Etoposide and doxorubicin conjugates for drug delivery

Abstract

The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides having a hydrolyzable covalent bond to a therapeutic agent that includes, etoposide, etoposide 4′-dimethylglycine or doxorubicin. These polypeptide conjugates can be used as vectors to transport the podophyllotoxin derivative across the blood brain barrier (BBB) or into particular cell types such as ovary, liver, lung, or kidney. The invention also relates to pharmaceutical compositions that include the compounds of the invention and to uses thereof in methods of treatment.

What is claimed is: 
     
         1 - 43 . (canceled) 
     
     
         44 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein Y is a hydrolyzable linker; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         45 . The compound of  claim 44 , wherein Y has the structure: 
       
         
           
           
               
               
           
         
         wherein each G and G′ is, independently, —C(O)—, —C(O)O—, —OC(O)—, —S(O) 2 O—, —OS(O) 2 —, —S(O) 2 NH—, —NHS(O) 2 —, or —OP(O)(OR 11 )O—; 
         X is -(optionally substituted aryl)-, —(CR 12 R 13 ) r , —O{(CR 12 R 13 ) 2 O} n —, —{(CR 12 R 13 ) 2 O(CR 12 R 13 ) 2 } n —, or —(CR 12 R 13 ) o R 14 (CR 12 R 13 ) p —; 
         each n, o, and p is, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 
         R 11  is H or C 1-6  alkyl; 
         R 12  and R 13  are each selected, independently, from H, OH, or C 1-6  alkyl; and 
         R 14  is O, NH, N(C 1-6  alkyl), or -optionally substituted aryl. 
       
     
     
         46 . The compound of  claim 45 , wherein G is —C(O)—. 
     
     
         47 . The compound of  claim 45 , wherein G′ is —C(O)—. 
     
     
         48 . The compound of  claim 45 , wherein X is —(CR 12 R 13 ) n —. 
     
     
         49 . The compound of  claim 48 , wherein n is 1, 2, 3, 4, 5, or 6. 
     
     
         50 . The compound of  claim 49 , wherein n is 2 or 3. 
     
     
         51 . The compound of  claim 50 , wherein n is 3. 
     
     
         52 . A pharmaceutical composition comprising the compound  claim 44  and a pharmaceutically acceptable carrier. 
     
     
         53 . A method of treating a cancer, said method comprising administering to a patient a therapeutically effective amount of the compound of  claim 44 . 
     
     
         54 . The method of  claim 53 , further comprising the administration of a second therapeutic agent. 
     
     
         55 . The method of  claim 54 , wherein said second therapeutic agent is a polypeptide comprising the sequence of Angiopep-2 (SEQ ID NO:97), and wherein said Angiopep-2 is conjugated to an anticancer agent. 
     
     
         56 . The method of  claim 55 , wherein said anticancer agent is paclitaxel. 
     
     
         57 . The method of  claim 56 , wherein said second therapeutic agent is ANG1005, which has the following structure