scholarly journals Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy

2020 ◽  
Vol 21 (8) ◽  
pp. 2690 ◽  
Author(s):  
Huai-An Chen ◽  
Yunn-Hwa Ma ◽  
Tzu-Yuan Hsu ◽  
Jyh-Ping Chen
Keyword(s):  
Magnetic Nanoparticles ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Glycolic Acid ◽  
Blood Clot ◽  
Recombinant Tissue Plasminogen Activator ◽  
Clot Lysis ◽  
High Dose ◽  
Tissue Plasminogen

Recombinant tissue plasminogen activator (rtPA) is the only thrombolytic agent that has been approved by the FDA for treatment of ischemic stroke. However, a high dose intravenous infusion is required to maintain effective drug concentration, owing to the short half-life of the thrombolytic drug, whereas a momentous limitation is the risk of bleeding. We envision a dual targeted strategy for rtPA delivery will be feasible to minimize the required dose of rtPA for treatment. For this purpose, rtPA and fibrin-avid peptide were co-immobilized to poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (PMNP) to prepare peptide/rtPA conjugated PMNPs (pPMNP-rtPA). During preparation, PMNP was first surface modified with avidin, which could interact with biotin. This is followed by binding PMNP-avidin with biotin-PEG-rtPA (or biotin-PEG-peptide), which was prepared beforehand by binding rtPA (or peptide) to biotin-PEG-maleimide while using click chemistry between maleimide and the single –SH group in rtPA (or peptide). The physicochemical property characterization indicated the successful preparation of the magnetic nanoparticles with full retention of rtPA fibrinolysis activity, while biological response studies underlined the high biocompatibility of all magnetic nanoparticles from cytotoxicity and hemolysis assays in vitro. The magnetic guidance and fibrin binding effects were also confirmed, which led to a higher thrombolysis rate in vitro using PMNP-rtPA or pPMNP-rtPA when compared to free rtPA after static or dynamic incubation with blood clots. Using pressure-dependent clot lysis model in a flow system, dual targeted pPMNP-rtPA could reduce the clot lysis time for reperfusion by 40% when compared to free rtPA at the same drug dosage. From in vivo targeted thrombolysis in a rat embolic model, pPMNP-rtPA was used at 20% of free rtPA dosage to restore the iliac blood flow in vascular thrombus that was created by injecting a blood clot to the hind limb area.

scholarly journals Minimally invasive evacuation of spontaneous intracerebral hemorrhage using sonothrombolysis

2011 ◽  
Vol 115 (3) ◽  
pp. 592-601 ◽  
Author(s):  
David W. Newell ◽  
M. Mohsin Shah ◽  
Robert Wilcox ◽  
Douglas R. Hansmann ◽  
Erik Melnychuk ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Intracerebral Hemorrhage ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Medical Center ◽  
Blood Clot ◽  
Recombinant Tissue Plasminogen Activator ◽  
Mass Effect ◽  
Clot Lysis ◽  
Tissue Plasminogen

Object Catheter-based evacuation is a novel surgical approach for the treatment of brain hemorrhage. The object of this study was to evaluate the safety and efficacy of ultrasound in combination with recombinant tissue plasminogen activator (rt-PA) delivered through a microcatheter directly into spontaneous intraventricular (IVH) or intracerebral (ICH) hemorrhage in humans. Methods Thirty-three patients presenting to the Swedish Medical Center in Seattle, Washington, with ICH and IVH were screened between November 21, 2008, and July 13, 2009, for entry into this study. Entry criteria included the spontaneous onset of intracranial hemorrhage ≥ 25 ml and/or IVH producing ventricular obstruction. Nine patients (6 males and 3 females, with an average age of 63 years [range 38–83 years]) who met the entry criteria consented to participate and were entered into the trial. A ventricular drainage catheter and an ultrasound microcatheter were stereotactically delivered together, directly into the IVH or ICH. Recombinant tissue plasminogen activator and 24 hours of continuous ultrasound were delivered to the clot. Gravity drainage was performed. In patients with IVHs, 3 mg of rt-PA was injected; in patients with intraparenchymal hemorrhages, 0.9 mg of rt-PA was injected. The rt-PA was delivered in 3 doses over 24 hours. Results All patients had significant volume reductions in the treated hemorrhage. The mean percentage volume reduction after 24 hours of therapy, as determined on CT and compared with pretreatment stability scans, was 59 ± 5% (mean ± SEM) for ICH and 45.1 ± 13% for IVH (1 patient with ICH was excluded from analysis because of catheter breakage). There were no intracranial infections and no significant episodes of rebleeding according to clinical or CT assessment. One death occurred by 30 days after admission. Clinical improvements as determined by a decrease in the National Institutes of Health Stroke Scale score were demonstrated at 30 days after treatment in 7 of 9 patients. The rate of hemorrhage lysis was compared between 8 patients who completed treatment, and patient cohorts treated for IVH and ICH using identical doses of rt-PA and catheter drainage but without the ultrasound (courtesy of the MISTIE [Minimally Invasive Surgery plus T-PA for Intracerebral Hemorrhage Evacuation] and CLEAR II [Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage II] studies). Compared with the MISTIE and CLEAR data, the authors observed a faster rate of lysis during treatment for IVH and ICH in the patients treated with sonolysis plus rt-PA versus rt-PA alone. Conclusions Lysis and drainage of spontaneous ICH and IVH with a reduction in mass effect can be accomplished rapidly and safely through sonothrombolysis using stereotactically delivered drainage and ultrasound catheters via a bur hole. A larger clinical trial with catheters specifically designed for brain blood clot removal is warranted.

