Photosensitizers for targeted photodynamic therapy

Abstract

The present invention relates to photosensitizer compounds based on functionalized fullerenes useful in targeted photodynamic therapy (PDT), and methods of use thereof.

1 . A functionized fullerene compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         Z is carbon, nitrogen or phosphorus; 
         R 1  and R 2  are independently selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 8 cycloalkyl, (aryl)C 0 -C 4 alkyl, (heteroaryl)C 0 -C 4 alkyl, or a group of the formula C(O)—N(R 4 )(R 5 )(R 6 ); or 
         ZR 1 R 2  taken in combination foil a 3-20 member heterocyclic ring having 1-6 ring heteroatoms selected from nitrogen and phosphorus and having at least one quaternary ammonium cation or quaternary phosphonium cation; 
         R 4  and R 5  are independently selected from hydrogen or a group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 8  (aryl)C 0 -C 4 alkyl, and (heteroaryl)C 0 -C 4 alkyl each of which groups is substituted with 0-3 substituents selected from hydroxy, amino, mono-, di-, or tri-(C 1 -C 4 alkyl)amino, halogen, quaternary ammonium cations, quaternary phosphonium cations; 
         R 6  is absent, hydrogen or a group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 8 cycloalkyl, (aryl)C 0 -C 4 alkyl, and (heteroaryl)C 0 -C 4 alkyl each of which groups is substituted with 0-3 substituents selected from hydroxy, amino, mono-, di-, or tri-(C 1 -C 4 alkyl)amino, halogen, quaternary ammonium cations, quaternary phosphonium cations; 
         X 1  and X 2  are independently selected at each occurrence from the group consisting of CH 2  and CHR 3 , wherein R 3  is a C 1 -C 6 alkyl which is independently selected at each occurrence of R 3 ; 
         r is 1, 2, 3, or 4; 
         p and q are independently selected from 0, 1, 2, or 3 such that 0≦(p+q)≦4; 
         ANION is at least one organic or inorganic anion; 
         m is a negative integer corresponding to the net negative charge of each ANION equivalent; 
         n is a positive integer corresponding to the net positive charge of the substituted buckminsterfullerene cation; and 
         k is the quotient of n/m. 
       
     
     
         2 . The compound of  claim 1 , wherein
 Z is nitrogen or phosphorus;   X 1  and X 2  are methylene;   p=q=1;   R 1  and R 2  are independently selected C 1 -C 6 alkyl, (aryl)C 0 -C 1 alkyl, or (heteroaryl)C 0 -C 1 alkyl;   r is 2, 3, or 4; and   n≧r.   
     
     
         3 . The compound of  claim 1 , wherein
 Z is nitrogen or phosphorus;   X 1  and X 2  are methylene;   p=q=1;   R 1  is C 1 -C 6 alkyl, (aryl)C 0 -C 1  alkyl, or (heteroaryl)C 0 -C 1 alkyl;   R 2  is (aryl)C 0 -C 1 alkyl, or (heteroaryl)C 0 -C 1 alkyl;   r is 1, 2, 3, or 4; and   n≧r.   
     
     
         4 . The compound of  claim 1 , wherein
 Z is nitrogen;   X 1  and X 2  are methylene;   p=q=1;   R 1  and R 2  are independently selected from methyl, ethyl, propyl or isopropyl;   r is 2, 3, or 4; and   n≧r.   
     
     
         5 . The compound of  claim 1 , wherein
 Z is carbon;   p=q=0;   R 1  and R 2  are independently selected groups of the formula C(O)—N(R 4 )(R 5 )(R 6 ); or   ZR 1 R 2  taken in combination form a 6-20 member heterocyclic ring having 1-6 ring heteroatoms selected from nitrogen and phosphorus and having at least one quaternary ammonium cation or quaternary phosphonium cation;   R 4  and R 5  are independently selected from hydrogen or a group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 2 cycloalkyl, C 3 -C 8  (aryl)C 0 -C 4 alkyl, and (heteroaryl)C 0 -C 4 alkyl each of which groups is substituted with 0-3 substituents selected from hydroxy, amino, di-, or tri-(C 1 -C 2 alkyl)amino, halogen, quaternary ammonium cations, quaternary phosphonium cations; and   R 6  is absent, hydrogen or a group selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 8 cycloalkyl, (aryl)C 0 -C 4 alkyl, and (heteroaryl)C 0 -C 4 alkyl each of which groups is substituted with 0-3 substituents selected from hydroxy, amino, mono-, di-, or tri-(C 1 -C 2 alkyl)amino, halogen, quaternary ammonium cations, quaternary phosphonium cations.   
     
     
         6 . The compound of  claim 5 , wherein
 R 1  and R 2  are independently selected groups of the formula C(O)—N(R 4 )(R 5 )(R 6 );   R 4  is C 2 -C 6 alkyl substituted with 1-3 substitutents selected from hydroxy, amino, di-, or tri-(C 1 -C 2 alkyl)amino, and quaternary ammonium cations;   R 5  is hydrogen, C 1 -C 6 alkyl substituted with 0-3 substitutents selected from hydroxy, amino, and quaternary ammonium cations; and   R 6  is absent, hydrogen, or C 1 -C 6 alkyl substituted with 0-3 substitutents selected from hydroxy, amino, di-, or tri-(C 1 -C 2 alkyl)amino, and quaternary ammonium cations.   
     
