Cyclodextrin-based polymers for therapeutics delivery

Abstract

The present invention relates to novel compositions comprising polymeric moieties covalently attached to therapeutic agents, wherein the therapeutic agent is attached to the polymeric moiety through a tether. By selecting from a variety of tether groups and targeting ligands the polymers present methods for controlled delivery of the therapeutic agents. The invention also relates to methods of treating subjects with the therapeutic compositions described herein.

1 . A polymer conjugate, comprising a therapeutic agent covalently attached to a polymer through a tether, wherein the tether comprises a self-cyclizing moiety. 
     
     
         2 . The polymer conjugate of  claim 1 , further characterized by one or more of:
 the tether further comprises a selectivity-determining moiety;   the polymer is a biocompatible polymer;   the selectivity-determining moiety is bonded to the self-cyclizing moiety between the self-cyclizing moiety and the polymer;   the selectivity-determining moiety promotes selectivity in the cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety;   the bond between the selectivity-determining moiety and the self-cyclizing moiety is selected from amide, carbamate, carbonate, ester, thioester, urea, and disulfide bonds;   the bond between the selectivity-determining moiety and the self-cyclizing moiety is selected from amide, carbamate, carbonate, and disulfide bonds;   the selectivity-determining moiety promotes enzymatic cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety;   the selectivity-determining moiety promotes cleavage by a cathepsin;   the selectivity-determining moiety promotes cleavage by cathepsin B;   the selectivity-determining moiety promotes cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety under acidic conditions;   the selectivity-determining moiety promotes cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety under basic conditions;
 the selectivity-determining moiety is a peptide; e.g., wherein 
 the peptide is a dipeptide, tripeptide or tetrapeptide; e.g., wherein
 the peptide is selected from GFYA, GFLG, GFA, GLA, AVA, GVA, GIA, GVL, GVF, AVF, KF, and FK; 
 the peptide is selected from GFYA and GFLG; or 
 the peptide is GFLG; 
 
   the selectivity-determining moiety is an aminoalkylcarbonyloxyalkyl moiety;   the self-cyclizing moiety is selected such that after cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety, cyclization of the self-cyclizing moiety occurs, thereby releasing the therapeutic agent;   upon cyclization of the self-cyclizing moiety, a five- or six-membered ring is formed; e.g., the five- or six-membered ring is a heterocycle that comprises at least one heteroatom selected from nitrogen, oxygen, and sulfur; e.g., an imidazolidinone;   the self-cyclizing moiety has a structure   
       
         
           
           
               
               
           
         
         
           wherein 
           U is selected from NR 1  and S; 
           X is selected from O, NR 5 , and S; 
           V is selected from O, S, and NR 4 ; 
           R 2  and R 3  are independently selected from hydrogen, alkyl, and alkoxy; or 
           R 2  and R together with the carbon atoms to which they are attached form a ring; and 
           R 1 , R 4 , and R 5  are independently selected from hydrogen and alkyl; e.g., wherein
 U is NR 1  and/or V is NR 4 , and R 1  and R 4  are independently selected from methyl, ethyl, propyl, and isopropyl; 
 both R 1  and R 4  are methyl; 
 both R 2  and R 3  are hydrogen; 
 R 2  and R 3  together are —(CH 2 ) n — wherein n is 3 or 4; 
 the self-cyclizing moiety is selected from 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               and/or 
             
             U is bonded to the self-cyclizing moiety; 
           
         
         the selectivity-determining moiety is represented by Formula A: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           S a sulfur atom that is part of a disulfide bond; 
           J is optionally substituted hydrocarbyl; and 
           Q is O or NR 13 , wherein R 13  is hydrogen or alkyl; e.g., wherein
 J is polyethylene glycol, polyethylene, polyester, alkenyl, or alkyl; 
 J represents a hydrocarbylene group comprising one or more methylene groups, wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —O—, C(═X) (wherein X is NR 30 , O or S), —OC(O)—, —C(═O)O, —NR 30 —, —NR 1 CO—, —C(O)NR 30 —, —S(O) n — (wherein n is 0, 1, or 2), —OC(O)—NR 30 , —NR 30 —C(O)—NR 30 —, —NR 30 —C(NR 30 )—NR 30 —, and —B(OR 30 )—; and R 30 , independently for each occurrence, represents H or a lower alkyl; 
 J is substituted or unsubstituted lower alkylene; e.g., wherein J is substituted or unsubstituted ethylene; and/or 
 the selectivity-determining moiety is 
 
         
       
       
         
           
           
               
               
           
         
         the selectivity-determining moiety is represented by Formula B: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           W is selected from NR 14 , S, O; 
           J, independently and for each occurrence, is hydrocarbyl or polyethylene glycol; 
           S is sulfur; 
           Q is O or NR 3 , wherein R 13  is hydrogen or alkyl; and 
           R 14  is selected from hydrogen and alkyl; e.g., wherein
 J comprises an aryl ring; e.g., a benzo ring; 
 W and S are in a 1,2-relationship on the aryl ring; 
 the aryl ring is optionally substituted with alkyl, alkenyl, alkoxy, aralkyl, aryl, heteroaryl, halogen, —CN, azido, —NR x R x , —CO 2 OR x , —C(O)—NR x R x , —C(O)—R x , —NR x —C(O)—R x , —NR x SO 2 R x , —SR x , —S(O)R x , SO 2 R x , —SO 2 NR x R x , —(C(R x ) 2 ) n —OR x , —(C(R x ) 2 ) n —NR x R x , and —(C(R x ) 2 ) n —SO 2 R x ; wherein R x  is, independently for each occurrence, H or lower alkyl; and n is, independently for each occurrence, an integer from 0 to 2; 
 J, independently and for each occurrence, is polyethylene glycol, polyethylene, polyester, alkenyl, or alkyl; 
 J, independently and for each occurrence, represents a hydrocarbylene group comprising one or more methylene groups, wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —O—, C(═X) (wherein X is NR 30 , O or S), —OC(O)—, —C(═O)O, —NR 30 —, —NR 1 CO—, —C(O)NR 30 —, —S(O) n — (wherein n is 0, 1, or 2), —OC(O)—NR 30 , —NR 30 —C(O)—NR 30 —, —NR 30 —C(NR 30 )—NR 30 —, and —B(OR 30 )—; and R 30 , independently for each occurrence, represents H or a lower alkyl; 
 J, independently and for each occurrence, is substituted or unsubstituted lower alkylene; e.g., J, independently and for each occurrence, is substituted or unsubstituted ethylene; and/or 
 the selectivity-determining moiety is selected from 
 
         
       
       
         
           
           
               
               
           
         
         the selectivity-determining moiety has a structure 
       
       
         
           
           
               
               
           
         
         
           wherein 
           Ar is a substituted or unsubstituted benzo ring; 
           J is optionally substituted hydrocarbyl; and 
           Q is O or NR 13 , wherein R 13  is hydrogen or alkyl; e.g., wherein
 Ar is unsubstituted; 
 Ar is a 1,2-benzo ring; and/or 
 the selectivity determining moiety is 
 
         
       
       
         
           
           
               
               
           
         
