Detection and visualization of neoplastic tissues and other tissues
First Claim
1. A diagnostic system containing a bioluminescence generating system, comprising:
- (a) a first composition comprising, in a pharmaceutically acceptable vehicle, a conjugate that comprises a targeted agent that is a luciferase or a luciferin and a targeting agent, wherein;
a bioluminescence generating system comprises a luciferase as one component and a luciferin as another component;
the conjugate binds to a cell surface receptor;
the targeting agent specifically binds to a cell surface protein; and
(b) a second composition, comprising, in a pharmaceutically acceptable vehicle;
a luciferin or a luciferase, wherein the composition comprises a luciferin if the targeted agent in the first composition is a luciferase, and a luciferase if the targeted agent in the first composition is a luciferin; and
(c) a compound that is a spectral shifter that shifts the spectrum of light generated by the bioluminescence generating system.
2 Assignments
0 Petitions
Accused Products
Abstract
Diagnostic systems that rely on bioluminescence for visualizing tissues in situ are provided. The systems are particularly useful for visualizing and detecting neoplastic tissue and specialty tissue during surgical procedures. Kits that provide the components of the systems and methods using the systems for visualizing the tissue are also provided. The systems include compositions containing conjugates that include a tissue specific, particularly a tumor-specific, targeting agent linked to a targeted agent, a luciferase or luciferin. The systems also include a second composition that contains the remaining components of a bioluminescence generating reaction. Administration of the compositions results production of light by targeted tissues that permits the detection and localization of neoplastic tissue for surgical removal. Therapeutic methods in which photosensitizing compounds are administered are also provided.
317 Citations
89 Claims
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1. A diagnostic system containing a bioluminescence generating system, comprising:
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(a) a first composition comprising, in a pharmaceutically acceptable vehicle, a conjugate that comprises a targeted agent that is a luciferase or a luciferin and a targeting agent, wherein;
a bioluminescence generating system comprises a luciferase as one component and a luciferin as another component;
the conjugate binds to a cell surface receptor;
the targeting agent specifically binds to a cell surface protein; and
(b) a second composition, comprising, in a pharmaceutically acceptable vehicle;
a luciferin or a luciferase, wherein the composition comprises a luciferin if the targeted agent in the first composition is a luciferase, and a luciferase if the targeted agent in the first composition is a luciferin; and
(c) a compound that is a spectral shifter that shifts the spectrum of light generated by the bioluminescence generating system. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27)
L is a linker;
the targeting agent is a protein or peptide that specifically binds to a cell surface protein;
at least one targeting agent is linked at any residue polypeptide via (L)q to at least one targeted agent;
m and n, which are selected independently, are at least 1;
q is 0 or more as long as the resulting conjugate binds to a cell surface protein on the targeted cells.
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3. The diagnostic system of claim 2, wherein m and n, which are selected independently, are 1-6.
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4. The diagnostic system of claim 2, wherein q is 1, n is 1 and m is 1.
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5. The diagnostic system of claim 2, wherein L is selected from the group consisting of protease substrates, linkers that increase the flexibility of the conjugate, linkers that increase the solubility of the conjugate, linkers that increase the serum stability of the conjugate, photocleavable linkers and acid cleavable linkers.
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6. The diagnostic system of claim 2, wherein the targeting agent is a monoclonal antibody or a growth factor.
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7. The system of claim 6, wherein the antibody is selected from the group consisting of FO23C5, A10, MN14 F(ab)2, MAb J28, MAb PA8-15, MAb C 50, MAb 19-9, MAb C 242, MAb AR-3, MAb DU-PAN-2, MAb Ypan-1, MAb Span-1, MAb BW494, MAb MUSE 11, MAb 17-1A, OC125, DF3, GA733MoAb, YH206MoAb and A78-G/A7.
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8. The method of claim 6, wherein the antibody is humanized.
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9. The diagnostic system of claim 2, wherein the targeting agent is a tumor specific antibody.
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10. The diagnostic system of claim 1, wherein the conjugate is a chimeric protein produced by fusing a luciferase to a targeting agent.
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11. The diagnostic system of claim 1, wherein the conjugate is a non-covalent complex containing a targeting agent and a luciferin or luciferase.
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12. The system of claim 1, wherein the spectral shifter is selected from the group consisting of fluorochrome, green fluorescent proteins, red fluorescent proteins, and luciferins altered chemically or enzymatically to cause shifts in frequency of emission.
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13. The system of claim 1, wherein the bioluminescence generating system is selected from the group consisting of those isolated from the ctenophores, coelenterases, mollusca, fish, ostracods, insects, bacteria, a crustacea, annelids, and earthworms.
