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Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors.

ABSTRACT: Dose control and effectiveness promotion of tissue plasminogen activator (t-PA) for thrombolysis are vitally important to alleviate serious side effects such as hemorrhage in stroke treatments. In order to increase the effectiveness and reduce the risk of stroke treatment, we use rotating magnetic nanomotors to enhance the mass transport of t-PA molecules at the blood clot interface for local ischemic stroke therapy. The in vitro experiments demonstrate that, when combined with magnetically activated nanomotors, the thrombolysis speed of low-concentration t-PA (50 ?g mL(-1)) can be enhanced up to 2-fold, to the maximum lysis speed at high t-PA concentration. Based on the convection enhanced transport theory due to rotating magnetic nanomotors, a theoretical model is proposed and predicts the experimental results reasonably well. The validity and efficiency of this enhanced treatment has been demonstrated in a rat embolic model.

SUBMITTER: Cheng R

PROVIDER: S-EPMC4148143 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors.

Cheng Rui R Huang Weijie W Huang Lijie L Yang Bo B Mao Leidong L Jin Kunlin K ZhuGe Qichuan Q Zhao Yiping Y

ACS nano 20140715 8

Dose control and effectiveness promotion of tissue plasminogen activator (t-PA) for thrombolysis are vitally important to alleviate serious side effects such as hemorrhage in stroke treatments. In order to increase the effectiveness and reduce the risk of stroke treatment, we use rotating magnetic nanomotors to enhance the mass transport of t-PA molecules at the blood clot interface for local ischemic stroke therapy. The in vitro experiments demonstrate that, when combined with magnetically acti ...[more]

PMID: 25006696

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Project description:Background and Purpose- Stroke is a leading cause of disability worldwide, mainly affecting the elderly. However, preclinical studies in aged ischemic animals are limited. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a naturally occurring tetrapeptide with vascular-protective properties. The present study investigated the effect of AcSDKP on tPA (tissue-type plasminogen activator)-induced thrombolysis in aged rats after ischemic stroke. Methods- Aged male rats (18 months) were subjected to embolic middle cerebral artery occlusion. Rats subjected to 4 hours of middle cerebral artery occlusion were randomized into the following groups: (1) AcSDKP; (2) tPA; (3) AcSDKP in combination with tPA; and (4) saline. Neurological deficits, cerebral microvascular patency and integrity, and infarction were examined at 1 day and 7 days after middle cerebral artery occlusion. In vitro experiments were performed to examine the effect of AcSDKP on aged cerebral endothelial cell permeability. Results- Compared with saline, AcSDKP, or tPA as monotherapy did not have any therapeutic effects, whereas AcSDKP in combination with tPA significantly reduced cerebral tissue infarction and improved neurological outcome without increasing cerebral hemorrhage. Concurrently, the combination treatment significantly augmented microvascular perfusion and reduced thrombosis and blood-brain barrier leakage. In vitro, compared with cerebral endothelial cells from ischemic adult rats, the endothelial cells from ischemic aged rats exhibited significantly increased leakage. AcSDKP suppressed tPA-induced aged endothelial cell leakage and reduced expression of ICAM-1 (intercellular adhesion molecule 1) and NF (nuclear factor)-κB. Conclusions- The present study provides evidence for the therapeutic efficacy of AcSDKP in combination tPA for the treatment of embolic stroke in aged rats at 4 hours after stroke onset. AcSDKP likely acts on cerebral endothelial cells to enhance the benefits of tPA by increasing tissue perfusion and augmenting the integrity of the blood-brain barrier. Visual Overview- An online visual overview is available for this article.

Project description:ObjectivesThe benefit of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for very old patients with acute ischemic stroke remains unclear. The aim of this study was to elucidate the efficacy and safety of intravenous rt-PA therapy for patients over 80 years old.MethodsOf 13,521 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 1999 to February 2013, 953 ischemic stroke patients who were over 80 years old, hospitalized within 3 h of onset, and not treated with endovascular therapy were included in this study. Among them, 153 patients were treated with intravenous rt-PA (0.6 mg/kg). For propensity score (PS)-matched case-control analysis, 148 patients treated with rt-PA and 148 PS-matched patients without rt-PA therapy were selected by 1:1 matching with propensity for using rt-PA. Clinical outcomes were neurological improvement, good functional outcome at discharge, in-hospital mortality, and hemorrhagic complications (any intracranial hemorrhage [ICH], symptomatic ICH, and gastrointestinal bleeding).ResultsIn the full cohort of 953 patients, rt-PA use was associated positively with neurological improvement and good functional outcome, and negatively with in-hospital mortality after adjustment for multiple confounding factors. In PS-matched case-control analysis, patients treated with rt-PA were still at lower risk for unfavorable clinical outcomes than non-treated patients (neurological improvement, odds ratio 2.67, 95% confidence interval 1.61-4.40; good functional outcome, odds ratio 2.23, 95% confidence interval 1.16-4.29; in-hospital mortality, odds ratio 0.30, 95% confidence interval 0.13-0.65). There was no significant association between rt-PA use and risk of hemorrhagic complications in the full and PS-matched cohorts.ConclusionsIntravenous rt-PA therapy was associated with improved clinical outcomes without significant increase in risk of hemorrhagic complications in very old patients (aged>80 years) with acute ischemic stroke.

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Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors.

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Acceleration of tissue plasminogen activator-mediated thrombolysis by magnetically powered nanomotors.

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