         the polymer comprises a plurality of cyclic moieties selected from cyclodextrins, crown ethers, cyclic oligopeptides, cryptands or cryptates, calixarenes, cavitands, or any combination thereof, 
         the polymer comprises cyclodextrins; and/or 
         the polymer conjugate has a structure of Formula I: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           P is a monomer moiety; 
           A, independently for each occurrence, is a selectivity-determining moiety or a direct bond; 
           B, independently for each occurrence, is a self-cyclizing moiety; 
           L 1 , L 2 , L 3  and L 4 , independently for each occurrence, are a linker group; 
           D and D′ are independently a therapeutic agent or prodrug thereof; 
           T and T′ are independently a targeting ligand or precursor thereof; 
           y and y′ are independently an integer from 1 to 10; 
           x, x′, z, and z′ are independently an integer from 0 to 10; and 
           h is an integer from 2 to 30,000; 
           wherein at least one occurrence of either x or x′ is an integer greater than 0; e.g., wherein
 A is a selectivity-determining moiety; 
 L 1 , L 2 , L 3  and L 4  are independently selected from an alkyl chain, a polyethylene glycol (PEG) chain, polysuccinic anhydride, poly-L-glutamic acid, poly(ethyleneimine), an oligosaccharide, and an amino acid chain; 
 any of L 1 , L 2 , L 3  and L 4  are independently an alkyl chain wherein one or more methylene groups is optionally replaced by a group Y (provided that none of the Y groups are adjacent to each other), wherein each Y, independently for each occurrence, is selected from aryl, heteroaryl, carbocyclyl, heterocyclyl, or —O—, C(═X) (wherein X is NR 1 , O or S), —OC(O)—, —C(═O)O, —NR 1 —, —NR 1 CO—, —C(O)NR 1 —, —S(O) n — (wherein n is 0, 1, or 2), —OC(O)—NR 1 , —NR 1 —C(O)—NR 1 —, —NR 1 —C(NR 1 )—NR 1 —, and —B(OR 1 )—; and R 1 , independently for each occurrence, is H or lower alkyl; 
 A is selected such that the selectivity-determining moiety promotes selectivity in the cleavage of the bond between the selectivity-determining moiety and the self-cyclizing moiety; 
 B is capable of self-cyclizing to release the therapeutic agent once the bond between A and B has been cleaved; 
 the polymer comprises a plurality of cyclic moieties selected from cyclodextrins, crown ethers, cyclic oligopeptides, cryptands or cryptates, calixarenes, cavitands, and any combination thereof; 
 the polymer comprises cyclodextrins; 
 the therapeutic agent is a small molecule; 
 the therapeutic agent contains an amino, hydroxyl, or thiol group; 
 the therapeutic agent is attached to the self-cyclizing group through the amino, hydroxyl, or thiol group; 
 the therapeutic agent is attached to the self-cyclizing group through a hydroxyl group; 
 the therapeutic agent is etoposide; 
 the therapeutic agent is a tubulysin, or an analog or derivative thereof; 
 the therapeutic agent is an epothilone, or an analog or derivative thereof; and/or 
 T is a hormone; e.g., wherein
 the hormone facilitates endocytosis; 
 the hormone is luteinizing hormone-releasing hormone (LHRH). 
 
 
         
       
     
     
         3 . A compound represented by Formula C: 
       
         
           
           
               
               
           
         
         wherein 
         P represents a polymer chain; 
         CD represents a cyclic moiety; 
         L 1 , L 2  and L 3 , independently for each occurrence, may be absent or represent a linker group, provided that a plurality of occurrences of L 2  represent linkers that are cleavable under biological conditions; 
         D, independently for each occurrence, is selected from etoposide, tubulysin, epothilone, or an analog or derivative thereof; 
         T, independently for each occurrence, represents a targeting ligand or precursor thereof; 
         a, m and v, independently for each occurrence, represent integers in the range of 1 to 10; 
         n and w, independently for each occurrence, represent an integer in the range of 0 to about 30,000; and 
         b represents an integer in the range of I to about 30,000; and 
         wherein either P comprises cyclodextrin moieties in the polymer chain or n is at least 1. 
       
     
     
         4 . The compound of  claim 3 , the compound is represented by Formula C′: 
       
         
           
           
               
               
           
         
         wherein 
         CD represents a cyclodextrin moiety, or derivative thereof; 
         L 4 , L 5 , L 6 , and L 7 , independently for each occurrence, may be absent or represent a linker group; 
         D and D′, independently for each occurrence, is selected from etoposide, tubulysin, epothilone, or an analog or derivative thereof; 
         T and T′, independently for each occurrence, represents the same or different targeting ligand or precursor thereof; 
         f and y, independently for each occurrence, represent an integer in the range of 1 and 10; 
         g and z, independently for each occurrence, represent an integer in the range of 0 and 10; and 
         h is an integer from 2 to 30,000; or 
       
       the compound is represented by Formula D: 
       
         
           
           
               
               
           
         
         wherein 
         γ represents a monomer unit of a polymer that comprises cyclodextrin moieties; 
         T, independently for each occurrence, represents a targeting ligand or a precursor thereof; 
         L 6 , L 7 , L 8 , L 9 , and L 10 , independently for each occurrence, may be absent or represent a linker group; 
         CD, independently for each occurrence, represents a cyclodextrin moiety or a derivative thereof; 
         D, independently for each occurrence, is selected from etoposide, tubulysin, epothilone, or an analog or derivative thereof; 
         m, independently for each occurrence, represents an integer in the range of 1 to 10; 
         o is an integer from 2 to 30,000; and 
         p, n, and q, independently for each occurrence, represent an integer in the range of 0 to 10, 
         wherein D is present at least once in the compound. 
       
