Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes.
BACKGROUND
Targeted delivery of thrombolytics to the site of occlusion is an attractive concept, with implications for the treatment of many thrombo-occlusive diseases. Ultrasound enhances thrombolysis, which can be augmented by the addition of a contrast agent. We have previously reported development of echogenic liposomes (ELIP) for targeted highlighting of structures with potential for drug and gene delivery. This study evaluated the potential of ELIP for thrombolytic loading, and the effect of ultrasound exposure of thrombolytic-loaded ELIP on thrombolytic efficacy.


METHODS
Tissue-plasminogen activator (tPA) was loaded into ELIP. Echogenicity was assessed and reported as mean grayscale values. Whole porcine clots were treated with plasma, free tPA, tPA+Optison (echocontrast agent), or tPA-loaded ELIP, with and without ultrasound (1 MHz, continuous wave, 2 W/cm(2), for 2 min). Clots were weighed before and after a 30-min treatment period, and results reported as percent clot mass loss.


RESULTS
tPA entrapment into ELIP was feasible with 50% entrapment, and retention of echogenicity. Treatment with tPA-loaded ELIP resulted in effective clot lysis with an effect similar to treatment with free tPA. Ultrasound exposure of tPA-loaded ELIP resulted in enhanced thrombolysis (49.5% relative improvement vs. no ultrasound). Much of the ultrasound effect appeared to be related to drug release from the tPA-ELIP complex.


CONCLUSIONS
We have demonstrated entrapment of tPA into ELIP with effective clot lysis and drug release using ultrasound. Our tPA-loaded ELIP has potential for specific highlighting of clots to confirm agent delivery and help focus ultrasound therapy for targeted ultrasound-facilitated thrombolysis.
Tiukinhoy-Laing
Susan D
SD
Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, IL, USA. Susan.T.Laing@uth.tmc.edu
Huang
Shaoling
S
Klegerman
Melvin
M
Holland
Christy K
CK
McPherson
David D
DD
D000818:Animals; D003287:Contrast Media; D005240:Feasibility Studies; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008081:Liposomes; D013552:Swine; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use; D014465:Ultrasonics
D003287:Contrast Media; D005343:Fibrinolytic Agents; D008081:Liposomes; D010959:Tissue Plasminogen Activator