IP Library › Granted Patent US 8,148,322
Granted Patent B2
US 8,148,322 · App. 12/631,048 · Granted Apr 3, 2012

Method and carrier complexes for delivering molecules to cells

Assignee: Cornell Research Foundation, Inc.
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Quick Facts
Patent No.
US 8,148,322
App. No.
12/631,048
Granted
Apr 3, 2012
Kind
B2
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 (563)

1. A carrier complex comprising a biological molecule conjugated to an aromatic cationic peptide, wherein the aromatic cationic peptide is selected from the group consisting of:

Lys-D-Arg-Tyr-NH 2 ,

Phe-D-Arg-His,

D-Tyr-Trp-Lys-NH 2 ,

Trp-D-Lys-Tyr-Arg-NH 2 ,

Tyr-His-D-Gly-Met,

Phe-Arg-D-His-Asp,

Tyr-D-Arg-Phe-Lys-Glu-NH 2 (SEQ ID NO: 3),

Met-Tyr-D-Lys-Phe-Arg (SEQ ID NO: 4),

D-His-Glu-Lys-Tyr-D-Phe-Arg (SEQ ID NO: 5),

Lys-D-Gln-Tyr-Arg-D-Phe-Trp-NH 2 (SEQ ID NO: 6),

Phe-D-Arg-Lys-Trp-Tyr-D-Arg-His (SEQ ID NO: 7),

Gly-D-Phe-Lys-Tyr-His-D-Arg-Tyr-NH 2 (SEQ ID NO: 8),

Val-D-Lys-His-Tyr-D-Phe-Ser-Tyr-Arg-NH −2 (SEQ ID NO: 9),

Trp-Lys-Phe-D-Asp-Arg-Tyr-D-His-Lys (SEQ ID NO: 10),

Lys-Trp-D-Tyr-Arg-Asn-Phe-Tyr-D-His-NH 2 (SEQ ID NO: 11),

Thr-Gly-Tyr-Arg-D-His-Phe-Trp-D-His-Lys (SEQ ID NO: 12),

Asp-D-Trp-Lys-Tyr-D-His-Phe-Arg-D-Gly-Lys-NH 2 (SEQ ID NO: 13),

D-His-Lys-Tyr-D-Phe-Glu-D-Asp-D-His-D-Lys-Arg-Trp-NH 2 (SEQ ID NO: 14),

Ala-D-Phe-D-Arg-Tyr-Lys-D-Trp-His-D-Tyr-Gly-Phe (SEQ ID NO: 15),

Tyr-D-Arg-Phe-Orn-NH 2 ,

Tyr-D-Arg-Phe-Dab-NH 2 ,

Tyr-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-Cys-NH 2 (SEQ ID NO: 16),

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-dns-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-atn-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsLys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Lys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Ahp-NH 2 ,

2′6′Dmt-D-Arg-Phe-Orn-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dab-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Ahp(2-aminoheptanoic acid)-NH 2 ,

3′5′Dmt-D-Arg-Phe-Lys-NH 2 ,

3′5′Dmt-D-Arg-Phe-Orn-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dab-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dap-NH 2 ,

Tyr-D-Arg-Tyr-Lys-NH 2 ,

Tyr-D-Arg-Tyr-Orn-NH 2 ,

Tyr-D-Arg-Tyr-Dab-NH 2 ,

Tyr-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Pap-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Dab-NH 2 ,

Tyr-D-Lys-Phe-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Phe-Lys-NH 2 ,

Tyr-D-Lys-Phe-Orn-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dab-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dap-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-NH 2 ,

2′6′Dmt-D-Lys-Phe-Lys-NH 2 ,

3′5′Dmt-D-Lys-Phe-Orn-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dab-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dap-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Tyr-Lys-NH 2 ,

Tyr-D-Lys-Tyr-Orn-NH 2 ,

Tyr-D-Lys-Tyr-Dab-NH 2 ,

Tyr-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsDap-NH 2 ,

2′6′Dmt-D-Arg-Phe-atnDap-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dab-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Orn-Phe-Arg-NH 2 ,