     
     
         5 . A compound represented by Formula C: 
       
         
           
           
               
               
           
         
         wherein 
         P represents a polymer chain; 
         CD represents a cyclodextrin moiety; 
         L 2  independently for each occurrence, may be absent or represents a linker group, wherein for one or more occurrences, L 2  is a linker group that comprises a phosphate group; 
         L 1  and L 3 , independently for each occurrence, may be absent or represent a linker group; 
         D, independently for each occurrence, represents a therapeutic agent or a prodrug thereof; 
         T, independently for each occurrence, represents a targeting ligand or precursor thereof; 
         a, m and v, independently for each occurrence, represent integers in the range of 1 to 10; 
         n and w, independently for each occurrence, represent an integer in the range of 0 to about 30,000; and 
         b represents an integer in the range of I to about 30,000; and 
         wherein either P comprises cyclodextrin moieties in the polymer chain or n is at least 1, and 
         wherein a plurality of therapeutic agents or prodrugs thereof are covalently attached to the polymer chain through attachments that are cleavable. 
       
     
     
         6 . The compound of  claim 5 , further characterized by one or more of:
 the attachments are cleavable under biological conditions;   for a plurality of occurrences, L 2  is a linker group comprising a phosphate group;   the compound is represented by Formula C′:   
       
         
           
           
               
               
           
         
         
           wherein 
           CD represents a cyclodextrin moiety, or derivative thereof; 
           L 4  and L 6 , independently for each occurrence, may be absent or represent a linker group, wherein for one or more occurrences, L 4  or L 6  is a linker group that comprises a phosphate group; 
           L 5  and L 7 , independently for each occurrence, may be absent or represent a linker group; 
           D and D′, independently for each occurrence, represent the same or different therapeutic agent or prodrugs thereof; 
           T and T′, independently for each occurrence, represents the same or different targeting ligand or precursor thereof; 
           f and y, independently for each occurrence, represent an integer in the range of I and 10; 
           g and z, independently for each occurrence, represent an integer in the range of 0 and 10; and 
           h is an integer from 2 to 30,000; 
         
         the compound represented by Formula D: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           γ represents a monomer unit of a polymer; 
           T, independently for each occurrence, represents a targeting ligand or a precursor thereof; 
           L 6 , L 7 , L 8 , and L 10 , independently for each occurrence, may be absent or represent a linker group; 
           L 9 , independently for each occurrence, may be absent or represents a linker group, wherein for one or more occurrences, L 9  is a linker group that comprises a phosphate group; 
           CD, independently for each occurrence, represents a cyclodextrin moiety or a derivative thereof; 
           D, independently for each occurrence, represents a therapeutic agent or a prodrug form thereof; 
           m, independently for each occurrence, represents an integer in the range of I to 10; 
           o is an integer from 2 to 30,000; and 
           p, n, and q, independently for each occurrence, represent an integer in the range of 0 to 10, 
           wherein CD and D are each present at least once in the compound; 
         
         at least one linker that connects the therapeutic agent or prodrug thereof to the polymer comprises a group represented by the formula 
       
       
         
           
           
               
               
           
         
         
           wherein 
           P is phosphorus; 
           O is oxygen; 
           E represents oxygen or NR 40 ; 
           K represents hydrocarbyl; 
           X is selected from OR 42  or NR 43 R 44 ; and 
           R 40 , R 41 , R 42 , R 43 , and R 44  independently represent hydrogen or optionally substituted alkyl; e,g,, wherein
 E is NR 40  and R 40  is hydrogen; 
 K is lower alkylene; 
 K is ethylene; 
 at least one linker comprises a group selected from 
 
         
       
       
         
           
           
               
               
           
         
         the linker is connected to the therapeutic agent through a hydroxyl group on the therapeutic agent; e.g., wherein the hydroxyl group is a phenolic hydroxyl group.