Monocyte-specific aptamers and uses thereof for delivering therapeutic agents to heart
Monocyte-specific nucleic acid aptamers and lipid nanoparticles comprising such for use in drug delivery. Also disclosed herein are use of the aptamer-based lipid nanoparticle drug delivery system for treating heart injury.
1 . A lipid nanoparticle capable of delivering an agent to a heart site, comprising a nucleic acid aptamer, and an agent capable of treating or diagnosing a heart injury, wherein the nucleic acid aptamer is attached to the lipid nanoparticle and the agent is encapsulated by the lipid nanoparticle, and wherein the nucleic acid aptamer comprises a core nucleotide sequence at least 85% identical to 5′-GGA TGG GAG GGA GGG GGC TCG TGG CGG CTA GGG GGT ATA A-3′ (SEQ ID NO:1).
2 . The lipid nanoparticle of claim 1 , wherein the aptamer comprises the core nucleotide set forth by SEQ ID NO:1.
3 . The lipid nanoparticle of claim 1 , wherein the aptamer comprises a 5′ primer site and 3′ primer site flanking the core nucleotide sequence.
4 . The lipid nanoparticle of claim 3 , wherein the 5′ primer site is set forth by the sequence 5′-AC GCT CGG ATG CCA CTA CAG-3′ (SEQ ID NO. 3), and/or wherein the 3′ primer site is set forth by the sequence 5′-CT CAT GGA CGT GCT GGT GAC-3′ (SEQ ID NO. 6).
5 . The lipid nanoparticle of claim 4 , wherein the aptamer is set forth by the sequence 5′-AC GCT CGG ATG CCA CTA CAG GGA TGG GAG GGA GGG GGC TCG TGG CGG CTA GGG GGT ATA ACT CAT GGA CGT GCT GGT GAC-3′ (SEQ ID NO: 2).
6 . The lipid nanoparticle of any one of claims 1-5 , wherein the aptamer is conjugated to an anchor nucleic acid fragment.
7 . The lipid nanoparticle of claim 6 , wherein the anchor nucleic acid fragment is set forth by the sequence 5′-CAA TAG AGT CGT ACA GGT CG-3′ (SEQ ID NO: 7), which optionally is located at the 5′ end of the aptamer.
8 . The lipid nanoparticle of claim 7 , wherein the lipid nanoparticle is conjugated to a docking nucleic acid fragment comprising a nucleotide sequence complementary to the anchor nucleic acid fragment wherein the anchor nucleic acid fragment forms base pairs with the docking nucleic acid fragment, thereby immobilizing the aptamer on the lipid nanoparticle.
9 . The lipid nanoparticle of claim 8 , wherein the lipid nanoparticle further comprises a PEGylated lipid, wherein the docking a nucleic acid fragment is attached to the lipid nanoparticle via the polyethylene glycol (PEG) moiety of the PEGylated lipid.
10 . The lipid nanoparticle of claim 9 , wherein the pegylated lipid is 1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE).
11 . The lipid nanoparticle of claim 1 , wherein the heart injury is ischemia reperfusion injury.
12 . The lipid nanoparticle of claim 1 , wherein the agent is a HIF-1 α prolyl hydroxylase-2 (PHD2) inhibitor.
13 . The lipid nanoparticle of claim 12 , wherein the PHD2 inhibitor is IOX2, MK-8617, 2-methoxyestradiol, AKB-4924, IOX3 (FG-2216), FG-4497, roxadustat (FG-4592) Vadadustat (AKB-6548), Daprodustat (GSK1278863), Desidustat (ZYAN-1), Molidustat (Bay 85-3934) IOX4, Enarodustat (JTZ-951)), or a combination thereof.
14 . The lipid nanoparticle of claim 1 , wherein the agent is the agent capable of diagnosing the heart injury.
15 . A pharmaceutical composition, comprising the lipid nanoparticle of claim 1 and a pharmaceutically acceptable carrier.
16 . A method for delivering a therapeutic or diagnostic agent to an injured heart site, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 15 .
17 . The method of claim 16 , wherein the subject is a human patient having or at risk for developing heart ischemia reperfusion injury.