Mmp-targeted therapeutic and/or diagnostic nanocarriers

Abstract

The present invention provides targeted delivery compositions and methods of using the compositions for treating and diagnosing a disease state in a subject.

1 - 73 . (canceled) 
     
     
         74 . A method of treating or diagnosing a cancerous condition in a subject comprising:
 (a) administering a targeted delivery composition, comprising:
 (i) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and 
 (ii) a conjugate having the formula:
   A-(LPEG)-MMP i ; 
 
   wherein,   A is an attachment component for attaching said conjugate to said nanocarrier;   (LPEG) is selected from:   1. a linking group having a linear assembly of from 1 to 3 polyethylene glycol components,   2. a linking group having the formula [(EG)(P)] m  wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; or   3. a linking group having the formula —Z 1 —Z 2 —Z 3 —, wherein   Z 1  and Z 3  are independently selected from the group consisting of a PEG component having a defined length and W n , wherein W is an amino acid and the subscript n is an integer from 0 to 3; and   Z 2  is selected from the group consisting of a PEG component having a defined length and a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting Z 1  and Z 3 ; and   MMP i  is a MMP enzyme inhibitor having the formula;   
       
         
           
           
               
               
           
         
         wherein 
         X is a member selected from the group consisting of O and S; 
         Y is a member selected from the group consisting of pyridyl and phenyl, wherein said phenyl is optionally substituted with OH, OCH 3 , OCF 3  and CH 3 ; and 
         the wavy line indicates the point of attachment to (LPEG); 
         wherein the therapeutic or diagnostic agent is sufficient to treat or diagnose the condition. 
       
     
     
         75 . The method of  claim 74 , wherein MMP i  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         76 . The method of  claim 74 , wherein MMP i  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         77 . The method of  claim 74 , wherein said nanocarrier has embedded in, encapsulated in, or tethered to a therapeutic agent selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane. 
     
     
         78 . The method of  claim 74 , wherein said nanocarrier has embedded in, encapsulated in, or tethered to a diagnostic agent selected from the group consisting of a radioactive agent, a fluorescent agent, and a contrast agent. 
     
     
         79 . A method of treating a cancerous condition in a subject comprising:
 (a) administering to the subject a targeted delivery composition, comprising:
 (i) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and 
 (ii) a conjugate having the formula:
   A-(LPEG)-MMP i ; 
 
   wherein,   A is an attachment component for attaching said conjugate to said nanocarrier;   (LPEG) is selected from:   1. a linking group having a linear assembly of from 1 to 3 polyethylene glycol components,   2. a linking group having the formula [(EG)(P)] m  wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; or   3. a linking group having the formula —Z 1 —Z 2 —Z 3 —, wherein   Z 1  and Z 3  are independently selected from the group consisting of a PEG component having a defined length and W n , wherein W is an amino acid and the subscript n is an integer from 0 to 3; and   Z 2  is selected from the group consisting of a PEG component having a defined length and a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting Z 1  and Z 3 ; and   MMP i  is a MMP enzyme inhibitor   
       wherein the therapeutic agent is sufficient to treat the condition; and 
       wherein the administration of the composition inhibits growth of the tumor cells by at least 25%. 
     
     
         80 . A method of treating a cancerous condition in a subject comprising:
 (a) administering to the subject a targeted delivery composition, comprising:
 (i) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and 
 (ii) a conjugate having the formula:
   A-(LPEG)-MMP i ; 
 
   wherein,   A is an attachment component for attaching said conjugate to said nanocarrier;   (LPEG) is selected from:   1. a linking group having a linear assembly of from 1 to 3 polyethylene glycol components,   2. a linking group having the formula [(EG)(P)] m  wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; or   3. a linking group having the formula —Z 1 —Z 2 —Z 3 —, wherein   Z 1  and Z 3  are independently selected from the group consisting of a PEG component having a defined length and W n , wherein W is an amino acid and the subscript n is an integer from 0 to 3; and   Z 2  is selected from the group consisting of a PEG component having a defined length and a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting Z 1  and Z 3 ; and   MMP i  is a MMP enzyme inhibitor   
       wherein the therapeutic agent is sufficient to treat the condition; and 
       wherein the administration of the composition reduces the tumor burden by at least 25%. 
     
     
         81 . A method of treating a cancerous condition in a subject comprising:
 (a) administering to the subject a targeted delivery composition, comprising:
 (i) a nanocarrier including a therapeutic or diagnostic agent or a combination thereof; and 
 (ii) a conjugate having the formula:
   A-(LPEG)-MMP i ; 
 
   wherein,   A is an attachment component for attaching said conjugate to said nanocarrier;   (LPEG) is selected from:   1. a linking group having a linear assembly of from 1 to 3 polyethylene glycol components,   2. a linking group having the formula [(EG)(P)] m  wherein each EG is an ethylene glycol group independently selected from the group consisting of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol and octaethylene glycol, P is a phosphoryl or thiophosphoryl group, and m is an integer of from 1 to 20; or   3. a linking group having the formula —Z 1 —Z 2 —Z 3 —, wherein   Z 1  and Z 3  are independently selected from the group consisting of a PEG component having a defined length and W n , wherein W is an amino acid and the subscript n is an integer from 0 to 3; and   Z 2  is selected from the group consisting of a PEG component having a defined length and a coupling group selected from an amide, thioamide, ester, carbamate or urea for connecting Z 1  and Z 3 ; and   MMP i  is a MMP enzyme inhibitor   
       wherein the therapeutic agent is sufficient to treat the condition; and 
       wherein the composition is administered at a dosage range of about 15 mg/kg to about 60 mg/kg. 
     
     
         82 . The method of  claim 79 , wherein MMP i  has an IC 50  of about 13 nM or lower. 
     
     
         83 . The method of  claim 80 , wherein MMP i  has an IC 50  of about 13 nM or lower. 
     
     
         84 . The method of  claim 81 , wherein MMP i  has an IC 50  of about 13 nM or lower. 
     
     
         85 . The method of  claim 79 , wherein the administration of the composition inhibits growth of the tumor cells by at least 50%. 
     
     
         86 . The method of  claim 80 , wherein the administration of the composition reduces the tumor burden by at least 50%.