Polyiodide binding compounds and methods of use thereof

Abstract

Polyiodide binding compounds are described herein along with compounds and methods that are useful in brachytherapy. A compound of the present invention may comprise: a polyiodide binding matrix; a protecting group attached to the polyiodide binding matrix optionally via a linker, and optionally a cross-linking moiety attached to the polyiodide binding matrix. Compounds and methods of the present invention may be used for localizing a radioactive compound.

That which is claimed is: 
     
         1 . A compound comprising:
 a polyiodide binding matrix;   a protecting group attached to the polyiodide binding matrix optionally via a linker; and   optionally a cross-linking moiety attached to the polyiodide binding matrix.   
     
     
         2 . The compound of  claim 1 , wherein the polyiodide binding matrix comprises a polysaccharide (e.g., a linear polysaccharide), optionally a modified polysaccharide. 
     
     
         3 . The compound of  claim 1  or  2 , wherein the polyiodide binding matrix comprises a helical structure, optionally wherein the helical structure has a mass per helical turn from about 900 Da to about 1,200 Da. 
     
     
         4 . The compound of any one of  claims 1 - 3 , wherein the polyiodide binding matrix comprises at least 5, 10, 25, 50, or 75 helical turns. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein the polyiodide binding matrix has a loading capacity of about 1 iodide atom per helical turn, optionally wherein the polyiodide binding matrix has a loading capacity of from about 5 or 10 iodide atoms to about 25, 50, or 75 iodide atoms. 
     
     
         6 . The compound of any one of  claims 1 - 5 , wherein the polyiodide binding matrix has an average molecular weight from about 5,000 or 10,000 Da to about 25,000, 50,000, or 100,000 Da. 
     
     
         7 . The compound of any one of  claims 1 - 6 , wherein the polyiodide binding matrix comprises amylose. 
     
     
         8 . The compound of any one of  claims 1 - 7 , wherein at least one unit (e.g., an anhydroglucose unit) of the polyiodide binding matrix comprises the protecting group. 
     
     
         9 . The compound of any one of  claims 1 - 8 , wherein the protecting group and optional cross-linking moiety are each attached to the polyiodide binding matrix via the linker. 
     
     
         10 . The compound of any one of  claims 1 - 9 , wherein the compound comprises the cross-linking moiety and the protecting group and cross-linking moiety are each attached to the polyiodide binding matrix via the linker, optionally wherein the protecting group and cross-linking moiety are attached to a terminus (e.g., reducing end or non-reducing end) of the polyiodide binding matrix via the linker. 
     
     
         11 . The compound of any one of  claims 1 - 10 , wherein at least one unit (e.g., an anhydroglucose unit) of the polyiodide binding matrix comprises at least one moiety having a structure of -L1-X-L2-PG, wherein L1 is the linker, X is the cross-linking moiety, L2 is absent or a second linker, and PG is the protecting group, optionally wherein the at least one moiety having the structure -L1-X-L2-PG is present at a 2-hydroxy group of the at least one unit (e.g., to provide a —O-L1-X-L2-PG group). 
     
     
         12 . The compound of any one of  claims 1 - 10 , wherein the linker is covalently bound to a terminus (e.g., reducing end or non-reducing end) of the polyiodide binding matrix and the linker is covalently bound to at least one moiety having a structure of —X-L2-PG, wherein X is the cross-linking moiety, L2 is absent or a second linker, and PG is the protecting group. 
     
     
         13 . The compound of  claim 12 , wherein at least one unit (e.g., an anhydroglucose unit) of the polyiodide binding matrix comprises at least one moiety having a structure of —X-L2-PG, wherein X is the cross-linking moiety, L2 is absent or a second linker, and PG is the protecting group, optionally wherein the at least one moiety having the structure —X-L2-PG is present at a 2-hydroxy group of the at least one unit (e.g., to provide a —O—X-L2-PG group). 
     
     
         14 . The compound of any one of  claims 1 - 13 , wherein the linker is multivalent. 
     