Tyr-D-Dap-Phe-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Orn-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-Phe-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-Phe-Arg-3′5′Dmt-NH 2 ,

Tyr-D-Lys-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Orn-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dab-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dap-Tyr-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Drnt-D-Lys-2′6′Dmt-Arg-2′6′Drnt-NH 2 ,

2′6′Dmt-D-Orn-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

Mmt-D-Arg-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dap-Mmt-NH 2 ,

Tmt-D-Arg-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Orn-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dap-Tmt-NH 2 ,

Hmt-D-Arg-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dap-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dap-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Tmt-D-Lys-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Om-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dap-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Arg-Tmt-NH 2 ,

Hmt-D-Lys-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dap-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Arg-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Mmt-D-Orn-Phe-Arg-NH 2 ,

Mmt-D-Dab-Phe-Arg-NH 2 ,

Mmt-D-Dap-Phe-Arg-NH 2 ,

Mmt-D-Arg-Phe-Arg-NH 2 ,

Tmt-D-Lys-Phe-Arg-NH 2 ,

Tmt-D-Orn-Phe-Arg-NH 2 ,

Tmt-D-Dab-Phe-Arg-NH 2 ,

Tmt-D-Dap-Phe-Arg-NH 2 ,

Tmt-D-Arg-Phe-Arg-NH 2 ,

Hmt-D-Lys-Phe-Arg-NH 2 ,

Hmt-D-Orn-Phe-Arg-NH 2 ,

Hmt-D-Dab-Phe-Arg-NH 2 ,

Hmt-D-Dap-Phe-Arg-NH 2 ,

Hmt-D-Arg-Phe-Arg-NH 2 ,

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Drnt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-D-Arg-Dmt-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 , and

Cha-D-Arg-Phe-Lys-NH 2 ,

and wherein the molecule is selected from the group consisting of: a polynucleotide, a polyamino acid, a cytotoxic agent, an antibiotic, an antioxidant, a growth factor, and a cytokine.

2. A carrier complex according to claim 1 , wherein the biological molecule is conjugated to the aromatic cationic peptide by a linker.

3. A carrier complex according to claim 1 , wherein the molecule and aromatic cationic peptide are chemically bonded.

4. A carrier complex according to claim 1 , wherein the molecule and aromatic cationic peptide are physically bonded.

5. A carrier complex according to claim 1 , wherein the polynucleotide is selected from the group consisting of RNA, double-stranded RNA, siRNA, DNA, single-stranded RNA, messenger RNA, an oligonucleotide, a ribozyme, an anti-sense RNA, an external guide sequence for a ribozyme, and an RNA decoy.

6. A carrier complex according to claim 1 , wherein polyamino acid is selected from the group consisting of an endogenous peptide or protein, an enzyme, and an antibody.

7. A carrier complex according to claim 1 , wherein cytotoxic agent is selected from the group consisting of doxorubicin and adriamycin.

8. A carrier complex according to claim 1 , wherein antioxidant is selected from the group consisting of vitamin E, vitamin C, and beta-carotene.

9. A carrier complex according to claim 1 , wherein the growth factor is a neurotrophic growth factor.

10. 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 conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of:

