Conjugation of lipophilic albumin-binding moiety to RNA for improved carrier-free in vivo pharmacokinetics and gene silencing
Provided herein are compounds and methods for gene silencing. The compound includes a RNA directly conjugated to an albumin-binding group. The method includes administering a compound comprising a RNA directly conjugated to an albumin-binding group to a subject in need thereof.
1. A compound comprising a RNA directly conjugated to a noncovalent albumin-binding group;
wherein the RNA is siRNA or miRNA;
wherein the noncovalent albumin-binding group is hydrophobic, anionic, or a combination thereof; and
wherein the noncovalent albumin-binding group is complexed with, or remains free to complex with, albumin.
2. The compound of claim 1 , wherein the albumin-binding group is hydrophobic.
3. The compound of claim 1 , wherein the albumin-binding group is hydrophobic and anionic.
4. The compound of claim 1 , wherein the albumin-binding group is a divalent lipidic moiety.
5. The compound of claim 4 , wherein the divalent lipid moiety is a diacyl lipid.
6. The compound of claim 4 , wherein the divalent lipidic moiety comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (L 2 ).
7. The compound of claim 1 , wherein the siRNA comprises a functionalized siRNA.
8. The compound of claim 7 , wherein the functionalized siRNA is functionalized with a dibenzocyclooctyne moiety.
9. The compound of claim 1 , wherein the compound is complexed with albumin.
10. A compound comprising siRNA functionalized with a dibenzocyclooctyne moiety and directly conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000], wherein the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] is complexed with, or remains free to complex with, albumin.
11. A method of gene silencing, the method comprising administering the compound according to claim 1 to a subject in need thereof.
12. The method of claim 11 , wherein the albumin-binding group is hydrophobic.
13. The method of claim 11 , wherein the albumin-binding group is hydrophobic and anionic.
14. The method of claim 11 , wherein the albumin-binding group is a diacyl lipid.
15. The method of claim 11 , wherein the albumin-binding group comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (L 2 ).
16. The method of claim 11 , wherein the siRNA comprises a functionalized siRNA.
17. The method of claim 11 , wherein the administering comprises intravenous administration.