In vitro thrombolytic efficacy of echogenic liposomes loaded with tissue plasminogen activator and octafluoropropane gas

被引:29
作者
Shekhar, Himanshu [1 ]
Bader, Kenneth B. [1 ]
Huang, Shenwen [2 ]
Peng, Tao [3 ]
Huang, Shaoling [3 ]
McPherson, David D. [3 ]
Holland, Christy K. [1 ,2 ]
机构
[1] Univ Cincinnati, Dept Internal Med, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA
[2] Univ Cincinnati, Biomed Engn Program, Cincinnati, OH USA
[3] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Cardiovasc Med, Houston, TX 77030 USA
关键词
sonothrombolysis; ultrasound-enhanced drug delivery; echogenic liposomes; ischemic stroke; cavitation; ULTRASOUND-ENHANCED THROMBOLYSIS; ACUTE ISCHEMIC-STROKE; CAVITATION; THERAPY; SAFETY; PILOT; CARE; MICROBUBBLES; MECHANISMS; THROMBOSIS;
D O I
10.1088/1361-6560/62/2/517
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Echogenic liposomes loaded with the thrombolytic recombinant tissue-type plasminogen activator (rt-PA) are under development for the treatment of ischemic stroke. These agents are designed to co-encapsulate cavitation nuclei to promote bubble activity in response to ultrasound exposure, and to enable localized delivery of thrombolytic. Stable cavitation improves the efficacy of the thrombolytic through enhanced fluid mixing. Echogenic liposomes that encapsulate air-filled microbubbles nucleate scant stable cavitation activity in response to 120 kHz intermittent ultrasound exposure, and have demonstrated thrombolytic efficacy equivalent to rt-PA alone. It was hypothesized that encapsulating octafluoropropane (OFP) gas within rt-PA-loaded liposomes instead of air will enhance ultrasound-mediated stable cavitation activity and increase thrombolytic efficacy compared to previous studies. The thrombolytic efficacy and cavitation activity nucleated from liposomes that encapsulate OFP microbubbles and rt-PA (OFP t-ELIP) was evaluated in vitro. Human whole blood clots were exposed to human fresh-frozen plasma alone, rt-PA (0, 0.32, 1.58, and 3.15 mu g ml(-1)), or OFP t-ELIP at equivalent enzymatic activity, with and without exposure to intermittent ultrasound. Further, numerical simulations were performed to gain insight into the mechanisms of cavitation nucleation. Sustained ultraharmonic activity was nucleated from OFP t-ELIP when exposed to ultrasound. Furthermore, the thrombolytic efficacy was enhanced compared to rt-PA alone at concentrations of 1.58 mu g ml(-1) and 3.15 mu g ml(-1) (p < 0.05). These results indicate that OFP t-ELIP can nucleate sustained stable cavitation activity and enhance the efficacy of thrombolysis.
引用
收藏
页码:517 / 538
页数:22
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