Lys-D-Arg-Tyr-NH 2 ,

Phe-D-Arg-His,

D-Tyr-Trp-Lys-NH 2 ,

Trp-D-Lys-Tyr-Arg-NH 2 ,

Tyr-His-D-Gly-Met,

Phe-Arg-D-His-Asp,

Tyr-D-Arg-Phe-Lys-Glu-NH 2 (SEQ ID NO: 3),

Met-Tyr-D-Lys-Phe-Arg (SEQ ID NO: 4),

D-His-Glu-Lys-Tyr-D-Phe-Arg (SEQ ID NO: 5),

Lys-D-Gln-Tyr-Arg-D-Phe-Trp-NH 2 (SEQ ID NO: 6),

Phe-D-Arg-Lys-Trp-Tyr-D-Arg-His (SEQ ID NO: 7),

Gly-D-Phe-Lys-Tyr-His-D-Arg-Tyr-NH 2 (SEQ ID NO: 8),

Val-D-Lys-His-Tyr-D-Phe-Ser-Tyr-Arg-NH −2 (SEQ ID NO: 9),

Trp-Lys-Phe-D-Asp-Arg-Tyr-D-His-Lys (SEQ ID NO: 10),

Lys-Trp-D-Tyr-Arg-Asn-Phe-Tyr-D-His-NH 2 (SEQ ID NO: 11),

Thr-Gly-Tyr-Arg-D-His-Phe-Trp-D-His-Lys (SEQ ID NO: 12),

Asp-D-Trp-Lys-Tyr-D-His-Phe-Arg-D-Gly-Lys-NH 2 (SEQ ID NO: 13),

D-His-Lys-Tyr-D-Phe-Glu-D-Asp-D-His-D-Lys-Arg-Trp-NH 2 (SEQ ID NO: 14),

Ala-D-Phe-D-Arg-Tyr-Lys-D-Trp-His-D-Tyr-Gly-Phe (SEQ ID NO: 15),

Tyr-D-Arg-Phe-Orn-NH 2 ,

Tyr-D-Arg-Phe-Dab-NH 2 ,

Tyr-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-Cys-NH 2 (SEQ ID NO: 16),

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-dns-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-atn-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsLys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Lys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Ahp-NH 2 ,

2′6′Dmt-D-Arg-Phe-Orn-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dab-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Ahp(2-aminoheptanoic acid)-NH 2 ,

3′5′Dmt-D-Arg-Phe-Lys-NH 2 ,

3′5′Dmt-D-Arg-Phe-Orn-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dab-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dap-NH 2 ,

Tyr-D-Arg-Tyr-Lys-NH 2 ,

Tyr-D-Arg-Tyr-Orn-NH 2 ,

Tyr-D-Arg-Tyr-Dab-NH 2 ,

Tyr-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Pap-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Dab-NH 2 ,

Tyr-D-Lys-Phe-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Phe-Lys-NH 2 ,

Tyr-D-Lys-Phe-Orn-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dab-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dap-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-NH 2 ,

2′6′Dmt-D-Lys-Phe-Lys-NH 2 ,

3′5′Dmt-D-Lys-Phe-Orn-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dab-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dap-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Tyr-Lys-NH 2 ,

Tyr-D-Lys-Tyr-Orn-NH 2 ,

Tyr-D-Lys-Tyr-Dab-NH 2 ,

Tyr-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsDap-NH 2 ,

2′6′Dmt-D-Arg-Phe-atnDap-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dab-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Orn-Phe-Arg-NH 2 ,

Tyr-D-Dap-Phe-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Orn-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-Phe-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-Phe-Arg-3′5′Dmt-NH 2 ,

Tyr-D-Lys-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Orn-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dab-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dap-Tyr-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Drnt-D-Lys-2′6′Dmt-Arg-2′6′Drnt-NH 2 ,

2′6′Dmt-D-Orn-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

Mmt-D-Arg-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dap-Mmt-NH 2 ,

Tmt-D-Arg-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Orn-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dap-Tmt-NH 2 ,

Hmt-D-Arg-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dap-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dap-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Tmt-D-Lys-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Om-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dap-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Arg-Tmt-NH 2 ,

Hmt-D-Lys-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dap-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Arg-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Mmt-D-Orn-Phe-Arg-NH 2 ,

Mmt-D-Dab-Phe-Arg-NH 2 ,

Mmt-D-Dap-Phe-Arg-NH 2 ,

Mmt-D-Arg-Phe-Arg-NH 2 ,

Tmt-D-Lys-Phe-Arg-NH 2 ,

Tmt-D-Orn-Phe-Arg-NH 2 ,

Tmt-D-Dab-Phe-Arg-NH 2 ,

Tmt-D-Dap-Phe-Arg-NH 2 ,

Tmt-D-Arg-Phe-Arg-NH 2 ,

Hmt-D-Lys-Phe-Arg-NH 2 ,

Hmt-D-Orn-Phe-Arg-NH 2 ,

Hmt-D-Dab-Phe-Arg-NH 2 ,

Hmt-D-Dap-Phe-Arg-NH 2 ,

Hmt-D-Arg-Phe-Arg-NH 2 ,

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

Arg-Phe-Lys-Dmt-NH 2 ,

Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Drnt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-D-Arg-Dmt-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-.Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 , and

Cha-D-Arg-Phe-Lys-NH 2 ,

and wherein the molecule is selected from the group consisting of: a polynucleotide, a polyamino acid, a cytotoxic agent, an antibiotic, an antioxidant, a growth factor, and a cytokine.