     
         7 . The compound of  claim 5 , wherein R 1  and R 2  are the same and are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 4  is methyl, ethyl or propyl or isopropyl; 
         R 5  and R 6  are independently selected from methyl, ethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N,N-trimethylammonium)ethyl, or 3-(N,N,N-trimethylammonium)propyl. 
       
     
     
         8 . The compound of  claim 7 , wherein r is 1. 
     
     
         9 . The compound of  claim 7 , wherein r is 2. 
     
     
         10 . The compound of  claim 7 , wherein r is 3. 
     
     
         11 . The compound of  claim 1 , wherein
 p=q=0; and   ZR 1 R 2 , taken in combination, form a 7-20 member heterocyclic ring having 2 to 6 nitrogen atoms wherein at least one of the nitrogen atoms is a quaternary ammonium cation.   
     
     
         12 . The compound of  claim 11 , wherein ZR 1 R 2  is a heterocyclic ring of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         w is independently selected at each occurrence from 1, 2 or 3; 
         v is 0, 1, 2, or 3; 
         R 7  is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl substituted with 0-3 substitutents selected from hydroxy, amino, and quaternary ammonium cations; and 
         R 8  is independently selected at each occurrence from absent, hydrogen, or C 1 -C 6 alkyl substituted with 0-3 substitutents selected from hydroxy, amino, di-, or tri-(C 1 -C 2 alkyl)amino, and quaternary ammonium cations; and wherein at least one NR 7 R 8  is a quaternary ammonium cation or is substituted by a quaternary ammonium cation. 
       
     
     
         13 . The compound of  claim 12 , wherein
 v is 1, 2 or 3;   w is 2;   R 7  is independently selected from the group of methyl, ethyl or propyl or isopropyl;   R 8  are independently selected from methyl, ethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-(N,N,N-trimethylammonium)ethyl, or 3-(N,N,N-trimethylammonium)propyl.   
     
     
         14 . A method for providing antimicrobial therapy, comprising:
 administering an effective amount of a composition comprising a functionalized fullerene compound of  claim 1  to a subject in need thereof;   directing light onto the administered fullerene compound to produce a cytotoxic species; and   killing microbes associated with or proximal to the fullerene compound by reaction with the cytotoxic species, thereby providing antimicrobial therapy.   
     
     
         15 . The method of  claim 14 , wherein the fullerene is functionalized with a cationic organic moiety. 
     
     
         16 . The method of  claim 14 , wherein the fullerene is functionalized with a nonionic organic moiety. 
     
     
         17 . The method of  claim 14 , further comprising:
 washing away excess fullerenes that are not associated with the microbial cells prior to the step of directing light onto the associated fullerene compound.   
     
     
         18 . The method of  claim 14 , wherein the composition is applied as a solution having a fullerene concentration of between 1 and 100 micromolar. 
     
     
         19 . The method of  claim 14 , wherein the light is visible light is provided at an intensity of 0.5 and 160 Joules per square centimeter. 
     
     
         20 . The method of  claim 14 , wherein visible light is provided at an intensity between 0.5 and 20 Joules per square centimeter. 
     
     
         21 . The method of  claim 14 , wherein the functionalized fullerene is water soluble. 
     
     
         22 . The method of  claim 14 , wherein the killing is selective for the microbe and infected cells of the subject. 
     
     
         23 . The method of  claim 14 , wherein the microbe is selected from the group consisting of bacteria, yeast and fungi. 
     
     
         24 . A pharmaceutical composition, comprising:
 a biocompatible carrier and an effective amount of a functionalized fullerene compound of  claim 1 .   
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the composition is a solution having a fullerene concentration of between 1 and 100 micromolar. 
     
     
         26 . The composition of  claim 24 , further comprising a hyperosmotically active chemical species. 
     
     
         27 . The composition of  claim 24 , wherein the fullerene is functionalized with a cationic organic moiety. 
     
     
         28 . The composition of  claim 24 , wherein the fullerene is functionalized with a nonionic organic moiety. 
     
     
         29 . A method for killing a microbe, comprising:
 providing a composition comprising a functionalized fullerene compound of  claim 1  to a microbe;   directing light onto the fullerene compound to produce a cytotoxic species; and   killing the microbe associated with or proximal to the fullerene compound by reaction with the cytotoxic species.   
     
     
         30 . The method of  claim 29 , wherein the composition is applied as a solution having a fullerene concentration of between 1 and 100 micromolar. 
     
     
         31 . The method of  claim 29 , wherein the light is visible light is provided at an intensity of 0.5 and 160 Joules per square centimeter. 
     
     
         32 . The method of  claim 29 , wherein visible light is provided at an intensity between 0.5 and 20 Joules per square centimeter. 
     
     
         33 . The method of  claim 29 , wherein the microbe is selected from the group consisting of bacteria, yeast and fungi. 
     
     
         34 . The method of  claim 29 , wherein the microbe is associated with an inaminate object. 
     
     
         35 . The method according to  claim 29  or  claim 14 , further comprising obtaining the functionalized fullerene compound.