Drug delivery systems containing oxidized cholesterols
Lipid nanoparticles and compositions thereof are disclosed herein. An exemplary nanoparticle composition includes an ionizable lipid, a phospholipid, a PEG-lipid, and a cholesterol modified with a hydroxyl group near the D-sterol ring. The disclosed nanoparticle compositions can target liver Kupffer cells and endothelial cells more preferentially than hepatocytes which should be beneficial in treating liver diseases in which dysfunctional Kupffer cells and endothelial cells are involved in disease pathogenesis.
1. A lipid nanoparticle composition comprising,
an ionizable lipid,
a phospholipid,
a polyethylene glycol (PEG), and
a side-chain oxidized cholesterol;
wherein the ionizable lipid, the phospholipid, the polyethylene glycol and the side-chain oxidized cholesterol are all selected together in combination to provide the lipid nanoparticle composition with a capability to more potently deliver a cargo that is encapsulated within the nanoparticle to non-hepatocytes than to hepatocytes in a liver microenvironment.
2. The nanoparticle composition of claim 1 , wherein the ionizable lipid is 3,6-bis({4-[bis(2-hydroxydodecyl)amino]-butyl})piperazine-2,5-dione (CKK-E12).
3. The nanoparticle composition of claim 1 , wherein the phospholipid is 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).
4. The nanoparticle composition of claim 1 , wherein the PEG is C 14 PEG 2000 or C 18 PEG 2000 .
5. The nanoparticle composition of claim 1 , wherein the oxidized cholesterol is selected from the group consisting of 20α-hydroxycholesterol, 7β,25-dihydroxylcholesterol, 27-hydroxycholesterol, and 25-hydroxycholesterol, or combinations thereof.
6. The nanoparticle composition of claim 1 , wherein the composition comprises about 30 mol % to about 80 mol % ionizable lipid, about 5 mol % to about 55 mol % side-chain oxidized cholesterol, about 10 mol % to about 35 mol % phospholipid, and about 0 mol % to about 20 mol % PEG-lipid.
7. The nanoparticle composition of claim 1 , further comprising a therapeutic or prophylactic agent.
8. The nanoparticle composition of claim 7 , wherein the therapeutic or prophylactic agent is encapsulated as the cargo within the lipid nanoparticle.
9. The nanoparticle composition of claim 7 , wherein the therapeutic or prophylactic agent is a ribonucleic acid (RNA).
10. The nanoparticle composition of claim 9 , wherein the RNA is messenger RNA (mRNA).
11. The nanoparticle composition of claim 1 , wherein the nanoparticle has a diameter from about 20 nm to about 215 nm.
12. A pharmaceutical composition comprising the lipid nanoparticles of claim 1 , and a pharmaceutically acceptable excipient.
13. The lipid nanoparticle composition of claim 1 , wherein
the ionizable lipid is CKK-E12,
the phospholipid is DOPE,
the polyethylene glycol (PEG) is C 18 PEG 2000 , and
the side chain oxidized cholesterol is 20α-hydroxycholesterol.
14. The lipid nanoparticle composition of claim 1 , wherein
the ionizable lipid is CKK-E12,
the phospholipid is DOPE,
the polyethylene glycol (PEG) is C 18 PEG 2000 , and
the side chain oxidized cholesterol is 25-hydroxycholesterol.
15. A method of delivering a therapeutic or prophylactic agent to a subject in need thereof, comprising, administering to the subject the lipid nanoparticle composition of claim 7 .
16. A method of preventing or treating liver disease in a subject in need thereof, comprising, administering to the subject the lipid nanoparticle of claim 1 in an amount effective to prevent or treat liver disease.
17. A method for delivering a drug to Kupffer cells of a subject in need thereof, comprising:
administering the lipid nanoparticles of claim 7 in an amount effective to deliver the drug to the Kupffer cells.
18. A method for delivering a drug to liver endothelial cells of a subject in need thereof, comprising:
administering the lipid nanoparticles of claim 7 in an amount effective to deliver the drug to the liver endothelial cells.
19. A method for delivering a drug to immune cells of a subject in need thereof, comprising:
administering the lipid nanoparticles of claim 7 in an amount effective to deliver the drug to the liver endothelial cells.