11. A method according to claim 10 , wherein the molecule is conjugated to the aromatic cationic peptide by a linker.

12. A method according to claim 10 , wherein the molecule and aromatic cationic peptide are chemically bonded.

13. A method according to claim 10 , wherein the molecule and aromatic cationic peptide are physically bonded.

14. A method according to claim 10 , wherein the polynucleotide is selected from the group consisting of RNA, double-stranded RNA, siRNA, DNA, single-stranded RNA, messenger RNA, an oligonucleotide, a ribozyme, an anti-sense RNA, an external guide sequence for a ribozyme, and an RNA decoy.

15. A method according to claim 10 , wherein polyamino acid is selected from the group consisting of an endogenous peptide or protein, an enzyme, and an antibody.

16. A method according to claim 10 , wherein cytotoxic agent is selected from the group consisting of doxorubicin and adriamycin.

17. A method according to claim 10 , wherein antioxidant is selected from the group consisting of vitamin E, vitamin C, and beta-carotene.

18. A method according to claim 10 , wherein the growth factor is a neurotrophic growth factor.

19. A method for delivering a molecule to a cell, the method comprising contacting the cell with a molecule conjugated to an aromatic-cationic peptide is selected from the group consisting of:

Lys-D-Arg-Tyr-NH 2 ,

Phe-D-Arg-His,

D-Tyr-Trp-Lys-NH 2 ,

Trp-D-Lys-Tyr-Arg-NH 2 ,

Tyr-His-D-Gly-Met,

Phe-Arg-D-His-Asp,

Tyr-D-Arg-Phe-Lys-Glu-NH 2 (SEQ ID NO: 3),

Met-Tyr-D-Lys-Phe-Arg (SEQ ID NO: 4),

D-His-Glu-Lys-Tyr-D-Phe-Arg (SEQ ID NO: 5),

Lys-D-Gln-Tyr-Arg-D-Phe-Trp-NH 2 (SEQ ID NO: 6),

Phe-D-Arg-Lys-Trp-Tyr-D-Arg-His (SEQ ID NO: 7),

Gly-D-Phe-Lys-Tyr-His-D-Arg-Tyr-NH 2 (SEQ ID NO: 8),

Val-D-Lys-His-Tyr-D-Phe-Ser-Tyr-Arg-NH −2 (SEQ ID NO: 9),

Trp-Lys-Phe-D-Asp-Arg-Tyr-D-His-Lys (SEQ ID NO: 10),

Lys-Trp-D-Tyr-Arg-Asn-Phe-Tyr-D-His-NH 2 (SEQ ID NO: 11),

Thr-Gly-Tyr-Arg-D-His-Phe-Trp-D-His-Lys (SEQ ID NO: 12),

Asp-D-Trp-Lys-Tyr-D-His-Phe-Arg-D-Gly-Lys-NH 2 (SEQ ID NO: 13),

D-His-Lys-Tyr-D-Phe-Glu-D-Asp-D-His-D-Lys-Arg-Trp-NH 2 (SEQ ID NO: 14),

Ala-D-Phe-D-Arg-Tyr-Lys-D-Trp-His-D-Tyr-Gly-Phe (SEQ ID NO: 15),

Tyr-D-Arg-Phe-Orn-NH 2 ,

Tyr-D-Arg-Phe-Dab-NH 2 ,

Tyr-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-Cys-NH 2 (SEQ ID NO: 16),

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-dns-NH 2 ,

2′6′Dmt-D-Arg-Phe-Lys-NH(CH2)2-NH-atn-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsLys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Lys-NH 2 ,

2′6′Dmt-D-Cit-Phe-Ahp-NH 2 ,

2′6′Dmt-D-Arg-Phe-Orn-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dab-NH 2 ,

