Nanomaterials

Abstract

Lipid nanoparticle compositions for delivery of nucleic acids are described. The lipid nanoparticle may contain a conformationally constrained ionizable lipid as part of the composition. These compositions may allow for delivery of cargo without the need for a targeting ligand.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 9 -C 20  alkyl or C 9 -C 20  alkenyl with 1-3 units of unsaturation; 
         X 1  and X 2  are each independently absent or selected from —O—, NR 2 , and 
       
       
         
           
           
               
               
           
         
       
       wherein R 2  is C 1 -C 6  alkyl, and wherein X 1  and X 2  are not both —O— or NR 2 ;
 a is an integer between 1 and 6; 
 X 3  and X 4  are each independently absent or selected from the group consisting of: 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, and —NR 3 —, wherein each R 3  is a hydrogen atom or C 1 -C 6  alkyl; 
 X 5  is —(CH 2 ) b —, wherein b is an integer between 0 and 6, 
 X 6  is hydrogen, C 1 -C 6  alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, or —NR 4 R 5 , wherein R 4  and R 5  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 4  and R 5  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 X 7  is hydrogen or —NR 6 R 7 , wherein R 6  and R 7  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 5  and R 7  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 at least one of X 1 , X 2 , X 3 , X 4 , and X 5  is present; and 
 provided that when either X 1  or X 2  is —O—, neither X 3  nor X 4  is 
 
       
         
           
           
               
               
           
         
       
       and when either X 1  or X 2  is —O—, R 4  and R 5  are not both ethyl. 
     
     
         2 . The compound of  claim 1 , provided that 
       
         
           
           
               
               
           
         
       
       is not selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 8  is hydrogen or C 1 -C 6  alkyl; 
         R 9  is C 9 -C 20  alkyl optionally fused with 1-4 C 3 -C 6  cycloalkyl groups, C 9 -C 20  alkenyl with 1-3 units of unsaturation, or —(CH 2 ) g —X 17 , wherein X 17  is optionally substituted C 4 -C 12  cycloalkyl; 
         X 8  and X 9  are each independently absent or selected from —O—, NR 10 , and 
       
       
         
           
           
               
               
           
         
       
       wherein R 10  is C 1 -C 6  alkyl, and wherein X 8  and X 9  are not both —O— or NR 10 ;
 X 10  and X 11  are each independently absent or selected from the group consisting of: 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, and —NR 11 —, wherein R 11  is a hydrogen atom or C 1 -C 6  alkyl; 
 X 12  is —(CH 2 ) i —; 
 X 13  is hydrogen, C 1 -C 6  alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, or —NR 12 R 13 , wherein R 12  and R 13  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 12  and R 13  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 X 14  is hydrogen or —NR 14 R 15 , wherein R 14  and R 15  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 14  and R 15  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 each of c, d, e, f, g, h, and i is independently an integer from 0-6; 
 at least one of X 8 , X 9 , X 10 , and X 11  is present; 
 R 16  is hydrogen or optionally substituted C 5 -C 6  aryl; 
 X 15  is optionally substituted C 4 -C 12  cycloalkyl or optionally substituted C 5 -C 10  aryl; and 
 X 16  is hydrogen or optionally substituted C 4 -C 12  cycloalkyl; 
 provided that when f is 1 and R 9  is 
 
       
         
           
           
               
               
           
         
       
       X 15  is not 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5 , wherein R 9  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 5 , wherein R 9  is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 5 , wherein i is 3, X 8 , X 9 , X 10 , and X 11 , are absent, X 13  is —NR 12 R 13 , and R 12  and R 13  are each methyl. 
     
     
         9 . The compound of  claim 5 , wherein X 8 , X 9 , and X 11  are absent, i is 0, X 10  is 
       
         
           
           
               
               
           
         
       
       and X 13  is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 5 , wherein c, d, and e are each 1. 
     
     
         11 . The compound of  claim 10 , wherein R 9  is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein R 8  is hydrogen. 
     
     
         13 . The compound of  claim 5 , wherein R 9  and 
       
         
           
           
               
               
           
         
       
       are each 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 5 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A lipid nanoparticle composition comprising:
 a conformationally constrained ionizable lipid;   a phospholipid;   a polyethylene glycol-lipid;   a cholesterol; and optionally   a nucleic acid.   
     
     
         16 . The lipid nanoparticle composition of  claim 15 , wherein the ionizable lipid is a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 9 -C 20  alkyl or C 9 -C 20  alkenyl with 1-3 units of unsaturation; 
         X 1  and X 2  are each independently absent or selected from —O—, NR 2 , and 
       
       
         
           
           
               
               
           
         
       
       wherein R 2  is C 1 -C 6  alkyl, and wherein X 1  and X 2  are not both —O— or NR 2 ;
 a is an integer between 1 and 6; 
 X 3  and X 4  are each independently absent or selected from the group consisting of: 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, and —NR 3 —, wherein each R 3  is a hydrogen atom or C 1 -C 6  alkyl; 
 X 5  is —(CH 2 ) b —, wherein b is an integer between 0 and 6; 
 X 6  is hydrogen, C 1 -C 6  alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, or —NR 4 R 5 , wherein R 4  and R 5  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 4  and R 5  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 X 7  is hydrogen or —NR 6 R 7 , wherein R 6  and R 7  are each independently hydrogen or C 1 -C 6  alkyl; or alternatively R 6  and R 7  join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C 1 -C 6  alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; 
 at least one of X 1 , X 2 , X 3 , X 4 , and X 5  is present; and 
 provided that when either X 1  or X 2  is —O—, neither X 3  nor X 4  is 
 
       
         
           
           
               
               
           
         
       
       and when either X 1  or X 2  is —O—, R 4  and R 5  are not both ethyl. 
     
     
         17 . The lipid nanoparticle composition of  claim 15 , wherein the amount of ionizable lipid is present in the range of about 35 to 65 mole percent, based on total moles. 
     
     
         18 . The lipid nanoparticle composition of  claim 15 , wherein the phospholipid is DSPC. 
     
     
         19 . The lipid nanoparticle composition of  claim 15 , wherein the phospholipid is DMPC. 
     
     
         20 . A method of delivering a nucleic acid to a subject in need thereof, comprising administering to the subject the lipid nanoparticle composition of  claim 15 . 
     
     
         21 . The lipid nanoparticle composition of  claim 15 , wherein the nucleic acid is siRNA, miRNA, anti-sense oligonucleotide, or immunostimulatory oligonucleotide. 
     
     
         22 . The compound of  claim 5 , wherein the compound is selected from the group consisting of: