Nucleic Acid Carriers And Therapeutic Methods Of Use

Abstract

The present disclosure provides nucleic acid carriers comprising targeting agents, pharmaceutical compositions comprising the same, and methods of making and using the same.

1 - 24 . (canceled) 
     
     
         25 . A nucleic acid carrier comprising:
 a first oligonucleotide comprising less than 102 nucleotides, and having a central portion, a first terminal arm, and a second terminal arm,   a second oligonucleotide comprising less than 102 nucleotides, and having a central portion, a first terminal arm, and a second terminal arm, wherein the first terminal arm of the second oligonucleotide is complementary to the first terminal arm of the first oligonucleotide, and   a third oligonucleotide comprising less than 102 nucleotides, and having a central portion, a first terminal arm, and a second terminal arm, wherein the first terminal arm of the third oligonucleotide is complementary to the second terminal arm of the first oligonucleotide;   wherein the first terminal arm of the first oligonucleotide hybridizes with or is conjugated to the first terminal arm of the second oligonucleotide,   wherein the second terminal arm of the first oligonucleotide hybridizes with or is conjugated to the first terminal arm of the third oligonucleotide, and   wherein the nucleic acid carrier has a melting temperature of greater than 50° C.   
     
     
         26 . The nucleic acid carrier of  claim 25 , further comprising an antibody, or an antigen binding fragment thereof, conjugated to the second terminal arm of the second or third oligonucleotide. 
     
     
         27 . The nucleic acid carrier of  claim 26 , wherein the antibody, or an antigen binding fragment thereof, is chemically coupled to a fourth oligonucleotide that hybridizes with or is conjugated to the second terminal arm of the second or third oligonucleotide. 
     
     
         28 . The nucleic acid carrier of  claim 25 , wherein the each of the first, second, and third oligonucleotides comprises around 97 nucleotides. 
     
     
         29 . The nucleic acid carrier of  claim 25 , wherein the melting temperature of the nucleic acid carrier is from 65-75° C. 
     
     
         30 . The nucleic acid carrier of  claim 25 , wherein the central portion of each of the first, second, and third oligonucleotides comprises from 3 and 7 thymidine-adenine (TpA) sites. 
     
     
         31 . The nucleic acid carrier of  claim 25 , wherein the first terminal arm of each of the first, second, and third oligonucleotides comprises from 3 and 7 thymidine-adenine (TpA) sites. 
     
     
         32 . The nucleic acid carrier of  claim 25 , wherein the second terminal arm of each of the first, second, and third oligonucleotides comprises from 3 and 7 thymidine-adenine (TpA) sites. 
     
     
         33 . The nucleic acid carrier of  claim 25 , wherein at least one of the first, second, and third oligonucleotides comprises nucleotides linked with a phosphorothioate (PS) nucleotide backbone. 
     
     
         34 . The nucleic acid carrier of  claim 25 , wherein at least one of the first, second, and third oligonucleotides comprises at least one nucleoside analog, wherein the analog increases the melting temperature of the nucleic acid carrier. 
     
     
         35 . The nucleic acid carrier of  claim 25 , further comprising an oligonucleotide complementary to the central portion of the first oligonucleotide having from 25 to 35 nucleotides, wherein the oligonucleotide complementary to the central portion of the first oligonucleotide forms a double-stranded region with the central portion of the first oligonucleotide. 
     
     
         36 . The nucleic acid carrier of  claim 34 , wherein the oligonucleotide complementary to the central portion of the first oligonucleotide is about 31 nucleotides. 
     
     
         37 . The nucleic acid carrier of  claim 25 , further comprising an oligonucleotide complementary to the central portion of the second oligonucleotide having from 25 to 35 nucleotides, wherein the oligonucleotide complementary to the central portion of the second oligonucleotide forms a double-stranded region with the central portion of the second oligonucleotide. 
     
     
         38 . The nucleic acid carrier of  claim 36 , wherein the oligonucleotide complementary to the central portion of the second oligonucleotide is about 31 nucleotides. 
     
     
         39 . The nucleic acid carrier of  claim 25 , further comprising an oligonucleotide complementary to the central portion of the third oligonucleotide having from 25 to 35 nucleotides, wherein the oligonucleotide complementary to the central portion of the third oligonucleotide forms a double-stranded region with the central portion of the third oligonucleotide. 
     
     
         40 . The nucleic acid carrier of  claim 38 , wherein the oligonucleotide complementary to the central portion of the third oligonucleotide is about 31 nucleotides. 
     
     
         41 . A pharmaceutical composition comprising the nucleic acid carrier of claim  1  and a pharmaceutically acceptable vehicle. 
     
     
         42 . A method of manufacturing the nucleic acid carrier of claim  1 , the method comprising bringing a mixture comprising equal amounts of the first, second, and third oligonucleotides to a temperature of about 37° C. and allowing the mixture to cool to room temperature to hybridize the first terminal arm of the first oligonucleotide to the first terminal arm of the second oligonucleotide and to hybridize the second terminal arm of the first oligonucleotide to the first terminal arm of the third oligonucleotide.