Sstr-targeted conjugates and particles and formulations thereof

Abstract

Conjugates of an active agent such as DM1 attached to a targeting moiety, such as a somatostatin receptor binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.

We claim: 
     
         1 . A method of reducing proliferation, increasing apoptosis or increasing cell cycle arrest of cells, comprising administering a conjugate to the cells, wherein the conjugate comprises an active agent coupled to a somatostatin receptor (SSTR) targeting moiety by a linker, wherein the active agent is mertansine (DM1). 
     
     
         2 . The method of  claim 1 , wherein the cells express a somatostatin receptor (SSTR). 
     
     
         3 . The method of  claim 2 , wherein the cells express SSTR2. 
     
     
         4 . The method of  claim 3 , wherein the cells are tumor cells. 
     
     
         5 . The method of  claim 4 , wherein the cells are neuroendocrine cancer cells. 
     
     
         6 . The method of  claim 5 , wherein the cells are selected from small cell lung cancer (SCLC), pheochromocytoma, neuroblastoma, ganglioneuroma, paraganglioma, carcinoids, gastrinoma, glucagonoma, vasoactive intestinal polypeptide-secreting tumor, pancreatic polypeptide-secreting tumor, nonfunctioning gastroenteropancreatic tumors, meduallary thyroid cancer, Merkel cell tumor of the skin, pituitary adenoma, and pancreatic cancer cells. 
     
     
         7 . The method of  claim 3 , wherein the cells are selected from brain cancer, ovarian cancer, and colorectal cancer cells. 
     
     
         8 . The method of  claim 1 , wherein the phospho-histone H3 levels in the cells increase. 
     
     
         9 . The method of  claim 1 , wherein the cleaved caspase-3 levels in the cells increase. 
     
     
         10 . The method of  claim 1 , wherein the conjugate is Conjugate 57. 
     
     
         11 . A method of treating a tumor, reducing volume of a tumor or delivering DM1 to a tumor in a subject, comprising:
 administering a conjugate to the subject, wherein the conjugate comprises an active agent coupled to a somatostatin receptor (SSTR) targeting moiety by a linker, wherein the active agent is mertansine (DM1), and   administering an additional active agent.   
     
     
         12 . The method of  claim 11 , wherein the tumor expresses a somatostatin receptor (SSTR). 
     
     
         13 . The method of  claim 12 , wherein the tumor expresses SSTR2. 
     
     
         14 . The method of  claim 12 , wherein the SSTR internalizes into cells after the conjugate is administered. 
     
     
         15 . The method of  claim 14 , wherein the SSTR internalizes faster than the SSTR on cells treated with octreotide. 
     
     
         16 . The method of  claim 11 , wherein tumor is a neuroendocrine cancer. 
     
     
         17 . The method of  claim 16 , wherein the neuroendocrine cancer is selected from small cell lung cancer (SCLC), pheochromocytoma, neuroblastoma, ganglioneuroma, paraganglioma, carcinoids, gastrinoma, glucagonoma, vasoactive intestinal polypeptide-secreting tumor, pancreatic polypeptide-secreting tumor, nonfunctioning gastroenteropancreatic tumors, meduallary thyroid cancer, Merkel cell tumor of the skin, pituitary adenoma, and pancreatic cancer. 
     
     
         18 . The method of  claim 17 , wherein the tumor is selected from neuroblastoma, breast cancer, brain cancer, ovarian cancer, and colorectal cancer. 
     
     
         19 . The method of  claim 11 , wherein the volume of the tumor is reduced by about 60%. 
     
     
         20 . The method of  claim 11 , wherein the subject has a positive scan result detected with SSTR scintigraphy or positron emission tomography (PET). 
     
     
         21 . The method of  claim 20 , wherein Indium-111-labelled pentetreotide is used in the SSTR scintigraphy or 68Ga-DOTA-TATE, 68Ga-DOTA-TOC, and 68Ga-DOTA-NOC in PET. 
     
     
         22 . The method of  claim 21 , wherein the body weight of the subject decreases less than about 30%, about 20%, about 15%, about 10% or about 5% after administering the conjugate. 
     
     
         23 . The method of  claim 11 , wherein the complete blood count (CBC) or white blood cell (WBC) count of the subject decreases less than about 30%, about 20%, about 15%, about 10%, or about 5% after administering the conjugate. 
     
     
         24 . The method of  claim 11 , wherein the AST or ALT level of the subject increases less than about 30%, about 20%, about 15%, about 10%, or about 5% after administering the conjugate. 
     
     
         25 . The method of  claim 11 , wherein the conjugate reaches at least about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400 or about 1500 μm into the tumor from the vascular surface of the tumor. 
     
     
         26 . The method of  claim 11 , wherein the conjugate penetrates to the core of the tumor. 
     
     
         27 . The method of  claim 11 , wherein the conjugate penetrates to the middle of the tumor. 
     
     
         28 . The method of  claim 11 , wherein the conjugate is selected from any conjugate in Tables 1, 2, 3, and 4. 
     
     
         29 . The method of  claim 11 , wherein the conjugate is Conjugate 57. 
     
     
         30 . The method of  claim 11 , wherein the additional active agent does not bind to SSTR. 
     
     
         31 . The method of  claim 11 , wherein the additional active agent is a cancer symptom relief drug. 
     
     
         32 . The method of  claim 11 , wherein the cancer symptom relief drug treats carcinoid syndrome. 
     
     
         33 . The method of  claim 31 , wherein the cancer symptom relief drug is telotristat or telotristat etiprate. 
     
     
         34 . The method of  claim 11 , wherein the additional active agent treats cancer. 
     
     
         35 . The method of  claim 34 , wherein the additional active agent treats a neuroendocrine tumor, kidney cancer, breast cancer, or brain cancer. 
     
     
         36 . The method of  claim 34 , wherein the additional active agent is a Lu-177-labeled somatostatin analogue peptide (lutathera), everolimus (Afinitor®), capecitabine (Xeloda®), etoposide (Etopophos®), sunitinib, dacarbazine, or fluorouracil.