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14. The system of claim 13, wherein the bioluminescence generating system is selected from those isolated from:
- fireflies, Mnemiopsis, Beroe ovata, Aequorea, Obelia, Pelagia, Renilla, Pholas Aristostomias, Pachystomias, Poricthys, Cypridina, Aristostomias, Pachystomias, Malacosteus, Gonadostomias, Gaussia, Watensia, Halisturia, Vampire squid, Glyphus, Mycotophids, Vinciguerria, Howella, Florenciella, Chaudiodus, Melanocostus, Sea Pens, Chiroteuthis, Eucleoteuthis, Onychoteuthis, Watasenia, cuttlefish, Sepiolina, Oplophorus, Acanthophyra, Sergestes, Gnathophausia, Argyropelecus, Yarella, Diaphus, Gonadostomias, Ptilosarcus and Neoscopelus.
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15. The diagnostic system of claim 1, wherein the compositions are formulated for topical, local or systemic administration.
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16. The diagnostic system of claim 15, wherein the first composition is formulated for systemic administration.
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17. A kit comprising the diagnostic system of claim 1:
wherein each of the compositions are contained within packaging that prevents mixing of the contents of each composition.
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18. The kit of claim 17, wherein the conjugate comprises the following components:
- (targeting agent)n, (L)q and (targeted agent)m, wherein;
L is a linker;
the targeting agent is a protein or peptide that specifically binds to a cell surface protein;
at least one targeting agent is linked at any residue polypeptide via (L)q to at least one targeted agent;
m and n, which are selected independently, are at least 1;
q is 0 or more as long as the resulting conjugate binds to a cell surface protein on the targeted cells.
- (targeting agent)n, (L)q and (targeted agent)m, wherein;
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19. The kit of claim 17, wherein the compositions are formulated in pharmaceutically acceptable vehicles for topical, local or systemic administration.
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20. The kit of claim 17, wherein the targeting agent is a tumor specific antibody.
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21. The kit of claim 20, wherein the antibody is selected from the group consisting of FO23C5, A10, MN14 F(ab)2, MAb J28, MAb PA8-15, MAb C 50, MAb 19-9, MAb C 242, MAb AR-3, MAb DU-PAN-2, MAb Ypan-1, MAb Span-1, MAb BW494, MAb MUSE 11, MAb 17-1A, OC125, DF3, GA733MoAb, YH206MoAb and A78-G/A7.
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22. The kit of claim 20, wherein the antibody is humanized.
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23. The kit of claim 17, wherein the conjugate is a chimeric protein produced by fusing a luciferase to a targeting agent.
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25. The kit of claim 17, wherein the spectral shifter is selected from the group consisting of fluorochrome, green fluorescent proteins, red fluorescent proteins, and luciferins altered chemically or enzymatically to cause shifts in the frequency of emission.
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26. The system of claim 17, wherein the compound that is a spectral shifter shifts the spectrum of the generated light towards the red end of the spectrum.
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27. The system of claim 1, wherein the compound that is a spectral shifter shifts the spectrum of the generated light towards the red end of the spectrum.
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24. The kit 17, wherein the conjugate is a non-covalent complex containing a targeting agent and a luciferin or luciferase.
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28. A kit, comprising:
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(a) a first composition comprising a conjugate that comprises a luciferase or a luciferin and a targeting agent, wherein;
the conjugate binds to a cell surface receptor and the targeting agent specifically binds to a cell surface protein; and
(b) a second composition, comprising in a pharmaceutically acceptable vehicle a luciferin or a luciferase; and
(c) a third composition that contains a spectral shifter.
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29. A method for in vivo labeling of selected tissues, comprising:
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contacting the tissue with a conjugate comprising a first component of a bioluminescence generating system, wherein the first component is a luciferin or luciferase; and
then contacting the tissue with the remaining components of the system, whereby light is generated, wherein;
contacting is effected in vivo; and
the luciferase is a red emitting luciferase or the bioluminescence generating system further comprises a compound that shifts light generated by the bioluminescence generating system to the red, whereby the generated light is visible through the skin. - View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37)
the conjugate further comprises a targeting agent, and the targeting agent is a tumor specific monoclonal antibody.
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32. The method of claim 31, wherein the antibody is selected from the group consisting of FO23C5, A10, MN14 F(ab)2, MAb J28, MAb PA8-15, MAb C 50, MAb 19-9, MAb C 242, MAb AR-3, MAb DU-PAN-2, MAb Ypan-1, MAb Span-1, MAb BW494, MAb MUSE 11, MAb 17-1A, OC125, DF3, GA733MoAb, YH206MoAb and A78-G/A7.
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33. The method of claim 31, wherein the antibody is humanized.
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34. The method of claim 29, wherein the bioluminescence generating system is selected from the group consisting of those isolated from the ctenophores, coelenterases, mollusca, fish, ostracods, insects, bacteria, a crustacea, annelids, and earthworms.
