Abstract 17367: Echogenic Liposomes for Clot Imaging and Combined Delivery of Thrombolytic/neuroprotective Agents with Ultrasound-Facilitated Drug Release for Stroke Treatment
Background: Currently, the only FDA-approved therapy for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (tPA). However, the therapeutic application of tPA requires optimization. Combining thrombolytic treatment with administration of neuroprotective agents is a promising strategy under development. We have previously developed tPA-loaded echogenic liposomes (tPA-ELIP) as an improved thrombolytic formulation. We hypothesized that tPA-ELIP can co-encapsulate another agent for combined treatment with the potential for ultrasound-controlled drug release.
MATERIALS AND METHODS: Calcein, a small (MW < 1 kDa) molecular fluorophore, was used as a prototypic hydrophilic drug. Calcein-tPA-ELIP, comprising the fluorophore, protein thrombolytic, phospholipids and cholesterol, were prepared by a lipid drying-rehydration-lyophilization method. Clots were incubated with calcein-tPA-ELIP for 2 minutes in vitro. Transvascular ultrasound imaging was performed before and after the incubation to demonstrate tPA-fibrin binding. Color Doppler ultrasound was applied for 30 seconds to trigger the release of calcein from targeted calcein-tPA ELIP. The fluorescent intensity of calcein in solution was measured before and after ultrasound application.
RESULTS: Fifteen percent of calcein was entrapped in tPA-ELIP with retention of ultrasound reflectivity. Transvascular B-mode ultrasound imaging demonstrated specific highlighting of clots by tPA-ELIP. The release of calcein from calcein-tPA-ELIP was triggered by application of Doppler ultrasound.
CONCLUSIONS: We have demonstrated co-encapsulation of a hydrophilic drug surrogate and a protein thrombolytic agent into ELIP with targeted clot highlighting and in situ ultrasound-triggered drug release. Co-encapsulation of drugs in tPA-ELIP has potential for thrombus-targeted combination thrombolysis and neuroprotective treatment for stroke.
- © 2011 by American Heart Association, Inc.