 83, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using the biologically active agent of said first prodrug alone is at least about ten or more.

102. The biocompatible matrix of claim 83, wherein said first biologically active agent comprises a type selected from the group consisting of anti-angiogenesis factors;

antiinfectives;

antibiotics agents;

antiviral agents;

analgesics;

anorexics;

antihelmintics;

antiarhritics;

antiasthmatic agents;

anticonvulsants;

antidepressants;

antidiuretic agents;

antidiarrheals;

antihistamines;

antiinflammatory agents;

antimigraine preparations;

antinauseants;

antineoplastics;

antiparkinsonism drugs;

antipruritics;

antipsychotics;

antipyretics, antispasmodics;

anticholinergics;

sympathomimetics;

xanthine derivatives;

cardiovascular preparations;

calcium channel blockers;

beta-blockers;

antiarrhythmics;

antihypertensives;

catecholamines;

diuretics;

vasodilators;

central nervous system stimulants;

cough preparations;

cold preparations;

decongestants;

growth factors;

hormones;

steroids;

corticosteroids;

hypnotics;

immunosuppressives;

muscle relaxants;

parasympatholytics;

psychostimulants;

sedatives;

tranquilizers;

proteins;

polysaccharides;

glycoproteins;

lipoproteins;

interferons;

cytokines;

chemotherapeutic agents;

anti-neoplastics;

antibiotics;

anti-virals;

anti-fungals;

anti-inflammatories;

anticoagulants;

lymphokines; and

antigenic materials.

103. The biocompatible matrix of claim 71, wherein said first reaction center comprises an enzyme that is member of a class of one of the following:

oxidoreductases;

transferases;

hydrolases;

isomerases;

or ligases.

104. The biocompatible matrix of claim 70, wherein said first reaction center replaces, augments or supplements some endogenous biological activity in said subject.

105. The biocompatible matrix of claim 71, wherein said first reaction center comprises an enzyme in which said subject is deficient.

106. The biocompatible matrix of claim 105, wherein said first reaction center is one of the following:

glucocerebrosidase;

α

-1,4-glucosidase;

α

-galactosidase;

α

-L-iduronidase;

β

-glucuronidase;

aminolaevulinate dehydratase;

bilirubin oxidase;

catalase;

fibrinolysin;

glutaminase;

hemoglobin;

heparinase;

L-arginine ureahydrolase (A1);

arginase;

liver microsomal enzymes;

phenylalanine ammonia lyase;

streptokinase;

superoxide dismutase;

terrilythin;

tyrosinase;

UDP glucuronyl transferase;

urea cycle enzymes;

urease;

uricase;

or urokinase.

107. The biocompatible matrix of claim 70, wherein said biocompatible matrix further comprises a second reaction center.

108. The biocompatible matrix of claim 107, wherein said first biologically active agent produced by said first reaction center from said first prodrug is a second prodrug for said second reaction center, and wherein said second reaction center produces a second biologically active agent that differs from said first biologically active agent.

109. The biocompatible matrix of claim 108, wherein said first reaction center comprises tyrosine monooxygenase, and said second reaction center is one of the following:

L-amino acid decarboxylase or L-tyrosine decarboxylase.

110. The biocompatible matrix of claim 70, wherein said biocompatible matrix is immunoisolatory.

111. The biocompatible matrix of claim 70, wherein said first prodrug is a deleterious agent to said subject and said first biologically active agent is less deleterious to said subject than said first prodrug.

112. The biocompatible matrix of claim 70, wherein the ratio of the therapeutic index of treatment using said first prodrug and said biocompatible matrix over the therapeutic index of treatment using the biologically active agent of said first prodrug alone is at least about ten or more.

113. A biologically active agent produced by a process comprising:

a. encapsulating a first cell-free reaction center in a biocompatible matrix; and

b. administering said biocompatible matrix to a subject;

wherein said biocompatible matrix comprises an inorganic-based sol-gel matrix, and wherein said biologically active agent is produced by said first reaction center from a first prodrug in said subject.

114. The biologically active agent of claim 113, wherein said biocompatible matrix comprises a silica-based sol-gel matrix.

115. The biologically active agent of claim 114, wherein said first reaction center comprises one of the following:

an enzyme, an antibody or a catalytic antibody.

116. The biologically active agent of claim 115, wherein said first reaction center is one of the following:

L-amino acid decarboxylase, L-tyrosine decarboxylase or tyrosine monooxygenase.

117. The biologically active agent of claim 114, wherein the process by which it is produced further comprises encapsulating a second reaction center in said biocompatible matrix before administering said biocompatible matrix to said subject.