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35. The method of claim 34, wherein the bioluminescence generating system is selected from those isolated from:
- fireflies, Mnemiopsis, Beroe ovata, Aequorea, Obelia, Pelagia, Renilla, Pholas Aristostomias, Pachystomias, Poricthys, Cypridina, Aristostomias, such Pachystomias, Malacosteus, Gonadostomias, Gaussia, Watensia, Halisturia, Vampire squid, Glyphus, Mycotophids, Vinciguerria, Howella, Florenciella, Chaudiodus, Melanocostus, Sea Pens, Chiroteuthis, Eucleoteuthis, Onychoteuthis, Watasenia, cuttlefish, Sepiolina, Oplophorus, Acanthophyra, Sergestes, Gnathophausia, Argyropelecus, Yarella, Diaphus, Gonadostomias and Neoscopelus.
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36. The method of claim 29, wherein one or both compositions are administered by topical, enteric, local, parenteral, intracystal, intracutaneous, intravitreal, subcutaneous, intramuscular, or intravenous administration.
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37. The method of claim 29, wherein one or both compositions are formulated for time release upon administration.
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38. A method for in situ visualization of selected tissues, comprising:
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(a) administering a first composition, comprising, in a pharmaceutically acceptable vehicle, a conjugate that comprises a targeted agent that is a luciferase or a luciferin, and a targeting agent, wherein the targeting agent specifically binds to a cell surface protein;
(b) performing surgery that exposes selected tissues; and
(c) administering a second composition, comprising, in a pharmaceutically acceptable vehicle, a luciferin or a luciferase and a spectral shifter, wherein the second composition comprises a luciferin and a spectral shifter if the targeted agent is a luciferase or it comprises a luciferase and a spectral shifter if the targeted agent is a luciferin, whereby, if the selected tissue includes cells that express the cell surface protein light is produced in the exposed tissue. - View Dependent Claims (39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67)
L is a linker;
the targeting agent is a protein or peptide that specifically binds to a cell surface protein;
at least one targeting agent is linked at any residue polypeptide via (L)q to at least one targeted agent;
m and n, which are selected independently, are at least 1;
q is 0 or more as long as the resulting conjugate binds to a cell surface protein on the targeted cells.
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40. The method of claim 39, wherein L is selected from the group consisting of protease substrates, linkers that increase the flexibility of the conjugate, linkers that increase the solubility of the conjugate, linkers that increase the serum stability of the conjugate, photocleavable linkers and acid cleavable linkers.
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41. The method of claim 39, wherein the targeting agent is a monoclonal antibody or a growth factor.
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42. The method of claim 41, wherein the antibody is selected from the group consisting of FO23C5, A10, MN14 F(ab)2, MAb J28, MAb PA8-15, MAb C 50, MAb 19-9, MAb C 242, MAb AR-3, MAb DU-PAN-2, MAb Ypan-1, MAb Span-1, MAb BW494, MAb MUSE 11, MAb 17-1A OC125, DF3, GA733MoAb, YH206MoAb and A78-G/A7.
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43. The method of claim 41, wherein the antibody is humanized.
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44. The method of claim 39, wherein the targeting agent is a tumor specific antibody.
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45. The method of claim 39, wherein the conjugate is a chimeric protein produced by fusing a luciferase to a targeting agent.
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46. The method of claim 39, wherein the conjugate is a non-covalent complex containing a targeting agent and a luciferin or luciferase.
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47. The method of claim 39, wherein the targeting agent is a tumor specific antibody is selected from the group consisting of FO23C5, A10, MN14 F(ab)2, MAb J28, MAb PA8-15, MAb C 50, MAb 19-9, MAb C 242, MAb AR-3, MAb DU-PAN-2, MAb Ypan-1, MAb Span-1, MAb BW494, MAb MUSE 11, MAb 17-1A, OC125, DF3, GA733MoAb, YH206MoAb and A78-G/A7.
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48. The method of claim 47, wherein the detecting method is non-invasive;
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both compositions are administered systemically; and
resulting light can be detected by scanning or viewing the surface of the body.
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49. The method of claim 39, wherein one or both compositions are administered by topical, local, enteric, parenteral, intracystal, intracutaneous, intravitreal, subcutaneous, intramuscular, or intravenous administration.
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50. The method of claim 47, wherein one or both compositions are formulated for time release upon administration.
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51. The method of claim 47, wherein the surgical procedure is a tumor excision or excision of specialty tissue.
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52. The method of claim 39, wherein one or both compositions are formulated for time release upon administration.
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53. The method of claim 38, wherein m and n, which are selected independently, are 1-6.
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54. The method of claim 53, wherein q is 1, n is 1 and m is 1.
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55. The method of claim 38, wherein the spectral shifter is selected from the group consisting of fluorochrome, green fluorescent proteins, red fluorescent proteins, and luciferins altered chemically or enzymatically to cause shifts in frequency of emission.
