Targeted Delivery and Controlled Release of Thrombolytic Drug Using Magnetic Liposomes

Thrombolytic drugs (plasminogen activators) play a critical role in the treatment of various cardiovascular diseases including acute myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis and peripheral vascular thromboembolism. However, thrombolytic agents, such as tissue plasminogen activator (tPA), tend to dissolve both pathological thrombi and fibrin deposit at sites of vascular injury, resulting in hemorrhagic toxicity at therapeutic doses. Plasminogen activators are short half-life and immunogenicity because of their foreign nature. By encapsulating proteins within novel carrier systems, an increased half-life and decreased immunogenicity might be obtained. Further, targeted delivery of thrombolytic agents may reduce the risks of haemorrhage and toxicity associated with systemic administration, thus offering a promising, minimally invasive approach that could control and treat the thrombosis. We will propose a more efficient tPA drug delivery system using PEGylated magnetic liposome modified with targeting moiety (peptide) for dual targeted delivery of thrombolytic agents to the site of thrombus followed by ultrasound-triggered controlled drug release. Site selective delivery of thrombolytic drugs will be achieved by peptide ligands showing targeting specificity to activated platelets and fibrin in thrombus. We have synthesized polymer-coated magnetic nanoparticles to covalently conjugate tPA. The magnetic targeting and therapeutic efficacy examined in a rat hind limb ischemia model by intra-arterial administration of MNP-tPA to left iliac artery indicated the magnetically targeted MNP-tPA achieve reproducible and effective target thrombolysis with ＜20% of a regular dose of tPA. To further improve our tPA delivery strategy, we herewith propose to use dual targeting long-circulating liposomal drug formulation. PEGylation of liposome will render intravenous administration of tPA possible. The nanoscale thrombolytic agent will be guided by an external magnetic field to the thrombus location, followed by targeting to activated platelets and/or fibrin in the thrombus to improve the therapeutic efficacy of the drug. Ultrasound will be applied to release the drug in the vicinity of thrombus at a desirable therapeutic concentration. The combined effect of magnetic- and ligand-targeting drug delivery and ultrasound-based controlled release will be expected to offer better and instant drug action and increase half-life and decrease immunogenicity of tPA while reduce side effect such as significant risk of intracranial hemorrhage. By addressing critical issues of circulating time, targeted magnetic guidance and specific ligand affinity, and controlled release, an effective drug delivery system for the management of thrombosis can be successfully achieved.

Project ID:PB10207-1922
External Project ID:NSC102-2221-E182-046