CA2524258A1 - Carrier complexes comprising cationic peptides for delivering molecules to cells - Google Patents

Carrier complexes comprising cationic peptides for delivering molecules to cells Download PDF

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CA2524258A1
CA2524258A1 CA002524258A CA2524258A CA2524258A1 CA 2524258 A1 CA2524258 A1 CA 2524258A1 CA 002524258 A CA002524258 A CA 002524258A CA 2524258 A CA2524258 A CA 2524258A CA 2524258 A1 CA2524258 A1 CA 2524258A1
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carrier complex
molecule
peptide
complex according
cell
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CA2524258C (en
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Hazel Szeto
Kesheng Zhao
Alex V. Birk
Hugh D. Robertson
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Cornell Research Foundation Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2468—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1) acting on beta-galactose-glycoside bonds, e.g. carrageenases (3.2.1.83; 3.2.1.157); beta-agarase (3.2.1.81)
    • C12N9/2471—Beta-galactosidase (3.2.1.23), i.e. exo-(1-->4)-beta-D-galactanase
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
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    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
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    • C12N2310/3513—Protein; Peptide
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    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Abstract

The invention relates to carrier complexes and methods for delivering molecules to cells. The carrier complexes comprises a molecule and an aromatic cationic peptide in accordance with the invention. In one embodiment, the method for delivering a molecule to a cell comprises contacting the cell with a carrier complex. In another embodiment, the method for delivering a molecule to a cell comprises contacting the cell with a molecule and an aromatic cationic peptide.

Claims (123)