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56. The method of claim 38, wherein the bioluminescence generating system is selected from the group consisting of those isolated from the ctenophores, coelenterases, mollusca, fish, ostracods, insects, bacteria, a crustacea, annelids, and earthworms.
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57. The method of claim 38, wherein the bioluminescence generating system is selected from those isolated from:
- fireflies, Mnemiopsis, Beroe ovata, Aequorea, Obelia, Pelagia, Renilla, Pholas Aristostomias, Pachystomias, Poricthys, Cypridina, Aristostomias, Pachystomias, Malacosteus, Gonadostomias, Gaussia, Watensia, Halisturia, Vampire squid, Glyphus, Mycotophids, Vinciguerria, Howella, Florenciella, Ptilosarcus, Chaudiodus, Melanocostus, Sea Pens, Chiroteuthis, Eucleoteuthis, Onychoteuthis, Watasenia, cuttlefish, Sepiolina, Oplophorus, Acanthophyra, Sergestes, Gnathophausia, Argyropelecus, Yarella, Diaphus, Gonadostomias and Neoscopelus.
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58. The method of claim 38, wherein the first composition is administered systemically.
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59. The method of claim 38, wherein the first and second composition are administered systemically.
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60. The method of claim 38, wherein the first composition is administered systemically prior to a surgical procedure, and, the second composition is applied topically during the surgical procedure.
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61. The method of claim 38, wherein the first composition is administered systemically prior to a surgical procedure, and, the second composition is administered locally the surgical procedure.
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62. The method of claim 38, wherein the first composition is administered locally during a surgical procedure, and, the second composition is applied topically or locally during the surgical procedure.
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63. The method of claim 38, wherein one or both compositions are administered by topical, local, enteric, parenteral, intracystal, intracutaneous, intravitreal, subcutaneous, intramuscular, or intravenous administration.
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64. The method of claim 38, further comprising detecting the emitted light.
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65. The method of claim 38, further comprising detecting the emitted light.
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66. The method of claim 38, wherein emitted light is detected by endoscopic localization.
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67. The method of claim 38, wherein emitted light is detected by endoscopic localization.
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68. A method of detecting of neoplasia or specialty tissue prior to surgical removal, comprising:
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preoperatively administering to a mammal a targeting agent conjugated, directly or through a linker, to one or more component(s) of a bioluminescence generating system, wherein the components are a luciferase or luciferin;
waiting a predetermined period of time following administration to localize the conjugate in the neoplasia or specialty tissue;
administering a composition containing an effective amount of any remaining components or activators of the bioluminescence generating system, whereby the bioluminescence generating system produces light; and
detecting neoplasia or specialty tissue that glows;
wherein a compound that is a spectral shifter, whereby the spectrum of light generated by the bioluminescence generating system is shifted, is administered with the composition that contains the remaining components of the bioluminescence generating system.- View Dependent Claims (69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)
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- 82. A pharmaceutical composition formulated as spray, foam or aerosol comprising one or more components of a bioluminescence generating system selected from the group consisting of luciferins and luciferases.
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85. A method of detecting neoplasia or specialty tissue, comprising:
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a) preoperatively administering to a mammal an effective amount of a composition wherein;
the composition comprises, in a pharmaceutically acceptable vehicle, a conjugate that comprises a targeted agent that is a component of a bioluminescence generating system, and a targeting agent;
a bioluminescence generating system comprises a luciferase as one component and a luciferin as another component;
the conjugate binds to a cell surface receptor, the targeted agent is a luciferase or luciferin, the targeting agent specifically binds to a cell surface protein;
b) waiting a predetermined period of time following administration to allow the targeting agent to preferentially localize in the neoplasia or specialty tissue;
c) exposing a predetermined area surrounding the neoplasia or specialty tissue using a surgical procedure;
d) contacting the predetermined area with a composition containing any remaining components or activators of the bioluminescence generating system, whereby any neoplasia or specialty tissue in the exposed area glows; and
e) detecting the glowing tissue. - View Dependent Claims (86)
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87. A method of photodynarnic therapy, comprising:
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administering to a mammal an effective amount of a photosensitizing drug;
administering composition containing a conjugate comprising a component of a bioluminescence generating system, wherein the first component is a luciferin or luciferase; and
then administering additional components of the system, wherein light generated by the bioluminescence generating system activates the drug.
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88. A method for in vivo labeling of selected tissues, comprising:
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contacting the tissue with a conjugate comprising a first component of a bioluminescence generating system, wherein the first component is a luciferin or luciferase;
then contacting the tissue with the remaining components of the system to generate light;
wherein;
the bioluminescence generating system further comprises a compound that shifts the spectrum of the light generated by the bioluminescence generating reaction; and
contacting is effected in vivo. - View Dependent Claims (89)
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Specification