Cxcr4 inhibiting carriers for nucleic acid delivery

Abstract

The present invention generally relates to carriers including polymers and lipids that comprise a CXCR4 inhibiting moiety. More specifically, these carriers are biodegradable and can be bioreducible polymers that comprise a CXCR4 inhibiting moiety. These carriers can be suitable for delivery of nucleic acids to cells. These carriers and pharmaceutical compositions comprising these carriers can be used to treat various conditions including cancers and inflammation conditions.

1 . A polymer comprising structural units of a CXCR4 inhibiting moiety and either (i) a structural unit of Formula 11, (ii) a structural unit of Formula 22, (iii) structural units of Formulae 11 and 22, (vi) structural units of Formulae 11 and 88, (vii) structural units of Formulae 22 and 88, (viii) structural units of Formulae 11, 22, and 77, (ix) structural units of Formulae 11, 22, and 88, or (x) structural units of Formulae 11, 22, 77, and 88); the structural units of Formulae 11, 22, 77, and 88 corresponding to the following structures: 
       
         
           
           
               
               
           
         
       
       wherein X 11  and X 22  are independently —NH—C(O)—CH 2 CH 2 —, —O—C(O)—CH 2 CH 2 —, —C(O)O—, —C(O)—, or —NH—C(O)—; R 77  is hydrogen or alkyl; R 12 , R 13 , R 14 , R 15  are independently hydrogen, alkyl, or substituted alkyl; R 88  and R 89  are independently alkyl or substituted alkyl; n 1  is independently an integer from 1 to 4; and n 2  is an integer from 1 to 8. 
     
     
         2 . The polymer of  claim 1  wherein the structural unit corresponds to Formula 11. 
     
     
         3 . The polymer of  claim 2  wherein X 11  is —NH—C(O)—CH 2 CH 2 — or —O—C(O)—CH 2 CH 2 — and R 12 , R 13 , R 14 , R 15  are independently hydrogen. 
     
     
         4 . The polymer of  claim 1  wherein R 12  and R 14  are hydrogen and R 13  and R 15  are —C(O)O-alkyl. 
     
     
         5 . The polymer of  claim 3  wherein X 11  is —NH—C(O)—CH 2 CH 2 — and n 1  is 2. 
     
     
         6 . The polymer of  claim 1  wherein the structural unit corresponds to Formula 22. 
     
     
         7 . The polymer of  claim 6  wherein X 22  is —NH—C(O)—CH 2 CH 2 — or —O—C(O)—CH 2 CH 2 —. 
     
     
         8 . The polymer of  claim 7  wherein X 22  is —NH—C(O)—CH 2 CH 2 — and n 2  is an integer from 4 to 6. 
     
     
         9 . The polymer of  claim 1  wherein the structural units correspond to Formulae 11 and 22. 
     
     
         10 - 15 . (canceled) 
     
     
         16 . The polymer of  claim 1  wherein CXCR4 inhibiting moiety is derived from a cyclam compound and the cyclam compound corresponds to either Formula 5 or Formula 6, wherein Formulae 5 and 6 correspond to the following structures: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , and R 4  are independently hydrogen or —R 8 —NH 2 ; 
 R 5 , R 6 , and R 7  are independently hydrogen or —R 8 —NH 2 ; and 
 R 8  is independently C 2  to C 12  alkylene, arylene, or C 2  to C 12  alkylene wherein one or more of the —CH 2 — groups of the alkylene group is replaced with an amide, an amine, a carbonyl, an ether, an ester, a cycloalkyl, an aryl, or a heterocyclo functional group. 
 
     
     
         17 - 46 . (canceled) 
     
     
         47 . The polymer of  claim 16  wherein the cyclam monomer has a structure corresponding to Formula 5 and at least one of R 1 , R 2 , R 3 , or R 4  is —R 8 —NH 2 . 
     
     
         48 . The polymer of  claim 16  wherein the cyclam monomer has a structure corresponding to Formula 6 and at least one of R 5 , R 6 , or R 7  is —R 8 —NH 2 . 
     
     
         49 . The polymer of  claim 16  wherein R 8  is independently —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —, —CH 2 —C 6 H 4 —CH 2 —N(CH 3 )—(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —, —CH 2 —C 6 H 4 —CH 2 —N(C(O)Ot-Bu)-(CH 2 ) 3 —, —CH 2 —C 6 H 4 —CH 2 —N(C(O)Ot-Bu)-(CH 2 ) 3 —N(C(O)Ot-Bu)-(CH 2 ) 3 —, or —CH 2 —C 6 H 4 —CH 2 —N(CH 3 )—CH 2 —C 5 H 3 N—CH 2 —. 
     
     
         50 . The polymer of  claim 49  wherein R 8  is independently —CH 2 —C 6 H 4 —CH 2 —N(C(O)Ot-Bu)-(CH 2 ) 3 — or —CH 2 —C 6 H 4 —CH 2 —N(C(O)Ot-Bu)-(CH 2 ) 3 —N(C(O)Ot-Bu)-(CH 2 ) 3 —. 
     
     
         51 . The polymer of  claim 49  wherein R 8  is independently —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —, —CH 2 —C 6 H 4 —CH 2 —N(CH 3 )—(CH 2 ) 2 —N(CH 3 )—(CH 2 ) 2 —, or —CH 2 —C 6 H 4 —CH 2 —N(CH 3 )—CH 2 —C 5 H 3 N—CH 2 —. 
     
     
         52 . The polymer of  claim 51  wherein R 8  is independently —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —, or —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —. 
     
     
         53 - 55 . (canceled) 
     
     
         56 . The polymer of  claim 16  wherein the weight average molecular weight is from about 1.5 kDa to about 20 kDa. 
     
     
         57 - 68 . (canceled) 
     
     
         69 . A polyplex comprising a polymer of  claim 16  and a nucleic acid. 
     
     
         70 . The polyplex of  claim 69  wherein the nucleic acid is plasmid DNA, shRNA, siRNA or microRNA. 
     
     
         71 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a polymer of  claim 16 . 
     
     
         72 - 96 . (canceled)