Cationic nanostructures for intra-cartilage delivery of therapeutics and contrast agents

Abstract

The present invention provides a platform for the delivery of small molecule drugs or contrast agents to joints and other soft tissues. The platform enables penetration of the drug through the full thickness of cartilage and long intra-cartilage residence time by leveraging electrostatic interactions between the cationic platform and the anionic cartilage matrix. Described herein are compounds and complexes that fit this platform. Also provided are methods of treating a joint disease with the compounds and complexes of the invention, and methods of imaging joints and other soft tissue.

1 . A compound, comprising:
 a residue of biotin;   a multi-arm polymeric scaffold;   one or more hydrolyzable linking moieties; and   one or more residues of an active pharmaceutical ingredient;   wherein the residue of biotin is covalently attached to the multi-arm polymeric scaffold;   each of the one or more hydrolyzable linking moieties are covalently attached to the multi-arm polymeric scaffold; and   each of the one or more residues of the active pharmaceutical ingredient are covalently attached to each of the one or more hydrolyzable linking moieties.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein one arm of the multi-arm polymeric scaffold is covalently attached to the residue of biotin, and each of the remaining arms of the multi-arm polymeric scaffold is attached to a hydrolyzable linking moiety, and each hydrolyzable linking moiety is attached to a residue of an active pharmaceutical ingredient. 
     
     
         5 .- 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the multi-arm polymeric scaffold comprises 8 arms. 
     
     
         9 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein each of the one of more hydrolyzable linking moieties is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         14 .- 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein the active pharmaceutical ingredient is a glucocorticoid or pharmaceutically acceptable salt thereof. 
     
     
         18 .- 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein:
 the multi-arm polymeric scaffold comprises an 8-arm polyethylene glycol scaffold;   each of the one of more hydrolyzable linking moieties is selected from the group consisting of   
       
         
           
           
               
               
           
         
       
       and
 the active pharmaceutical ingredient is dexamethasone. 
 
     
     
         22 . The compound of  claim 1 , having the structure: 
       
         
           
           
               
               
           
         
       
       wherein X is a hydrolyzable linking moiety selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and
 n is an integer from 1 to 500,000; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . (canceled) 
     
     
         24 . A complex, comprising avidin and one or more compounds of  claim 1 . 
     
     
         25 . The complex of  claim 24 , wherein the one or more compounds are bound to avidin through electrostatic interactions. 
     
     
         26 . The complex of  claim 24 , wherein avidin and the one or more compounds are in a molar ratio of 1:4; and
 all four biotin-binding sites of avidin are bound to one of the one or more compounds.   
     
     
         27 .- 34 . (canceled) 
     
     
         35 . A method of treating a joint disease in a subject in need thereof, comprising administering to the subject a compound of  claim 1 . 
     
     
         36 .- 39 . (canceled) 
     
     
         40 . A method of preventing glycosaminoglycan (GAG) loss in a subject in need thereof, comprising administering to the subject a complex of  claim 24 . 
     
     
         41 . (canceled) 
     
     
         42 . A compound, comprising:
 a residue of biotin;   a multi-arm polymeric scaffold; and   one or more residues of a contrast agent;   wherein the residue of biotin is covalently attached to the multi-arm polymeric scaffold; and   each of the one or more residues of a contrast agent are covalently attached to the multi-arm polymeric scaffold.   
     
     
         43 .- 48 . (canceled) 
     
     
         49 . The compound of  claim 42 , wherein the multi-arm polymeric scaffold comprises 8 arms. 
     
     
         50 .- 53 . (canceled) 
     
     
         54 . The compound of  claim 42 , wherein the contrast agent is selected from the group consisting of diatrizoate, metrizoate, iothalamate, and ioxaglate. 
     
     
         55 . (canceled) 
     
     
         56 . The compound of  claim 42 , having the structure: 
       
         
           
           
               
               
           
         
         n is an integer from 1 to 500,000; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         57 . A complex, comprising avidin and one or more compounds of  claim 42 . 
     
     
         58 .- 63 . (canceled) 
     
     
         64 . A method of diagnosing a joint disease, comprising administering to a subject a complex of  claim 57 ;
 imaging the joint; and   assessing the resultant images to determine whether the subject is suffering from a joint disease.   
     
     
         65 .- 68 . (canceled) 
     
     
         69 . A method of imaging soft tissue, comprising administering to a subject a complex of  claim 57 ; and
 imaging the soft tissue.   
     
     
         70 .- 71 . (canceled) 
     
     
         72 . A method of delivering a contrast agent or an active pharmaceutical ingredient to a negatively charged tissue in a subject, comprising administering to the subject a complex;
 wherein the complex comprises a residue of a contrast agent or an active pharmaceutical ingredient and a cationic peptide, wherein the peptide comprises from 2 to 40 amino acid residues, and the net charge of the peptide is from +7 to +20 inclusive; and   the residue of the contrast agent or the active pharmaceutical ingredient is covalently bonded to the peptide.   
     
     
         73 .- 84 . (canceled)