     
         15 . The compound of  claim 14 , wherein the linker comprises two or more (e.g., 2, 3, 4, 5, or more) moieties having a structure of —X-L2-PG, wherein X is the cross-linking moiety, L2 is absent or a second linker, and PG is the protecting group. 
     
     
         16 . The compound of any one of  claims 1 - 15 , further comprising a targeting agent (e.g., cancer targeting agent such as transferrin), optionally wherein the targeting agent is present at a terminus of the polyiodide binding matrix. 
     
     
         17 . The compound of any one of  claims 1 - 16 , further comprising a circulation enhancing agent (e.g., human serum albumin, a polymer such as polyethylene glycol (PEG), etc.), optionally wherein the circulation enhancing agent is present at a terminus of the polyiodide binding matrix. 
     
     
         18 . The compound of any one of  claims 1 - 17 , wherein the protecting group is a glucuronide. 
     
     
         19 . The compound of any one of  claims 1 - 18 , wherein the protecting group is a glucoside. 
     
     
         20 . The compound of any one of  claims 1 - 19 , wherein the cross-linking moiety is an indoxyl. 
     
     
         21 . The compound of any one of  claims 1 - 20 , wherein the linker is selected from an alkyl, PEG, and/or alkylaryl. 
     
     
         22 . The compound of any one of  claims 1 - 21 , wherein the polyiodide binding matrix comprises at least one unit having a structure of Formula Ia or Formula Ib: 
       
         
           
           
               
               
           
         
         wherein:
 R 10  is O or CRR (e.g., CH 2 ); and 
 R is each independently selected from: —H, —OH, alkyl, alkoxy, acyloxy, carboxy, amino, —O-PG, —O-L1-PG, —O-L1-X-PG, —O—X-L1-PG, and —O-L1-X-L2-PG; 
 L1 and L2 are each independently a linker (e.g., a polymer such as PEG or a self-immolative linker) (e.g., a polymer such as PEG): 
 X is the cross-linking moiety; and 
 PG is the protecting group. 
 
       
     
     
         23 . The compound of  claim 22 , wherein the polyiodide binding matrix comprises 1, 2, 4, 6, 8, or 10 to about 100, 250, 500, 1,000, 5,000, 10,000, or 20,000 of the at least one units. 
     
     
         24 . The compound of any one of  claims 1 - 23 , wherein the polyiodide binding matrix comprises a unit having a structure of Formula Ia′ or Formula Ib′: 
       
         
           
           
               
               
           
         
         wherein: 
         R, L, X, and PG are each as defined above, 
         optionally wherein the unit is present at a terminus (e.g., the non-reducing terminus) of the polyiodide binding matrix. 
       
     
     
         25 . The compound of  claim 24 , wherein R is an alkyl, alkoxy, or acyloxy. 
     
     
         26 . The compound of any one of  claims 1 - 25 , wherein the compound has a structure of Formula IIa or Formula IIb: 
       
         
           
           
               
               
           
         
         wherein: 
         Z is the polyiodide binding matrix (e.g., amylose); 
         L is a linker (e.g., a hydrocarbon or polymer such as polyethylene glycol (PEG) each of which may be unsubstituted or substituted); 
         X 1  is absent or is —O— or —S—; 
         Q is absent or is each independently a targeting agent, water-solubilizing agent, or a circulation enhancing agent; 
         each R 1  is independently selected from a halogen, alkyl, alkenyl, alkynyl, —OH, alkoxy, acyloxy, carboxy, carboxylic ester, boronate ester, thioalkoxy, and amino; 
         each R 2  is independently —CH 2 OH or —C(O)OH; 
         each X 2  is independently —O—, —S—, or a self-immolative linker; 
         each n is independently an integer of 1 to 4; 
         p is an integer of 1 to 6; and 
         b is an integer of 0 to 6; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The compound of any one of  claims 1 - 26 , wherein the linker has the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         A is a linking moiety (e.g., a nitrogen atom, an aryl, or a heteroaryl); 
         each r is independently an integer of 0 to 10, 20, 30, 40, 50, 60, 70, or 100. 
       