1. A method for delivering a molecule to a cell, the method comprising contacting the cell with a carrier complex, wherein the carrier complex comprises the molecule and an aromatic cationic peptide, wherein the aromatic cationic peptide comprises:
(a) at least one net positive charge;
(b) a minimum of three amino acids;
(c) a maximum of ten amino acids;
(d) a relationship between the minimum number of net positive charges (pm) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1; and (e) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (pt) wherein 3a is the largest number that is less than or equal to pt + 1, except that when a is 1, pt may also be 1.
2. A method according to claim 1, wherein 2a is the largest number that is less than or equal to pt + 1.
3. A method according to claim 1, wherein a is equal to p.
4. A method according to claim 1, wherein the peptide has a minimum of two positive charges.
5. A method according to claim 1, wherein the peptide has a minimum of three positive charges.
6. A method according to claim 1, wherein the peptide is a tripeptide comprising two positively charged amino acids and one aromatic amino acid.
7. A method according to claim 1, wherein the peptide is water soluble.
8. A method according to claim 1, wherein the peptide comprises one or more D-amino acids.
9. A method according to claim 1, wherein the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
10. A method according to claim 1, wherein the peptide comprises one or more non-naturally occurring amino acids.
11. A method according to claim 1, wherein the peptide has a minimum of four amino acids.
12. A method according to claim 1, wherein the peptide has a maximum of about eight amino acids.
13. A method according to claim 1, wherein the peptide has a maximum of about six amino acids.
14. A method according to claim 1, wherein the peptide has four amino acids.
15. A method according to claim 1, wherein the peptide has the formula Tyr-D-Arg-Phe-Lys-NH2 (DALDA).
16. A method according to claim 1, wherein the peptide has the formula 2',6'-Dmt-D-Arg-Phe-Lys-NH2 (Dmt1-DALDA).
17. A method according to claim 1, wherein the peptide has the formula Phe-D-Arg-Phe-Lys-NH2 (Phe1-DALDA).
18. A method according to claim 1, wherein the peptide has the formula D-Arg-2',6'Dmt-Lys-Phe-NH2.
19. A method according to claim 1, wherein the peptide has the formula 2',6'-Dmp-D-Arg-Phe-Lys-NH2 (Dmp1-DALDA).
20. A method according to claim 1 wherein the molecule is a small molecule.
21. A method according to claim 20, wherein the small molecule is a pharmaceutically active molecule.
22. A method according to claim 21, wherein the pharmaceutically active molecule is an antibiotic.
23. A method according to claim 21 wherein the pharmaceutically active molecule is a cytotoxic agent.
24. A method according to claim 23, wherein the cytotoxic agent is doxorubicin.
25. A method according to claim 23, wherein the cytotoxic agent is adriamycin.
26. A method according to claim 21, wherein the pharmaceutically active molecule is an antioxidant.
27. A method according to claim 26 wherein the antioxidant is vitamin E.
28. A method according to claim 26, wherein the antioxidant is vitamin C.
29. A method according to claim 26, wherein the antioxidant is beta carotene.
30. A method according to claim 1, wherein the molecule is a biological molecule.
31. A method according to claim 30, wherein the biological molecule is a polyamino acid.
32. A method according to claim 30, wherein biological molecule is a pharmaceutically active molecule.
33. A method according to claim 32, wherein the pharmaceutically active molecule is an endogenous peptide or protein.
34. A method according to claim 32, wherein the pharmaceutically active molecule is an enzyme.
35. A method according to claim 32, wherein the pharmaceutically active molecule is an antibody.
36. A method according to claim 32, wherein the pharmaceutically active molecule is a neurotrophic growth factor.
37. A method according to claim 32, wherein the pharmaceutically active molecule is a cytokine.
38. A method according to claim 32, wherein the pharmaceutically active molecule is a polynucleotide.
39. A method according to claim 32, wherein the pharmaceutically active molecule is an oligonucleotide.
40. A method according to claim 39, wherein the oligonucleotide is RNA
41. A method according to claim 40, wherein the RNA is double-stranded RNA.
42. A method according to claim 41, wherein the double-stranded RNA is siRNA.
43. A method according to claim 39, wherein the oligonucleotide is DNA.
44. A method according to claim 39, wherein the oligonucleotide is single-stranded RNA.
45. A method according to claim 44, wherein the single-stranded RNA is messenger RNA (mRNA).
46. A method according to claim 39, wherein the oligonucleotide is a ribozyme.
47. A method according to claim 39, wherein the oligonucleotide is an anti-sense RNA.
48. A method according to claim 39, wherein the oligonucleotide is an external guide sequence for a ribozyme.
49. A method according to claim 39, wherein the oligonucleotide is an RNA
decoy.
50. A method according to claim 30, wherein the biological molecule is a polyamino acid.
51. A method according to claim 1, wherein the cell is a bacterial cell.
52. A method according to claim 1, wherein the cell is a plant cell.
53. A method according to claim 1, wherein the cell is an animal cell.
54. A method according to claim 53, wherein the animal cell is a mammalian cell.
55. A method according to claim 53, wherein the cell is a neuronal cell.
56. A method according to claim 53, wherein the cell is a renal epithelial cell.
57. A method according to claim 53, wherein the cell is an intestinal epithelial cell.
58. A method according to claim 53, wherein the cell is a vascular endothelial cell.
59. A method according to claim 53, wherein the endothelial cell is a blood-brain barrier endothelial cell.
60. A method according to claim 53, wherein the cell is a glial cell.
61. A method according to claim 53, wherein the cell is a hepatocyte.
62. A method according to claim 1, wherein the aromatic-cationic peptide comprises a linker.
63. A method according to claim 1, wherein the molecule comprises a linker.
64. A method according to claim 1, wherein the molecule and aromatic cationic peptide are chemically bonded.
65. A method according to claim 1, wherein the molecule and aromatic cationic peptide are physically bonded.
66. A carrier complex comprising a molecule and an aromatic cationic peptide, wherein the aromatic cationic peptide comprises:
(a) at least one net positive charge;
(b) a minimum of three amino acids;
