Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke.
Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.
Asahi
Minoru
M
Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, Program in Neuroscience, Harvard Medical School Charlestown, Charlestown, Massachusetts, U.S.A.
Rammohan
Ram
R
Sumii
Toshihisa
T
Wang
Xiaoying
X
Pauw
Robert Jan
RJ
Weissig
Volkmar
V
Torchilin
Vladimir P
VP
Lo
Eng H
EH
D000199:Actins / Q000276:immunology*; D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020766:Intracranial Embolism / Q000188:drug therapy*; D008081:Liposomes; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
D000199:Actins; D008081:Liposomes; D010959:Tissue Plasminogen Activator