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WO 2015/187677 Al 10 December 2015 (10.12.2015) P O P C T

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WO 2015/187677 Al 10 December 2015 (10.12.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/187677 Al 10 December 2015 (10.12.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 41/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2015/033759 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 2 June 2015 (02.06.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/006,790 2 June 2014 (02.06.2014) US (84) Designated States (unless otherwise indicated, for every 62/017,165 25 June 2014 (25.06.2014) US kind of regional protection available): ARIPO (BW, GH, 62/066,807 2 1 October 20 14 (2 1.10.20 14) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/082,052 19 November 2014 (19. 11.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: LI-COR, INC. [US/US]; 4647 Superior Street, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lincoln, Nebraska 68504 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: KOVAR, Joy L.; 4647 Superior Street, Lincoln, GW, KM, ML, MR, NE, SN, TD, TG). Nebraska 68504 (US). (74) Agents: SNYDER, Joseph, R. et al; Kilpatrick Townsend Published: and Stockton LLP, Two Embarcadero Center, Eighth — with international search report (Art. 21(3)) Floor, San Francisco, California 941 11 (US). (54) Title: PHTHALOCYANINE PROBES AND USES THEREOF Photodynamlc Therapy FIG. 1 (57) Abstract: The present invention relates to compositions and methods for destroying target cells in a patient using photodynamic therapy. In particular, the present invention provides a photosensitizing agent based on a small molecular weight (< 50 kDa) protein or peptide or a small molecule that is conjugated to a phthalocyanine dye, such as IRDye® 700DX. PHTHALOCYANINE PROBES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application Nos. 62/006,790, filed June 2, 2014; 62/017,165, filed June 25, 2014; 62/066,807, filed October 21, 2014 and 62/082,052, filed November 19, 2014, the teachings all of which are hereby incorporated by reference in their entireties for all purposes. BACKGROUND OF THE INVENTION [0002] Photodynamic therapy is a treatment method that uses a photosensitizing agent and irradiating light to destroy cells of interest in the body. When the photosensitizer is exposed to a specific wavelength of light, it produces a cytotoxic reactive oxygen species that can induce apoptosis, necrosis and/or autophagy of nearby cells. [0003] Current photodynamic therapy methods rely on using antibodies or fragments thereof to localize the photosensitizing agent to the target cells. There is, however, a need for improved photosensitizing probes based on small molecule conjugates to induce apoptosis in target cells, e.g., diseased cells, in a subject using photodynamic therapy. The present invention satisfies this need and provides related advantages as well. BRIEF SUMMARY OF THE INVENTION [0004] In one embodiment, the present invention provides a method for inducing cytotoxicity, e.g., apoptosis in a subject having a disease or condition. The method includes (a) administering to the subject a therapeutically effective agent comprising a phthalocyanine dye such as IRDye® 700DX conjugated to a probe that specifically binds to a cell in the subject; and (b) irradiating the cell with an appropriate excitation light in an amount to effectively induce cell death. The phthalocyanine dye IRDye® 700DX conjugated to a probe is a compound of Formula la. [0005] In some aspects, the disease or condition is selected from the group of a vascular disease, cancer, infection due to a bacterial biofilm, an antibiotic-resistant wound infection, actinic keratosis, rosacea, acne, and psoriasis. The vascular disease can be wet age-related macular degeneration. In some instances, the cancer is selected from the group consisting of breast cancer, colorectal cancer, esophageal cancer, endobronchial cancer, high-grade dyslasia in Barrett's esophagus, lung cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, pancreatic cancer, liver cancer, bladder cancer, brain cancer, head and neck cancer, neuroendocrine cancer, skin cancer, and combinations thereof. [0006] In some aspects, the subject has a solid tumor or has had a solid tumor. The cell in the subject can be in the solid tumor, in the subject's blood, or at the site of metastasis. [0007] In some instances, the appropriate excitation light has a wavelength of 660 to 740 nm, e.g., 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, or 740 nm. [0008] In some aspects, the probe is selected from the group of a ligand, peptide, small protein, small molecule, and combinations thereof. In some instances, the probe has a molecular weight of less than about 50 kDa. In other instances, the probe has a molecular weight of less than about 10 kDa. The ligand can be EGF. The peptide can be selected from the group of YC-27, cRGDfK, vasoactive intestinal peptide, gastrin-releasing peptide, neurotensin, AHl 11585, FPPRGD2, PKl 1195, SPARC, bombesin, neurotensin, substance P, somatostatin, cholecystokinin, glucagon-like peptide- 1, neuropeptide Y, octreotide, DOTA- TOC, DOTA-TATE, exendin-4, RGD, analogs thereof, derivatives thereof, and combinations thereof. In some aspects, the peptide is selected from the group of soricidin, SOR-13 and SOR-C27. In other aspects, the small molecule is selected from the group of a VEGFR inhibitor, a TNFRl inhibitor, a growth factor receptor inhibitor and combinations thereof. In some instances, the small molecule VEGFR inhibitor is selected from the group of pazopanib, semaxanib, axitinib, cabozantinib, aflibercept, brivanib, tivozanib, ramucirumab, motesanib, vatalanib, cediranib, and combinations thereof. Alternatively, the probe can be a member selected from the group of DTPA-octreotide, [Gluc-Lys]-TOCA, galacto-RGD, 40 AHl 11585, RGD-K5, FPPRGD2, RP-527, BZH3, [DTPA-Lys ]-Exendin-4, and Tc-NT-Xl. In some instances, the probe is a peptide ligand, an Affibody ® or a derivative thereof. [0009] In some aspects, the probe is conjugated to a radionuclide or has a radionuclide incorporated therein. The probe can also be conjugated to a fluorophore. [0010] In some aspects, the administering of step (a) includes injecting the therapeutically effective agent, the phthalocyanine dye IRDye® 700DX conjugated to a probe into the subject's blood. In some aspects, the irradiating of step (b) comprises using a device comprising a near infrared (NIR) light emitting diode. The method described herein can also include administering an anticancer drug to the subject. The phthalocyanine dye IRDye 700DX conjugated to a probe is a compound of Formula la. [0011] In another embodiment, the present invention provides a method for treating a solid tumor in a subject having cancer. The method includes (a) administering to the subject a therapeutically effective agent comprising a phthalocyanine dye conjugated to a probe that specifically binds to a cell of the solid tumor; and (b) irradiating the cell with an appropriate excitation light in an amount to effectively reduce the size of the solid tumor. [0012] In some aspects, the solid tumor is selected from the group of breast tumor, colorectal tumor, lung tumor, prostate tumor, ovarian tumor, gastric tumor, pancreatic tumor, liver tumor, bladder tumor, brain tumor, neuroendocrine tumor, and combinations thereof. [0013] In some aspects, the phthalocyanine dye is IRDye® 700DX. In some instances, the appropriate excitation light has a wavelength of 660 to 740 nm, e.g., 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, or 740 nm. [0014] In some aspects, wherein the probe is selected from the group of a ligand, peptide, small protein, small molecule, and combinations thereof. In some instances, the probe has a molecular weight of less than about 50 kDa. In other instances, the probe has a molecular weight of less than about 10 kDa. The ligand can be EGF. The peptide can be selected from the group of YC-27, cRGDfK, vasoactive intestinal peptide, gastrin-releasing peptide, neurotensin, AHl 11585, FPPRGD2, PKl 1195, SPARC, bombesin, neurotensin, substance P, somatostatin, cholecystokinin, glucagon-like peptide- 1, neuropeptide Y, octreotide, DOTA- TOC, DOTA-TATE, exendin-4, analogs thereof, derivatives thereof, and combinations thereof. In some aspects, the peptide is selected from the group of soricidin, SOR-13 and SOR-C27. In other aspects, the small molecule is selected from the group of a VEGFR inhibitor, a TNFRl inhibitor, a growth factor receptor inhibitor and combinations thereof. In some instances, the small molecule VEGFR inhibitor is selected from the group of pazopanib, semaxanib, axitinib, cabozantinib, aflibercept, brivanib, tivozanib, ramucirumab, motesanib, vatalanib, cediranib, and combinations thereof. Alternatively, the probe can be a member selected from the group of DTPA-octreotide, [Gluc-Lys]-TOCA, galacto-RGD, 40 AHl 11585, RGD-K5, FPPRGD2, RP-527, BZH3, [DTPA-Lys ]-Exendin-4, and Tc-NT-Xl.
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