2′6′Dmt-D-Arg-Phe-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-Ahp(2-aminoheptanoic acid)-NH 2 ,

3′5′Dmt-D-Arg-Phe-Lys-NH 2 ,

3′5′Dmt-D-Arg-Phe-Orn-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dab-NH 2 ,

3′5′Dmt-D-Arg-Phe-Dap-NH 2 ,

Tyr-D-Arg-Tyr-Lys-NH 2 ,

Tyr-D-Arg-Tyr-Orn-NH 2 ,

Tyr-D-Arg-Tyr-Dab-NH 2 ,

Tyr-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Arg-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Pap-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Dab-NH 2 ,

Tyr-D-Lys-Phe-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Phe-Lys-NH 2 ,

Tyr-D-Lys-Phe-Orn-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dab-NH 2 ,

2′6′Dmt-D-Lys-Phe-Dap-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-NH 2 ,

2′6′Dmt-D-Lys-Phe-Lys-NH 2 ,

3′5′Dmt-D-Lys-Phe-Orn-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dab-NH 2 ,

3′5′Dmt-D-Lys-Phe-Dap-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Lys-Tyr-Lys-NH 2 ,

Tyr-D-Lys-Tyr-Orn-NH 2 ,

Tyr-D-Lys-Tyr-Dab-NH 2 ,

Tyr-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Lys-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Orn-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dab-NH 2 ,

2′6′Dmt-D-Lys-Tyr-Dap-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Lys-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Orn-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dab-NH 2 ,

2′6′Dmt-D-Lys-2′6′Dmt-Dap-NH 2 ,

2′6′Dmt-D-Arg-Phe-dnsDap-NH 2 ,

2′6′Dmt-D-Arg-Phe-atnDap-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Lys-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Orn-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dab-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Dap-NH 2 ,

Tyr-D-Lys-Phe-Arg-NH 2 ,

Tyr-D-Orn-Phe-Arg-NH 2 ,

Tyr-D-Dap-Phe-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Lys-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Orn-Phe-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-Phe-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-Phe-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-Phe-Arg-3′5′Dmt-NH 2 ,

Tyr-D-Lys-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Orn-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dab-Tyr-Arg-Tyr-NH 2 ,

Tyr-D-Dap-Tyr-Arg-Tyr-NH 2 ,

2′6′Dmt-D-Arg-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Drnt-D-Lys-2′6′Dmt-Arg-2′6′Drnt-NH 2 ,

2′6′Dmt-D-Orn-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

2′6′Dmt-D-Dab-2′6′Dmt-Arg-2′6′Dmt-NH 2 ,

3′5′Dmt-D-Dap-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Arg-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Lys-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

3′5′Dmt-D-Orn-3′5′Dmt-Arg-3′5′Dmt-NH 2 ,

Mmt-D-Arg-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Arg-Phe-Dap-Mmt-NH 2 ,

Tmt-D-Arg-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Orn-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Arg-Phe-Dap-Tmt-NH 2 ,

Hmt-D-Arg-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Arg-Phe-Dap-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Lys-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Orn-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dab-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Dap-Mmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Tmt-D-Lys-Phe-Lys-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Om-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dab-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Dap-Tmt-NH 2 ,

Tmt-D-Lys-Phe-Arg-Tmt-NH 2 ,

Hmt-D-Lys-Phe-Lys-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Orn-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dab-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Dap-Hmt-NH 2 ,

