Detection and treatment of intravascular lesions
Optical agents that contain a fibrin binding moiety covalently linked to an optical dye are described, as well as methods of treating intravascular lesions in a patient using such optical agents.
1 . A method for treating an intravascular lesion in a patient comprising:
a) administering an optical agent, wherein the optical agent comprises a fibrin binding moiety and an optical dye, wherein the optical agent forms a fibrin-optical agent complex at the site of the lesion;
b) detecting a signal from the fibrin-optical agent complex using a device inserted near the lesion;
c) obtaining data about the lesion based on the signal from the fibrin-optical agent complex; and
d) delivering a therapy to at least a portion of the lesion based on the obtained data.
2 . The method of claim 1 , wherein the fibrin binding moiety comprises a peptide.
3 . The method of claim 2 , wherein the optical dye is covalently bound to the N-terminal amino acid of the peptide.
4 . The method of claim 2 , wherein the optical dye is covalently bound to the N-terminal amino acid of the peptide via a linker.
5 . The method of claim 2 , wherein the fibrin binding moiety comprises the amino acid sequence Cys-Asp-Tyr-Tyr-Gly-Thr-Cys (SEQ ID NO:1).
6 . The method of claim 2 , wherein the fibrin binding moiety comprises the amino acid sequence Cys-Pro-Tyr-Xaa-Leu-Cys (SEQ ID NO:2), wherein Xaa is Gly or Asp.
7 . The method of claim 2 , wherein the fibrin binding moiety comprises the amino acid sequence Cys-Hyp-Tyr(3×)-Xaa-Leu-Cys (SEQ ID NO:3), wherein 3× is selected from the group consisting of halogen, nitro-, and a trifluoromethyl group at the 3 position of the benzyl ring of the tyrosine, and wherein Xaa is Gly or Asp.
8 . The method of claim 2 , wherein the fibrin binding moiety comprises the amino acid sequence Phe-His-Cys-Hyp-Tyr(3-I)-Asp-Leu-Cys-His-Ile-Leu (SEQ ID NO:4).
9 . The method of claim 3 , wherein the N-terminal amino acid is selected from the group consisting of β-alanine, 6-aminohexanoic acid, and lysine.
10 . The method of claim 2 , wherein the optical dye is covalently bound to the C-terminal amino acid of the peptide.
11 . The method of claim 2 , wherein the optical dye is covalently bound to the C-terminal amino acid of the peptide via a linker.
12 . The method of claim 3 , wherein the C-terminus of the peptide is capped as a C-terminal amide.
13 . The method of claim 3 , wherein the C-terminus of the peptide is capped with a non-optical moiety.
14 . The method of claim 3 , wherein the C-terminal amino acid is in the D-configuration.
15 . The method of claim 1 , wherein the optical dye is selected from the group consisting of fluorescein, rhodamine, hematoporphyrin, fluoresdamine, indocyanine, tetramethylrhodamine, Cosin, erythrosine, coumarin, methyl-coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade Blue, Texas Red, and derivatives thereof.
16 . The method of claim 1 , wherein the optical agent is selected from the group consisting of:
17 . The method of claim 1 , wherein the lesion is selected from the group consisting of a thrombus, a clot, an atherosclerotic plaque, and an embolus.
18 . The method of claim 1 , wherein the lesion comprises fibrin that is exposed to blood flowing in the blood vessel.
19 . The method of claim 1 , wherein the fibrin-optical agent complex has a dissociation constant value of less than about 10 μM.
20 . The method of claim 1 , wherein the fibrin-optical agent complex has a dissociation constant value of less than about 5 μM.
21 . The method of claim 1 , wherein the fibrin-optical agent complex has a dissociation constant value of less than about 1 μM.
22 . The method of claim 1 , wherein the fibrin-optical agent complex has a dissociation constant value of less than about 0.3 μM.
23 . The method of claim 1 , wherein the optical agent is administered orally or parenterally.
24 . The method of claim 23 , wherein the parenteral administration is intravenous, intraarterial, interstitial, intrathecal, subcutaneous, or intracavity administration.
25 . The method of claim 1 , wherein the device comprises a catheter and an optical detector.
26 . The method of claim 25 , wherein the optical detector is a fluorescence emission detector.
27 . The method of claim 25 , wherein the device further comprises an excitation source.
28 . The method of claim 25 , wherein the device is inserted near the lesion in a cavity, a tissue, an interstitial space, or a blood vessel.
29 . The method of claim 25 , wherein the device is inserted in the same blood vessel as the lesion.
30 . The method of claim 1 , wherein the device is capable of delivering the therapy to at least a portion of the lesion.
31 . The method of claim 1 , wherein the therapy comprises a thrombolytic agent.
32 . The method of claim 31 , wherein the thrombolytic agent is selected from the group consisting of tissue plasminogen activator, streptokinase, antistreplase, and urokinase.
33 . The method of claim 31 , wherein the thrombolytic agent is administered intravenously at a site remote from the lesion.
34 . The method of claim 31 , wherein the thrombolytic agent is delivered to at least about 90% of the surface of the lesion.
35 . The method of claim 31 , wherein the thrombolytic agent is delivered to at least about 50% of the surface of the lesion.
36 . The method of claim 31 , wherein the thrombolytic agent is delivered to about 10% of the surface of the lesion.
37 . The method of claim 1 , wherein the therapy comprises mechanical manipulation of the lesion.
38 . The method of claim 37 , wherein the mechanical manipulation is selected from the group consisting of balloon angioplasty and laser ablation of the lesion.
39 . The method of claim 1 , further comprising e) detecting the signal from the fibrin-optical agent complex during the delivery of the therapy.
40 . The method of claim 39 , further comprising f) stopping the delivery of the therapy when the signal of the fibrin-optical agent complex decreases to a predetermined value.
41 . The method of claim 40 , wherein the therapy is stopped when the signal of the fibrin-optical agent complex is less than about 90% of the signal before delivery of the therapy.
42 . The method of claim 40 , wherein the therapy is stopped when the signal of the fibrin-optical agent complex is less than about 50% of the signal before delivery of the therapy.
43 . The method of claim 40 , wherein the therapy is stopped when the signal of the fibrin-optical agent complex is less than about 10% of the signal before delivery of the therapy.
44 . The method of claim 10 , wherein the N-terminus of the peptide is alkylated.
45 . The method of claim 10 , wherein the N-terminal amino acid is in the D-configuration.
46 . A composition comprising an optical agent, wherein the optical agent comprises an optical dye covalently linked to the N-terminus of a peptide fibrin binding moiety (FBM) via a linker, said optical agent having the general formula:
47 . The composition of claim 46 , wherein the optical agent is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.
48 . A formulation comprising the composition of claim 47 , wherein the formulation comprises at least one ingredient selected from the group consisting of solubilizing agents, excipients, carriers, adjuvants, vehicles, preservatives, a local anesthetic, flavorings, and colorings
49 . A kit comprising the composition of claim 47 .
50 . A method to treat a thrombus in a blood vessel in a patient, said method comprising:
a) administering an optical agent, said agent having the structure:
to form a fibrin-optical agent complex;
b) inserting a catheter in the blood vessel having said thrombus to obtain information about said thrombus, said information based on detecting a fluorescence emission signal of said fibrin-optical agent complex; and
c) delivering with said catheter a thrombolytic therapy comprising tissue plasminogen activator (tPA) based on said information to about 90% of said thrombus so that the size of said thrombus is reduced.