Pyropheophorbides conjugates and their use in photodynamic therapy

Abstract

Conjugate are formed by covalently linking a target-specific compound to pyropheophorbide compound which conjugated are injected into a host and accumulate in tumor tissue to a higher degree than surrounding normal tissues. When the pyropheophorbide compound component of the conjugate is exposed to a particular wavelength of light the compound becomes cytotoxic destroying the tumor or diseased tissue without causing irreversible normal tissue damage. The pyropheophorbide compounds have been shown to have a variety of characteristics when used in photodynamic therapy. These characteristics are further improved when the compounds are bound to a target specific component such as a ligand capable of binding to a specific cellular receptor (e.g. growth hormones and growth factors) or an antibody capable of binding to a particular antigen.

1. A conjugate comprising a target-specific component covalently bound to a compound of formula I: 
                 
 
       wherein R 1  is CH 2 OR 2  where R 2  is a primary or secondary alkyl containing 1 to 20 carbons; and R 3  is —CO 2 R 4   —CH 2   CH   2   CO   2   R   4  where R 4  is H or an alkyl containing 1 to 20 carbons. 
     
     
       2. The conjugate of  claim 1 , wherein the target-specific component is selected from the group consisting of a ligand capable of binding to a specific cellular receptor, and an antibody capable of binding to a particular antigen. 
     
     
       3. The conjugate of  claim 2 , wherein the antibody is a monoclonal antibody. 
     
     
       4. The conjugate of  claim 2 , wherein the ligand is selected from the group consisting of steroid hormones, and growth factors. 
     
     
       5. The conjugate of  claim 2 , wherein the conjugate is further attached to a detectable label. 
     
     
       6. The conjugate as claimed in  claim 1 , wherein R 1  is CH 2 —O—Hexyl, R 2  is —CH 3 , and R 3  is —CO 2 CH 3 . 
     
     
       7. A method to effect the destruction of a target virus, cell or tissue, comprising:
 contacting said target with an effective amount of the conjugate of  claim 1 ; and  
 irradiating with light absorbed by said conjugate.  
 
     
     
       8. A pharmaceutical composition useful in treatment of a target virus, cells or tissue, comprising:
 an effective amount of the conjugate of  claim 1  in admixture with a pharmaceutically acceptable excipient.  
 
     
     
       9. A conjugate comprising a target-specific component covalently bound to a compound of formula II: 
                 
 
       wherein R 5  is —OR 6  where R 6  is a primary or secondary alkyl containing 1 to 20 carbons and R 7  is —CO 2 R 8   —CH 2   CH   2   CO   2   R   8  where R 8  is H or an alkyl containing 1 to 20 carbons. 
     
     
       10. The conjugate of  claim 9 , wherein the target-specific component is selected from the group consisting of a ligand capable of binding to a specific cellular receptor, and an antibody capable of binding to a particular antigen. 
     
     
       11. The conjugate of  claim 10 , wherein the antibody is a monoclonal antibody. 
     
     
       12. The conjugate of  claim 10 , wherein the ligand is selected from the group consisting of steroid hormones, and growth factors. 
     
     
       13. The conjugate of  claim 10 , wherein the conjugate is further attached to a detectable label. 
     
     
       14. The compound as claimed in  claim 9 , wherein R 5  is —O—hexyl and R 7  is —CO 2 CH 3 . 
     
     
       15. The compound as claimed in  claim 9 , wherein R 5  is —O—(CH 2 ) 5 CH 3  and R 7  is selected from the group consisting of CO 2 CH 3  and —CO 2 H. 
     
     
       16. A method to effect the destruction of target virus, cells or tissue, comprising:
 contacting said target with an effective amount of the conjugate of  claim 9 ; and  
 irradiating with light absorbed by said conjugate.  
 
     
     
       17. A pharmaceutical composition useful in treatment of a target virus, cells or tissue, comprising:
 an effective amount of the compound of  claim 9  in admixture with a pharmaceutically acceptable excipient.  
 
     
     
       18. A method of treating a human with abnormal cells which replicate at an abnormally high rate, comprising the steps of:
 administering to the human therapeutically effective amount of a conjugate comprising a target-specific component covalently bound to a compound of formula II 
                 
 
  wherein R 5  is —OR 6  where R 6  is a primary or secondary alkyl containing 5 to 20 carbons and R 7  is —CO 2 R 8   —CH 2   CH   2   CO   2   R   8  where R 8  is H or —CH 3 ;  
 allowing the conjugate to accumulate on the abnormal cells; and  
 irradiating the conjugate with a wavelength of light which is absorbed by the compound of formula II and thereby generating a cytotoxic effect with respect to the abnormal cells, wherein the conjugate is administered in an amount in the range of 0.01 mg/kg to 1.0 mg/kg of body weight.  
 
     
     
       19. The method as claimed in  claim 18  wherein the conjugate is administered at timed intervals in the range of from every 3 hours to every 72 hours for over a period of from 1 day to 30 days and wherein the wavelength of the light is in the range of 600 to 700 nm. 
     
     
       20. The method as claimed in  claim 18 , wherein R 5  is —O—hexyl and R 7  is —CO 2 H and wherein the wavelength of the light is about 660 nm.