Hmt-D-Lys-Phe-Arg-Hmt-NH 2 ,

Mmt-D-Lys-Phe-Arg-Mmt-NH 2 ,

Mmt-D-Orn-Phe-Arg-NH 2 ,

Mmt-D-Dab-Phe-Arg-NH 2 ,

Mmt-D-Dap-Phe-Arg-NH 2 ,

Mmt-D-Arg-Phe-Arg-NH 2 ,

Tmt-D-Lys-Phe-Arg-NH 2 ,

Tmt-D-Orn-Phe-Arg-NH 2 ,

Tmt-D-Dab-Phe-Arg-NH 2 ,

Tmt-D-Dap-Phe-Arg-NH 2 ,

Tmt-D-Arg-Phe-Arg-NH 2 ,

Hmt-D-Lys-Phe-Arg-NH 2 ,

Hmt-D-Orn-Phe-Arg-NH 2 ,

Hmt-D-Dab-Phe-Arg-NH 2 ,

Hmt-D-Dap-Phe-Arg-NH 2 ,

Hmt-D-Arg-Phe-Arg-NH 2 ,

D-Arg-Dmt-Lys-Phe-NH 2 ,

D-Arg-Dmt-Phe-Lys-NH 2 ,

D-Arg-Phe-Lys-Dmt-NH 2 ,

D-Arg-Phe-Dmt-Lys-NH 2 ,

D-Arg-Lys-Drnt-Phe-NH 2 ,

D-Arg-Lys-Phe-Dmt-NH 2 ,

Phe-Lys-Dmt-D-Arg-NH 2 ,

Phe-Lys-D-Arg-Dmt-NH 2 ,

Phe-D-Arg-Dmt-Lys-NH 2 ,

Phe-D-Arg-Lys-Dmt-NH 2 ,

Phe-Dmt-D-Arg-Lys-NH 2 ,

Phe-Dmt-Lys-D-Arg-NH 2 ,

Lys-Phe-D-Arg-Dmt-NH 2 ,

Lys-Phe-Dmt-D-Arg-NH 2 ,

Lys-Dmt-D-Arg-Phe-NH 2 ,

Lys-Dmt-Phe-D-Arg-NH 2 ,

Lys-D-Arg-Phe-Dmt-NH 2 ,

Lys-D-Arg-Dmt-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Phe-NH 2 ,

D-Arg-Dmt-D-Arg-Dmt-NH 2 ,

D-Arg-Dmt-D-Arg-Tyr-NH 2 ,

D-Arg-Dmt-D-Arg-Trp-NH 2 ,

Trp-D-Arg-Phe-Lys-NH 2 ,

Trp-D-Arg-Tyr-Lys-NH 2 ,

Trp-D-Arg-Trp-Lys-NH 2 ,

Trp-D-Arg-Dmt-Lys-NH 2 ,

D-Arg-Trp-Lys-.Phe-NH 2 ,

D-Arg-Trp-Phe-Lys-NH 2 ,

D-Arg-Trp-Lys-Dmt-NH 2 ,

D-Arg-Trp-Dmt-Lys-NH 2 ,

D-Arg-Lys-Trp-Phe-NH 2 ,

D-Arg-Lys-Trp-Dmt-NH 2 , and

Cha-D-Arg-Phe-Lys-NH 2 ,

and wherein the molecule is selected from the group consisting of: a polynucleotide, a polyamino acid, a cytotoxic agent, an antibiotic, an antioxidant, a growth factor, and a cytokine.

20. A method according to claim 19 , wherein the molecule and aromatic-cationic peptide are chemically bonded.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE TO RE-RECORD THE ASSIGNMENT PREVIOUSLY RECORDED TO CORRECT THE <APPL. NO.> FROM <12/164,902> TO <12/631,048> PREVIOUSLY RECORDED ON REEL 028090 FRAME 0159. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF INVENTION BY ASSIGNEES (INVENTORS) TO ASSIGNORS. Recorded May 15, 2012
From: SZETO, HAZEL H.; ZHAO, KESHENG; ROBERTSON, HUGH D.; BIRK, ALEX V.
To: CORNELL RESEARCH FOUNDATION, INC.
Reel/Frame 028214/0277 →
CONFIRMATORY LICENSE Recorded Apr 25, 2012
From: CORNELL UNIVERSITY / CORNELL RESEARCH FOUNDATION, INC.
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 028103/0189 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 23, 2012
From: SZETO, HAZEL H.; ZHAO, KESHENG; ROBERTSON, HUGH D.; BIRK, ALEX V.
To: CORNELL RESEARCH FOUNDATION, INC.
Reel/Frame 028090/0159 →
Continuity (3)
Continuation 10838135 · May 3, 2004
Provisional Application 60467516 · May 1, 2003
Related Publication 20100204448A1 · Aug 12, 2010