     
     
         28 . The compound of any one of  claims 1 - 27 , wherein the compound has a structure of Formula III: 
       
         
           
           
               
               
           
         
         wherein: 
         A is a linking moiety (e.g., a nitrogen atom, an aryl, or a heteroaryl); 
         each R 3  is independently hydrogen, the polyiodide binding matrix, a moiety having a structure of Formula IIa′, a moiety having a structure of Formula IIb′, a targeting agent, or a circulation enhancing agent, 
       
       
         
           
           
               
               
           
         
         each r is independently an integer of 0 to 10, 20, 30, 40, 50, 60, 70, or 100; and 
         X 1 , X 2 , R 1 , R 2 , and n are each as defined above. 
       
     
     
         29 . The compound of any one of  claims 1 - 28 , wherein the compound has a structure of Formula IV: 
       
         
           
           
               
               
           
         
         wherein: 
         A is a linking moiety (e.g., a nitrogen atom, an aryl, or a heteroaryl); 
         R 6  is a hydrogen, alkyl, alkoxy, acyloxy, —OH, carboxy, amino, -PG, -L1-PG, -L1-X-PG, —X-L1-PG, and —O-L1-X-L2-PG, wherein L1 and L2 are each, independently a linker (e.g., a polymer such as PEG or a self-immolative linker), X is a cross-linking moiety, and PG is a protecting group; 
         R 4  is a moiety having a structure of Formula Ia or Formula Ib: 
       
       
         
           
           
               
               
           
         
         R 10  is O or CRR (e.g., CH 2 ); 
         each R is independently selected from: —H, —OH, alkyl, alkoxy, acyloxy, carboxy, amino, —O-PG, —O-L3-PG, —O-L3-X-PG, —O—X-L3-PG, and —O-L3-X-L2-PG, wherein L3 and L2 are each independently absent or a linker as described herein, X is a crosslinking moiety as described herein, and PG is a protecting group as described herein; 
         each R 5  is independently hydrogen, a moiety having a structure of Formula IIa′, a moiety having a structure of Formula IIb′, a targeting agent, or a circulation enhancing agent, 
       
       
         
           
           
               
               
           
         
         each R 1  is independently selected from a halogen, alkyl, alkenyl, alkynyl, —OH, alkoxy, acyloxy, carboxy, carboxylic ester, boronate ester, thioalkoxy, and amino; 
         each R 2  is independently —CH 2 OH or —C(O)OH; 
         X 1  is absent or is —O— or —S—; 
         each X 2  is independently —O—, —S—, or a self-immolative linker; 
         each n is independently an integer of 1 to 4; 
         each r is independently an integer of 0 to 10, 20, 30, 40, 50, 60, 70, or 100; and 
         d is an integer of 1 to 20,000. 
       
     
     
         30 . A method of treating a subject having a solid tumor and/or reducing the size of a solid tumor in a subject, the method comprising:
 administering a compound comprising a polyiodide binding matrix to the subject; and   administering a radionuclide to the subject, thereby treating the subject having the solid tumor and/or reducing the size the solid tumor in the subject.   
     
     
         31 . The method of  claim 30 , wherein the method administers a radionuclide (e.g.,  131 I) to the solid tumor at a concentration of at least 20 nM, 50 nM, or 100 nM. 
     
     
         32 . The method of  claim 30  or  31 , wherein the compound is intravenously administered to the subject. 
     
     
         33 . The method of any one of  claims 30 - 32 , wherein the radionuclide is orally and/or intravenously administered to the subject. 
     
     
         34 . The method of any one of  claims 30 - 33 , wherein the compound and the radionuclide are administered in succession and the compound is administered prior to the radionuclide. 
     
     
         35 . The method of any one of  claims 30 - 34 , wherein the compound and the radionuclide are administered concurrently, optionally in the same composition or in separate compositions. 
     
     
         36 . The method of any one of  claims 30 - 35 , further comprising administering an amylase inhibitor (e.g., miglitol) to the subject. 
     
     
         37 . The method of any one of  claims 30 - 36 , wherein the compound is a compound of any one of  claims 1 - 29 .