(c) a maximum of ten amino acids;
(d) a relationship between the minimum number of net positive charges (pm) and the total number of amino acid residues (r) wherein 3pm is the largest number that is less than or equal to r + 1; and (e) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (pt) wherein 3a is the largest number that is less than or equal to pt + 1, except that when a is l, pt may also be 1.
67. A carrier complex according to claim 66, wherein 2a is the largest number that is less than or equal to pt + 1.
68. A carrier complex according to claim 66, wherein a is equal to pt.
69. A carrier complex according to claim 66, wherein the peptide has a minimum of two positive charges.
70. A carrier complex according to claim 66, wherein the peptide has a minimum of three positive charges.
71. A carrier complex according to claim 66, wherein the peptide is a tripeptide comprising two positively charged amino acids and one aromatic amino acid.
72. A carrier complex according to claim 66, wherein the peptide is water soluble.
73. A carrier complex according to claim 66, wherein the peptide comprises one or more D-amino acids.
74. A carrier complex according to claim 66, wherein the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
75. A carrier complex according to claim 66, wherein the peptide comprises one or more non-naturally occurring amino acids.
76. A carrier complex according to claim 66, wherein the peptide has a minimum of four amino acids.
77. A carrier complex according to claim 66, wherein the peptide has a maximum of about eight amino acids.
78. A carrier complex according to claim 66, wherein the peptide has a maximum of about six amino acids.
79. A carrier complex according to claim 66, wherein the peptide has four amino acids
80. A carrier complex according to claim 66, wherein the peptide has the formula Tyr-D-Arg-Phe-Lys-NH2 (DALDA).
81. A carrier complex according to claim 66, wherein the peptide has the formula 2',6'-Dmt-D-Arg-Phe-Lys-NH2 (Dmt1-DALDA).
82. A carrier complex according to claim 66, wherein the peptide has the formula Phe-D-Arg-Phe-Lys-NH2 (Phe1-DALDA).
83. A carrier complex according to claim 66, wherein the peptide has the formula D-Arg-2',6'Dmt-Lys-Phe-NH2.
84. A carrier complex according to claim 66, wherein the peptide has the formula 2',6'-Dmp-D-Arg-Phe-Lys-NH2 (Dmp1-DALDA).
85. A carrier complex according to claim 66, wherein the molecule is a small molecule.
86. A carrier complex according to claim 66, wherein the small molecule is a biological molecule.
87. A carrier complex according to claim 86, wherein the biological molecule is a polyamino acid.
88. A carrier complex according to claim 85, wherein the small molecule is a pharmaceutically active molecule.
89. A carrier complex according to claim 88, wherein the pharmaceutically active molecule is an antibiotic.
90. A carrier complex according to claim 88, wherein the pharmaceutically active molecule is a cytotoxic agent.
91. A carrier complex according to claim 90, wherein the cytotoxic agent is doxorubicin.
92. A carrier complex according to claim 90, wherein the cytotoxic agent is adriamycin.
93. A carrier complex according to claim 88, wherein the pharmaceutically active molecule is an antioxidant.
94. A carrier complex according to claim 93, wherein the antioxidant is vitamin E.
95. A carrier complex according to claim 93, wherein the antioxidant is vitamin C.
96. A carrier complex according to claim 93, wherein the antioxidant is beta carotene.
97. A carrier complex according to claim 66, wherein the molecule is a biological molecule.
98. A carrier complex according to claim 97, wherein biological molecule is a pharmaceutically active molecule.
99. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is an endogenous peptide or protein.
100. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is an enzyme.
101. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is an antibody.
102. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is a neurotrophic growth factor.
103. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is a cytokine.
104. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is a polynucleotide.
105. A carrier complex according to claim 98, wherein the pharmaceutically active molecule is an oligonucleotide.
106. A carrier complex according to claim 105, wherein the oligonucleotide is RNA
107. A carrier complex according to claim 106 wherein the RNA is double-stranded RNA.
108. A carrier complex according to claim 107, wherein the double-stranded RNA
is siRNA.
109. A carrier complex according to claim 106, wherein the oligonucleotide is DNA.
110. A carrier complex according to claim 105, wherein the oligonucleotide is single-stranded RNA.
111. A carrier complex according to claim 110, wherein the single-stranded RNA
is messenger RNA (mRNA).
112. A carrier complex according to claim 105, wherein the oligonucleotide is a ribozyme.
113. A carrier complex according to claim 105, wherein the oligonucleotide is an anti-sense RNA.
114 A carrier complex according to claim 105, wherein the oligonucleotide is an external guide sequence for a ribozyme.
115. A carrier complex according to claim 105, whereint eh oligonucleotide is an RNA
decoy.
116. A carrier complex according to claim 97, wherein the biological molecule is a polyamino acid.
117. A carrier complex according to claim 66, wherein the aromatic cationic peptide comprises a linker.
118. A carrier complex according to claim 66, wherein the molecule comprises a linker.
119. A carrier complex according to claim 66, wherein the molecule and aromatic cationic peptide are chemically bonded.
120. A carrier complex according to claim 66, wherein the molecule and aromatic cationic peptide are physically bonded.
121. A method for delivering a molecule to a cell, the method comprising contacting the cell with a molecule and an aromatic cationic peptide, wherein the aromatic cationic peptide comprises:
(a) at least one net positive charge;
(b) a minimum of three amino acids;
(c) a maximum of ten amino acids;
(d) a relationship between the minimum number of net positive charges (p m) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1; and (e) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t) wherein 3a is the largest number that is less than or equal to p t + 1, except that when a is 1, p t may also be 1.
122. A method according to claim 121, wherein the molecule and aromatic cationic peptide are chemically bonded.
123. A method according to claim 121, wherein the molecule and aromatic cationic peptide are physically bonded.
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