Compositions for delivery to and treatment of atherosclerotic plaques

Abstract

Disclosed are compositions and methods for treatment of atherosclerosis and atherosclerotic plaques. In some forms, the compositions and methods can prevent, inhibit, or reduce atherosclerosis. In some forms, the compositions and methods can prevent, inhibit, or reduce atherosclerotic plaques. In particular, compositions comprising a plaque-homing element, a CendR-activating element, and a plaque-inhibiting element are disclosed.

1 . A composition comprising a plaque-homing element, a CendR-activating element, and a plaque-inhibiting element, wherein the plaque-homing element is the same as, overlaps with, is coupled to, or is conjugated to the CendR-activating element, wherein the plaque-inhibiting element is the same as, overlaps with, is coupled to, is conjugated to, or is not covalently coupled or directly non-covalently associated with the plaque-homing element, the CendR-activating element, or both. 
     
     
         2 . The composition of  claim 1 , wherein the plaque-homing element binds to p32. 
     
     
         3 . The composition of  claim 1 , wherein the plaque-homing element is a small molecule compound. 
     
     
         4 . (canceled) 
     
     
         5 . The composition of  claim 3 , wherein the plaque-homing element is a compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
         wherein X 5 , X 6 , X 7 , X 8 , and X 9  are independently C, N, S, or O, wherein at least one of X 5 , X 6 , X 7 , X 8 , and X 9  is C or N, wherein at least one of X 5 , X 6 , X 7 , X 8 , and X 9  is N; 
         wherein R 1 , R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, C 1 -C 10  phosphonyl, or absent if valency requires, wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         wherein R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  are independently absent, hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         wherein X 9 , R 5 , and R 12  together can be absent; 
         wherein X 10  is N, O, or S; 
         wherein R 6  is —(CH 2 ) n — or —(CH 2 ) n —CHR 14 —(CH 2 ) m —, or —(CH 2 ) n —O—(CH 2 ) m —, wherein n and m are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein R 14  is halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         wherein R 7  is —NR 15 R 16 , wherein R 15  is hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl, wherein R 16  is hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, C 1 -C 10  phosphonyl, or a group having the structure of Formula II: 
       
       
         
           
           
               
               
           
         
         wherein X 11 , X 12 , X 13 , X 14 , and X 15  are independently C, N, S, or O, wherein at least one of X 11 , X 12 , X 13 , X 14 , and X 15  is C or N, wherein at least one of X 11 , X 12 , X 13 , X 14 , and X 15  is N; 
         wherein R 17 , R 18 , R 19 , R 20 , and R 21  are independently hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, C 1 -C 10  phosphonyl, or absent if valency requires, wherein at least one of R 17 , R 18 , R 19 , R 20 , and R 21  is substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         wherein R 23 , R 24 , R 25 , R 26 , R 27 , and R 28  are independently absent, hydrogen, halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         wherein X 15 , R 21 , and R 27  together can be absent; 
         wherein X 16  is N, O, or S; and 
         wherein R 22  is —(CH 2 ) j — or —(CH 2 ) j —CHR 29 —(CH 2 ) k —, or —(CH 2 ) j —O—(CH 2 ) k —, wherein j and k are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein R 29  is halogen, azide, hydroxyl, amino, thiol, oxo, phosphate, nitro, nitrile, imino, amido, phosphonate, phosphinate, silyl, ether, ketone, aldehyde, ester, heterocyclyl, —CF 3 , —CN, or substituted or unsubstituted C 1 -C 10  alkyl, C 1 -C 10  alkylene, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 1 -C 10  alkoxy, C 1 -C 10  alkylamino, C 1 -C 10  alkylthio, C 1 -C 10  carbonyl, C 1 -C 10  carboxyl, C 1 -C 10  amido, C 1 -C 10  sulfonyl, C 1 -C 10  sulfonic acid, C 1 -C 10  sulfamoyl, C 1 -C 10  sulfoxide, C 1 -C 10  phosphoryl, or C 1 -C 10  phosphonyl; 
         or a pharmaceutically acceptable salt or ester of the compound. 
       
     
     
         6 . The composition of  claim 5 , wherein R 1  is —CH 3 , R 2 , R 4 , R 5 , R 15 , R 16 , and R 17  are hydrogen, R 3  and R 8 -R 12  are absent, R 6  is —(CH 2 ) n —, n is 2, R 7  is —NR 15 R 16 , R 15  and R 16  are hydrogen, X 5 , X 6 , X 5 , and X 9  are C, and X 7  and X 10  are N. 
     
     
         7 . The composition of  claim 5 , wherein R 7  is a group having the structure of Formula II, R 1 , R 4 , R 5 , R 8 -R 12 , R 17 , R 20 , R 21 , and R 23 -R 27  are absent, R 3 , R 10 , R 19 , and R 25  are —CH 3 , R 2 , R 13 , R 18 , and R 28  are hydrogen, R 6  is —(CH 2 ) n —, n is 1, X 5 , X 10 , X 11 , and X 16  are N, X 6 , X 7 , X 12 , and X 13  are C, X 8  and X 14  are S, X 9  and X 15  are absent, R 22  is —(CH 2 ) j —, and j is 1. 
     
     
         8 . The composition of  claim 1 , wherein the CendR-activating element binds to NRP-1, NRP-2, or both. 
     
     
         9 . The composition of  claim 1 , wherein the CendR-activating element is a peptide or a small molecule compound. 
     
     
         10 . (canceled) 
     
     
         11 . The composition of  claim 1 , wherein the plaque-inhibiting element is a small molecule compound. 
     
     
         12 . (canceled) 
     
     
         13 . The composition of  claim 11 , wherein the plaque-inhibiting element is GW3965. 
     
     
         14 . The composition of  claim 1 , wherein the plaque-inhibiting element promotes apoptosis of a cell in which it is internalized. 
     
     
         15 . The composition of  claim 1 , wherein the plaque-inhibiting element binds p32. 
     
     
         16 . The composition of  claim 1 , wherein one or more of the plaque-homing element, CendR-activating element, and plaque-inhibiting element is a peptide, wherein one or more of the one or more plaque-homing element, CendR-activating element, and plaque-inhibiting element that is a peptide conjugates to albumin in blood. 
     
     
         17 . The composition of  claim 1 , wherein one or more of the plaque-homing element, CendR-activating element, and plaque-inhibiting element is a peptide, wherein one or more of the one or more plaque-homing element, CendR-activating element, and plaque-inhibiting element that is a peptide is conjugated to a lipid. 
     
     
         18 . The composition of  claim 1 , wherein the composition is comprised in a micelle. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . A method of treating atherosclerosis in a subject, the method comprising administering the composition of  claim 1  to the subject. 
     
     
         23 . The method of  claim 22 , wherein the subject is at risk of atherosclerosis. 
     
     
         24 . The method of  claim 22 , wherein the subject has atherosclerosis.