Drug carriers

Abstract

Compositions that can include a cationic polymeric carrier, targeting agent, and therapeutic agent are disclosed herein. The therapeutic agent may have a therapeutic activity such as inhibiting fibrosis within a target organ or tissue or inhibiting the growth of a cancer cell.

1 . A therapeutic composition comprising:
 a cationic polymeric carrier;   a targeting agent operatively associated with the cationic polymeric carrier, wherein the targeting agent comprises a retinoid; and   a therapeutic agent operatively associated with the cationic polymeric carrier, wherein the therapeutic agent exhibits a therapeutic activity upon delivery to a target organ or tissue, and wherein the therapeutic activity is selected from the group consisting of inhibiting fibrosis within the target organ or tissue and inhibiting the growth of a cancer cell within the target organ or tissue.   
     
     
         2 . The therapeutic composition of  claim 1 , wherein the retinoid is selected from the group consisting of retinol, retinal and retinoic acid. 
     
     
         3 . The therapeutic composition of  claim 1 , wherein the retinoid is selected from the group consisting of all-trans retinol, all-trans retinoic acid, retinyl palmitate, 11-cis-retinal, and 13-cis-retinoic acid. 
     
     
         4 . The therapeutic composition of  claim 1 , wherein the target organ is selected from the group consisting of liver, pancreas, kidney, lung, esophagus, larynx, bone marrow, and brain. 
     
     
         5 . The therapeutic composition of  claim 1 , wherein the targeting agent provides an increase in the delivery selectivity of the therapeutic composition, upon delivery to the target organ or tissue, that is at least about two-fold as compared to that of an otherwise comparable therapeutic composition without the targeting agent. 
     
     
         6 . The therapeutic composition of  claim 5 , wherein the increase in delivery selectivity is at least about 3-fold. 
     
     
         7 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier comprises a recurring unit of Formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier comprises poly-L-lysine. 
     
     
         9 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier comprises a recurring unit selected from the group consisting of Formula (II), (III), (IV), (V) and (VI): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier comprises polyethyleneimine. 
     
     
         11 . The therapeutic composition of  claim 10 , wherein the polyethyleneimine is selected from the group consisting of linear polyethyleneimine and branched polyethyleneimine. 
     
     
         12 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier comprises:
 (a) a recurring polyethylene glycol (PEG) unit,   (b) a recurring cationic polyethyleneimine (PEI) unit, and   (c) a recurring degradable unit that comprises a pendant lipid group.   
     
     
         13 . The therapeutic composition of  claim 12 , wherein the recurring degradable unit is a recurring unit of Formula (VII): 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is absent or an optionally substituted substituent selected from the group consisting of: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and —(CH 2 ) n1 -D-(CH 2 ) n2 —;
 wherein n1 and n2 are each independently 0 or an integer in the range of 1 to 10; and 
 D is an optionally substituted substituent selected from the group consisting of cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl; 
 
         A 2  is absent, an oxygen atom or —N(R N ), wherein R N  is H or C 1-6  alkyl; 
         R 1  is an electron pair, hydrogen, or an optionally substituted substituent selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, and heterocyclyl,
 wherein if R 1  is hydrogen, or an optionally substituted substituent selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, and heterocyclyl, then the nitrogen atom to which R 1  is attached has a positive charge; and 
 
         R 2  is selected from the group consisting of C 2 -C 50  alkyl, C 2 -C 50  heteroalkyl, C 2 -C 50  alkenyl, C 2 -C 50  heteroalkenyl, C 2 -C 50  alkynyl, C 2 -C 50  heteroalkynyl, C 5 -C 50  aryl, C 5 -C 50  heteroaryl, —(CH 2 ) p1 -E-(CH 2 ) p2 —, and sterol;
 wherein p1 and p2 are each independently 0 or an integer in the range of 1 to 40; and 
 E is an optionally substituted substituent selected from the group consisting of cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl. 
 
       
     
     
         14 . The therapeutic composition of  claim 13 , wherein R 2  is selected from the group consisting of oleyl, lauryl, myristyl, palmityl, margaryl, stearyl, arachidyl, behenyl, lignoceryl and a sterol. 
     
     
         15 . The therapeutic composition of  claim 13 , wherein R 2  is oleyl. 
     
     
         16 . The therapeutic composition of  claim 13 , wherein the recurring degradable unit is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier is a microparticle. 
     
     
         18 . The therapeutic composition of  claim 1 , wherein the cationic polymeric carrier is a nanoparticle. 
     
     
         19 . The therapeutic composition of  claim 1 , wherein the therapeutic agent, upon delivery to the target organ or tissue, substantially inhibits the activity of an agent selected from the group consisting of a tissue inhibitor of metalloproteinases (TIMP) and a molecular chaperone. 
     
     
         20 . The therapeutic composition of  claim 19 , wherein the molecular chaperone is HSP47. 
     
     
         21 . The therapeutic composition of  claim 1 , wherein the therapeutic agent is selected from the group consisting of siRNA, DNA, RNA, and an antisense nucleic acid. 
     
     
         22 . The therapeutic composition of  claim 1 , wherein the therapeutic agent is an anti-cancer agent. 
     
     
         23 . The therapeutic composition of  claim 1 , further comprising at least one selected from a pharmaceutically acceptable excipient and a diluent. 
     
     
         24 . A method for treating a condition characterized at least in part by abnormal fibrosis, comprising administering a therapeutically effective amount of the therapeutic composition of  claim 1  to a subject in need thereof. 
     
     
         25 . The method of  claim 24 , wherein the condition is selected from the group consisting of cancer and a fibrotic disease. 
     
     
         26 . The method of  claim 24 , wherein the condition is hepatic fibrosis. 
     
     
         27 . The method of  claim 24 , wherein the condition is pancreatic cancer.