Amphiphilic nucleotide cochleate compositions and methods of using the same

Abstract

The present invention is directed to cochleate compositions that include a nucleotide that is associated with a positively charged amphiphile. The present invention also includes methods for making and using the compositions provided herein.

1 . A nucleotide-cochleate composition comprising:
 a cochleate; and   a nucleotide associated with the cochleate;   
     wherein the nucleotide is associated with a positively charged amphiphile. 
   
   
       2 . The composition of  claim 1 , wherein the positively charged amphiphile is a compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein:
 R is selected from H, a C2-C26 acyl group and a C4-C26 aliphatic group; 
 R 1  is selected from 
 
     
     
       
         
         
             
             
         
       
       
         R 2  and R 3  are each independently a C4-C26 aliphatic group; 
         optionally one or more of R, R 2  and R 3  can be: 
       
     
     
       
         
         
             
             
         
       
       
         R 4  and R 5  are each independently a C3-C20 acyl group; 
         n is an integer from 1 to 3; and 
         X is an anion of a pharmaceutically acceptable compound. 
       
     
   
   
       3 . The composition of  claim 2 , wherein R is selected from nonanoyl, dodecanoyl, myristoyl, palmitoyl, steroyl and oleoyl. 
   
   
       4 . The composition of  claim 2 , wherein R is selected from oleyl, nonyl, undecyl, tetradecyl, and hexadecyl. 
   
   
       5 . The composition of any of  claims 2 - 4 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       6 . The composition of  claim 5 , wherein R 3  is selected from oleyl, nonyl, undecyl, tetradecyl, and hexadecyl. 
   
   
       7 . The composition of  claim 1 , wherein the positively charged amphiphile is a compound of formula (II): 
     
       
         
         
             
             
         
       
       wherein:
 R is selected from H, a C2-C26 acyl group and a C4-C26 aliphatic group; 
 R 2  is a C4-C26 aliphatic group; 
 optionally one or both of R and R 2  can be: 
 
     
     
       
         
         
             
             
         
       
       
         R 4  and R 5  are each independently a C3-C20 acyl group; 
         n is an integer from 1 to 3; and 
         X is an anion of a pharmaceutically acceptable compound. 
       
     
   
   
       8 . The composition of  claim 7 , wherein R is selected from nonanoyl, dodecanoyl, myristoyl, palmitoyl, steroyl and oleoyl. 
   
   
       9 . The composition of  claim 7 , wherein R is selected from oleyl, nonyl, undecyl, tetradecyl, and hexadecyl. 
   
   
       10 . The composition of any of  claims 7 - 9 , wherein R 2  is selected from oleyl, nonyl, undecyl, tetradecyl and hexadecyl. 
   
   
       11 . The composition of  claim 1 , wherein the positively charged amphiphile is a compound of formula (III): 
     
       
         
         
             
             
         
       
       wherein:
 R is selected from a C2-C26 acyl group, a C4-C26 aliphatic group and H; 
 R 4  and R 5  are each independently a C3-C20 acyl group; 
 n is an integer from 1 to 3; and 
 X is an anion of a pharmaceutically acceptable compound. 
 
     
   
   
       12 . The composition of  claim 11 , wherein R is selected from nonanoyl, dodecanoyl, myristoyl, palmitoyl, steroyl and oleoyl. 
   
   
       13 . The composition of  claim 11 , wherein R is selected from oleyl, nonyl, undecyl, tetradecyl, and hexadecyl. 
   
   
       14 . The composition of  claim 11 , wherein R is selected from acetyl, propionyl, butyryl, valeryl and isovaleryl. 
   
   
       15 . The composition of any of  claims 11 - 14 , wherein R 4  and R 5  are each independently selected from hexanoyl, undecanoyl, myristoyl, palmitoyl and oleoyl. 
   
   
       16 . The composition of any of  claims 1 - 15 , wherein the nucleotide is an oligonucleotide. 
   
   
       17 . The composition of any of  claims 1 - 15 , wherein the nucleotide is an siRNA. 
   
   
       18 . The composition of any of  claims 1 - 15 , wherein the nucleotide is an antisense oligonucleotide. 
   
   
       19 . The composition of any of  claims 1 - 15 , wherein the nucleotide is a morpholino oligonucleotide. 
   
   
       20 . The composition of any of  claims 1 - 15 , wherein the morpholino oligonucleotide is an antisense morpholino oligonucleotide. 
   
   
       21 . The composition of any of  claims 1 - 15 , wherein the nucleotide is a short double-stranded DNA. 
   
   
       22 . The composition of any of  claims 1 - 15 , wherein the nucleotide is a ribozyme. 
   
   
       23 . The composition of any of  claims 1 - 15 , wherein the nucleotide is an aptamer. 
   
   
       24 . The composition of any of  claims 1 - 15 , wherein the nucleotide is a transcription factor decoy. 
   
   
       25 . The composition of any of  claims 1 - 15 , wherein the nucleotide comprises at least one mismatch. 
   
   
       26 . The composition of any of  claims 1 - 15 , wherein the nucleotide comprises at least one substitution. 
   
   
       27 . The composition of any of  claims 1 - 15 , wherein the nucleotide is about 18-25 nucleotides long. 
   
   
       28 . The composition of any of  claims 1 - 15 , wherein the nucleotide is about 21-23 nucleotides long. 
   
   
       29 . The composition of any of  claims 1 - 15 , wherein the nucleotide mediates RNA interference against a target mRNA. 
   
   
       30 . The composition of  claim 29 , wherein the target mRNA expresses a protein selected from the group consisting of: a cancer protein, a virus protein, an HIV protein, a fungus protein, a bacterial protein, an abnormal cellular protein, and a normal cellular protein. 
   
   
       31 . The composition of any of  claims 1 - 15 , wherein the nucleotide mediates inhibition of translation of a target mRNA. 
   
   
       32 . The composition of  claim 31 , wherein the target mRNA expresses a protein selected from the group consisting of: a cancer protein, a virus protein, an HIV protein, a fungus protein, a bacterial protein, an abnormal cellular protein, and a normal cellular protein. 
   
   
       33 . The composition of any of  claims 1 - 15 , further comprising a second nucleotide directed against a second target mRNA. 
   
   
       34 . A method of forming a nucleotide-cochleate composition comprising: precipitating a liposome and a nucleotide to form a nucleotide-cochleate, wherein the nucleotide is associated with a positively charged amphiphile. 
   
   
       35 . A method of administering a nucleotide to a host comprising: administering a biologically effective amount of a nucleotide-cochleate composition to a host comprising a cochleate and a nucleotide associated with the cochleate, wherein the nucleotide is associated with a positively charged amphiphile. 
   
   
       36 . A method of treating a subject having a disease or disorder associated with expression of a target mRNA, comprising: administering to a subject a therapeutically effective amount of a nucleotide-cochleate composition, comprising a cochleate and a nucleotide directed against a target mRNA associated with a disease or disorder, wherein the nucleotide is associated with a positively charged amphiphile, such that the disease or disorder is treated. 
   
   
       37 . The method of  claim 36 , wherein the disease is influenza.