Near infrared fluorescent dyes, formulations and related methods
Provided herein is a pharmaceutical composition comprising an effective amount of cypate-Cyclo(Cys-Gly-Arg-Asp-Ser-Pro-Cys)-Lys-OH (LS301), cypate-Cyclo(Cys-Gly-Arg-Asp-Ser-Pro-Cys)-Tyr-OH (LS838) or pharmaceutically acceptable salts thereof, wherein each amino acid residue is independently in a D or L configuration; a divalent metal ion; and a pharmaceutically acceptable carrier. Further provided are lyophilized products comprising a dye-conjugate and m methods for identifying compromised and for binding phosphorylated annexin A2 (pANXA2) protein in a biological sample using a composition described herein.
1. A lyophilized product comprising
a dye-conjugate chosen from cypate-Cyclo(Cys-Gly-Arg-Asp-Ser-Pro-Cys)-Lys-OH (LS301), cypate-Cyclo(Cys-Gly-Arg-Asp-Ser-Pro-Cys)-Tyr-OH (LS838) or pharmaceutically acceptable salts thereof, wherein each amino acid residue is independently in a D or L configuration, and
albumin, wherein the dye-conjugate and the albumin are in a 1:50 (w/w) ratio.
2. The lyophilized product of claim 1 , wherein the albumin is chosen from human serum albumin, mouse serum albumin, and bovine serum albumin.
3. The lyophilized product of claim 1 , formed by a method comprising
suspending the dye-conjugate in 1% albumin solution at a ratio of 1 gram of dye-conjugate per 10 liters of the albumin solution;
mixing the suspension;
filtering the mixed suspension; and
lyophilizing the filtered suspension to form the lyophilized product.
4. The lyophilized product of claim 3 , wherein the suspension is mixed on a shaker of at least about 30 minutes.
5. The lyophilized product of claim 3 , the dye-conjugate and albumin concentration in the suspension are measured via absorbance.
6. A vial comprising about 102 mg of the lyophilized product of claim 1 .
7. An injectable solution comprising about 102 mg of the lyophilized product of claim 1 and about 10 mL of phosphate-buffered saline.
8. The injectable solution of claim 7 , comprising about 0.2 mg/mL dye-conjugate.
9. A method of preparing an injectable solution, the method comprising mixing about 10 mL of phosphate-buffered saline into a vial comprising about 102 mg of the lyophilized product of claim 1 to form an injectable solution comprising about 0.2 mg/mL dye-conjugate.
10. A method for identifying compromised fibroblasts, comprising administering an effective amount of a lyophilized product claim 1 to a subject in need thereof.
11. The method of claim 10 , wherein the compromised fibroblasts are proximal to dormant cancer cells.
12. The method of claim 11 , wherein the dormant cancer cells are chosen from acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas, breast cancer, bronchial adenomas/carcinoids, Burkitt lymphoma, carcinoid tumors, carcinoma of unknown primary, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma in the Ewing family of tumors, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancers, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumors, gestational trophoblastic tumor, gliomas, gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma-, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemias, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone/osteosarcoma, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, mesotheliomas, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, skin carcinoma, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, stomach cancer, supratentorial primitive neuroectodermal tumor, T Cell lymphoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unknown primary site, ureter and renal pelvis transitional cell cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.
13. The method of claim 11 , wherein the dormant cancer cells are pancreatic cancer.
14. The method of claim 11 , wherein the lyophilized product is administered intravenously.
15. The method of claim 11 , wherein the lyophilized product is administered topically.
16. The method of claim 15 , wherein the topical administration is to the subject's colon.
17. A method of binding phosphorylated annexin A2 (pANXA2) protein in a biological sample comprising contacting the biological sample with a lyophilized product of claim 1 .
18. The method of claim 17 , wherein the binding is selective over annexin A1 (ANXA1), non-activated ANXA2, and annexin A3 (ANXA3).
19. The method of claim 17 , wherein tumor margins of cancer are defined.
20. The method of claim 17 , wherein accuracy of cancer resection is improved during surgery.
21. The method of claim 17 , wherein cancer is treated simultaneously from periphery and interior core of a tumor.
22. The method of claim 19 , wherein the cancer is chosen from acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas, breast cancer, bronchial adenomas/carcinoids, Burkitt lymphoma, carcinoid tumors, carcinoma of unknown primary, central nervous system lymphoma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma in the Ewing family of tumors, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic tumor, glioma, gastric carcinoid, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone/osteosarcoma, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorder, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasma cell neoplasia, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, skin carcinoma, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, stomach cancer, supratentorial primitive neuroectodermal tumor, T-Cell lymphoma, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unknown primary site, ureter and renal pelvis transitional cell cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.