Bioactive agent-loaded targeting micelles
A composition of bioactive agent-loaded micelles with tissue-targeting properties and methods of using the same are disclosed.
1. A composition for targeted delivery of a bioactive agent to diseased tissues of the vasculature, comprising:
a micelle;
a bioactive agent encapsulated within, adhered to a surface of or integrated into the structure of the micelle;
a targeting ligand,
wherein the targeting ligand is a chelating agent that targets the micelle to calcium in the diseased tissue of the vasculature,
wherein the chelating agent is covalently bound to or integrated into the surface of the micelle, and
wherein the chelating agent is selected from the group consisting of ethylenediamine tetraacetic acid, diethylenetriamine pentaacetic acid, N-(2-hydroxyethyl)ethylenedinitrilotriacetic acid, nitrilotriacetic acid, citrate, tetracycline, ethylene diamine disuccinic acid, ethylene diaminebis, O-hydroxyphenyl acetic acid, ethylene diamine-N,N′ diacetic acid, derivatives thereof and combinations thereof; and
a poly(ethylene glycol) group operatively coupled to the surface of the micelle through a cleavable linker.
2. The composition according to claim 1 , wherein the cleavable linker is selected from the group consisting of a photoreactive moiety, an ester, an azo linkage, a hydrazone, an orthoester, a boron complex, an imino carbonate, a Schiff base, a hemi-acetal, an acetal, a ketal, a hemi-ketal, an enzymatically cleavable peptide, an analyte-receptor complex, a group susceptible to oxidative cleavage, or a group susceptible to reductive cleavage.
3. The composition according to claim 2 , wherein the cleavable linker further comprises a hydrophobic lipid anchor.
4. The composition according to claim 3 , wherein the hydrophobic lipid anchor comprises a lysolipid or a di-acyl phospholipid.
5. The composition according to claim 3 , wherein the hydrophobic lipid anchor comprises a biocompatible, biodegradable polymer.
6. The composition according to claim 5 , wherein the biocompatible, biodegradable polymer is selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(L-lactic acid), poly(DL-lactic acid), poly(lactic-co-glycolic acid), poly(butyl acrylate), polycaprolactone and parylene.
7. The composition according to claim 2 , wherein the analyte-receptor complex comprises streptavidin-biotin.
8. The composition according to claim 1 , wherein the cleavable linker comprises a cyclodextrin complex.
9. The composition according to claim 1 , wherein the bioactive agent is selected from the group consisting of an anti-stenosis agent, an antiproliferative agent, an anti-inflammatory agent, an antineoplastic, an antimitotic, an antiplatelet, an anticoagulant, an antifibrin, an antithrombin, a cytostatic agent, an antibiotic, an anti-allergic agent, an anti-enzymatic agent, an angiogenic agent, a cyto-protective agent, a cardioprotective agent, a proliferative agent, an ABC A1 agonist, an antioxidant, a cholesterol-lowering agent, aspirin, an angiotensin-converting enzyme, a beta blocker, a calcium channel blocker, nitroglycerin, a long-acting nitrate, a glycoprotein IIb-IIIa inhibitor and combinations thereof.
10. A method for treating a disease comprising administering a therapeutically effective amount of the composition of claim 1 to a patient in need thereof.
11. The method according to claim 10 , wherein the disease comprises a vascular disease selected from the group consisting of atherosclerosis, stenosis, restenosis and vulnerable plaque.
12. The method according to claim 10 , wherein administering the composition comprises intra-arterial delivery.
13. The method according to claim 12 , wherein intra-arterial delivery comprises percutaneous transluminal coronary arterial delivery.
14. The method according to claim 12 , wherein intra-arterial delivery comprises using a catheter.