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 pharmaceutical composition comprising a conjugate and at least one excipient, 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 pharmaceutical composition of  claim 1 , wherein the conjugate has a structure of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the conjugate has a concentration of between about 2.0-about 5.0 mg/mL. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the conjugate has a concentration of about 2.5 mg/mL. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the pH of the composition is between about 4.0 to about 5.0. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the pH of the composition is between about 4.0 to about 4.8. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the pH of the composition is about 4.0. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the composition comprises acetate buffer. 
     
     
         9 . The pharmaceutical composition of  claim 2 , wherein the composition further comprises mannitol. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the mannitol has a concentration of between about 25 to about 75 mg/mL. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the mannitol has a concentration of about 50 mg/mL. 
     
     
         12 . The pharmaceutical composition of  claim 2 , wherein the composition further comprises polyoxyl 15 hydroxystearate. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the polyoxyl 15 hydroxystearate has a concentration of between about 10 to about 50 mg/mL. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the polyoxyl 15 hydroxystearate has a concentration of about 20 mg/mL. 
     
     
         15 . A method of treating tumor of a subject, comprising conducting a Somatostatin Analog Radioisotope Imaging (SARI) scanning on the subject and administering a pharmaceutical composition comprising a conjugate and at least one excipient to the subject if the SARI result is positive, 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). 
     
     
         16 . The method of  claim 15 , wherein the SARI scanning comprises using a radioisotope linked to a somatostatin analog. 
     
     
         17 . The method of  claim 16 , wherein the radioisotope comprises  111 In,  68 Ga, or  99m Tc. 
     
     
         18 . The method of  claim 16 , wherein the SARI scanning comprises using a  111 In pentetreotide. 
     
     
         19 . The method of  claim 16 , wherein the SARI scanning comprises using  68 Ga derivatives of somatostatin analogs. 
     
     
         20 . The method of  claim 19 , wherein the  68 Ga derivatives of somatostatin analogs comprise  68 Ga-DOTATATE or  68 Ga-DOTATOC. 
     
     
         21 . The method of  claim 16 , wherein the SARI scanning is conducted with single-photon emission computed tomography (SPECT) or concurrent positron emission tomography (PET) and Computed tomography (CT). 
     
     
         22 . The method of  claim 19 , further comprising administering at least one additional active agent. 
     
     
         23 . The method of  claim 22 , wherein the additional active agent is a drug for treating nausea, vomiting, diarrhea, constipation, anemia, neutropenia, or a somatostatin analog. 
     
     
         24 . The method of  claim 15 , wherein the tumor is a neuroendocrine tumor (NET). 
     
     
         25 . The method of  claim 24 , wherein the tumor selected from the group consisting of gastroenteropancreatic (GEP), lung, prostate, and thymus neuroendocrine tumor. 
     
     
         26 . The method of  claim 25 , wherein the tumor is small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of the lung. 
     
     
         27 . The method of  claim 15 , wherein the conjugate is Conjugate 57. 
     
     
         28 . The method of  claim 27 , wherein the dosage of Conjugate 57 is at least about 0.016 mg/kg. 
     
     
         29 . The method of  claim 27 , wherein the dosage of Conjugate 57 is at least about 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg. 
     
     
         30 . The method of  claim 27 , wherein the dosage of Conjugate 57 is about 25 mg.