118. The biologically active agent of claim 116, wherein administering said biocompatible matrix comprises administering said biocompatible matrix to one of the following regions of the brain:

basal ganglia, substantia nigra or striatum.

119. The biologically active agent of claim 114, wherein the process by which it is produced further comprises preparing said biocompatible matrix from at least one type of oxysilane at substantially the same time as said encapsulating of said first reaction center.

120. The biologically active agent of claim 114, wherein said biocompatible matrix consists essentially of siloxane.

121. The biologically active agent of claim 114, wherein administering said biocompatible matrix to a subject comprises surgical implantation.

122. The biologically active agent of claim 119, wherein the process further comprises administering said first prodrug to said subject.

123. The biologically active agent of claim 114, wherein said first prodrug comprises a prodrug exogenous to said subject.

124. The biologically active agent of claim 114, wherein said process results in long-term, stable production of said biologically active agent in said subject.

125. The biologically active agent of claim 123, wherein said first prodrug is administered to said subject on at least more than one occasion.

126. The biologically active agent of claim 114, wherein said first prodrug is a deleterious agent to said subject and said first biologically active agent is less deleterious to said subject than said first prodrug.

127. The biologically active agent of claim 114, wherein said subject is human.

128. The biologically active agent of claim 114, wherein said first biologically active agent comprises a type selected from the group consisting of anti-angiogenesis factors;

antiinfectives;

antibiotics agents;

antiviral agents;

analgesics;

anorexics;

antihelmintics;

antiarthritics;

antiasthmatic agents;

anticonvulsants;

antidepressants;

antidiuretic agents;

antidiarrheals;

antihistamines;

antiinflammatory agents;

antimigraine preparations;

antinauseants;

antineoplastics;

antiparkinsonism drugs;

antipruritics;

antipsychotics;

antipyretics, antispasmodics;

anticholinergics;

sympathomimetics;

xanthine derivatives;

cardiovascular preparations;

calcium channel blockers;

beta-blockers;

antiarrhythmics;

antihypertensives;

catecholamines;

diuretics;

vasodilators;

central nervous system stimulants;

cough preparations;

cold preparations;

decongestants;

growth factors;

hormones;

steroids;

corticosteroids;

hypnotics;

immunosuppressives;

muscle relaxants;

parasympatholytics;

psychostimulants;

sedatives;

tranquilizers;

proteins;

polysaccharides;

glycoproteins;

lipoproteins;

interferons;

cytokines;

chemotherapeutic agents;

anti-neoplastics;

antibiotics;

anti-virals;

anti-fungals;

anti-inflammatories;

anticoagulants;

lymphokines; and

antigenic materials.

129. The biologically active agent of claim 114, wherein said first reaction center comprises an enzyme that is member of a class selected from the group consisting of oxidoreductases;

transferases;

hydrolases;

isomerases; and

ligases.

130. The biologically active agent of claim 120, wherein said first reaction center comprises an enzyme in which said subject is deficient.

131. A kit for treatment of a subject, comprising:

a. a inorganic-based sol-gel matrix that is biocompatible; and

,

b. a first cell-free reaction center encapsulated in said matrix, wherein said first reaction center, after administration of said matrix to a subject, produces a therapeutically effective amount of a first biologically active agent from a first prodrug in said subject.

132. The kit of claim 131, wherein said biocompatible matrix comprises a silica-based sol-gel matrix.

133. The kit of claim 132, further comprising instructions for treatment of said subject using said kit.

134. The kit of claim 132, further comprising one or more doses of said first prodrug for administration to said subject.

135. The kit of claim 134, wherein said dose of said first prodrug is formulated for controlled release of said first prodrug upon administration to said subject.

136. The kit of claim 131, further comprising instructions for treatment of said subject using said kit.

137. The kit of claim 131, further comprising one or more doses of said first prodrug for administration to said subject.

138. The kit of claim 137, wherein said does of said first prodrug is formulated for controlled release of said first prodrug upon administration to said subject.

139. A method of treatment of a subject, comprising:

a. a step for encapsulating a first cell-free reaction center in a biocompatible matrix; and

b. a step for administering said biocompatible matrix to a subject;

wherein said biocompatible matrix comprises a silica-based sol-gel matrix, and wherein said first reaction center converts a first prodrug into a first biologically active agent in said subject.

140. The method of treatment of claim 139, further comprising a step for administering said prodrug to said subject before, at the same time or after said step for administering said biocompatible matrix to said subject.