A Fibrin-Binding Peptide for Targeting Drug-Loaded Liposomes to Atherosclerotic Plaques
Melvin Klegerman
Professor, University of Texas Health Science Center at Houston
The predominant treatment for coronary arterial or peripheral arterial narrowing is introduction of a catheter into the blocked artery to clear the clot and introduce a stent to keep the vessel open, a procedure known as percutaneous intervention (PCI). Often, the atherosclerotic plaque, or atheroma, that caused the clot regrows around the stent, creating another risk for clot formation. Currently, patients are kept on chronic anticoagulant protocols to reduce risk of recurrent thrombosis. We have developed a targeted controlled release nanomedical technology for prevention of neoatherosclerosis in these cases. The approach consists of simultaneous local administration of two ultrasound-sensitive liposomal formulations with external ultrasound application at the time of stent placement. One echogenic liposome (ELIP) is loaded with pioglitazone (PGN), an anti-inflammatory thiazolidinedione drug, and conjugated to a fibrin-binding nonapeptide, GPRPPGGGC (PAFb), through a thioether linkage to a maleimidophenylbutyrate phosphatidylethanolamine (MPB-PE) component of the liposome. The N-terminal pentapeptide is the fibrin-binding sequence, followed by a tri-glycyl spacer and a C-terminal cysteinyl thiol for conjugation. Fibrin is a late-stage atheroma marker. The other liposome is loaded with nitric oxide gas (NO-ELIP) to increase arterial wall permeability so that the atheroma-stabilizing agent can get into all parts of the arterial wall, maximizing product delivery. In an in vivo proof-of-principle procedure, we demonstrated atheroma neointimal and medial localization of fluorophore-labeled PAFb-PGN-ELIP in a Yucatan miniswine atherosclerosis model. Anti-ICAM-1 conjugated PGN-ELIP showing similar atheroma localization demonstrated appreciable inhibition of atheroma progression in the same model. We are now conducting further miniswine experiments to confirm efficacy of the peptide formulation prior to FDA submission for Phase 1 and Phase 2 clinical trials.