scholarly journals Preparation of polyethylene glycol-tissue plasminogen activator adducts that retain functional activity: characteristics and behavior in three animal species

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1641-1647 ◽  
Author(s):  
H Jr Berger ◽  
SV Pizzo
Keyword(s):  
Polyethylene Glycol ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Activity ◽  
Recombinant Tissue Plasminogen Activator ◽  
Rat Plasma ◽  
Thrombolytic Activity ◽  
Wide Range ◽  
Tissue Plasminogen

Abstract Conditions were defined for the derivatization of recombinant tissue plasminogen activator (rt-PA) with polyethylene glycol (PEG) so as to retain functional activity as a possible means of producing a t-PA species with a prolonged circulating lifetime. Derivatives with a wide range of retention of activities were prepared by varying the concentration and species of activated PEG. The specific activities of the PEG-rt-PA derivatives were dependent on the method of assay. Assays using preformed fibrin gave higher estimates of retention of activity than assays using soluble components. Plasma elimination studies in mice and rats indicated prolonged circulating lifetimes for the radiolabeled PEG-rt-PA derivatives after a rapid clearance and distribution phase; however, the disappearance of functional activity was much more rapid than the disappearance of radiolabeled material. The PEG-rt-PA derivatives appeared to accumulate in tissues above their interstitial fluid concentrations and were rapidly inactivated, apparently by reaction with the plasma protease inhibitors. These results were consistent with the inactivation of the PEG-rt-PA derivatives in rat plasma in vitro. A somewhat longer half-life (t1/2) of the one derivative studied was observed in dogs (t1/2, 16 minutes) as compared with the rat (t1/2, five minutes). This was sufficient to confer thrombolytic activity upon the derivative (administered by bolus injection) in contrast to native rt-PA. The potential of PEG-modified rt-PA as a long-lived thrombolytic agent in humans will depend, however, on whether there will be a further extension of the t1/2 because of a reduction in clearance and/or a reduction in the rate of inactivation.

The effect of 40 kHz ultrasound on tissue plasminogen activator-induced clot lysis in three in vitro models

2004 ◽  
Vol 30 (11) ◽  
pp. 1545-1552 ◽  
Author(s):  
Marlien Pieters ◽  
Rob T. Hekkenberg ◽  
Marrie Barrett-Bergshoeff ◽  
Dingeman C. Rijken
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
In Vitro Models ◽  
Clot Lysis ◽  
Tissue Plasminogen

scholarly journals Severe SARS-CoV-2 infection inhibits fibrinolysis leading to changes in viscoelastic properties of blood clot: A descriptive study of fibrinolysis

2021 ◽  
Author(s):  
Stefanie Hammer ◽  
Helene Haeberle ◽  
Christian Schlensak ◽  
Michael Bitzer ◽  
Nisar Malek ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Point Of Care ◽  
Blood Clot ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Blood Samples ◽  
Lysis Time ◽  
Tissue Plasminogen ◽  
Pai 1

Background: Accumulating evidence indicates towards an association between SARS-CoV-2 infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis. Objectives: We investigated the hypothesis that the procoagulatory state in COVID-19 patients is caused by impaired fibrinolysis system. Methods: COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in the study. Whole blood samples were investigated by thromboelastography. Additionally, global parameters of coagulation and factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and alpha 2-antiplasmin (A2AP) were determined. Results and conclusion: A significantly increased lysis-resistance and a significantly longer time of lysis after adding tissue plasminogen activator was observed in blood samples from ICU COVID-19 patients compared to controls (maximal lysis: 3.25% ± 0.56 vs. 6.20% ± 0.89, p=0.0127; lysis time: 365.7s ± 44.6 vs. 193.2s ± 16.3, p=0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92U/ml ± 0.91 vs. 1.28U/ml ± 0.33, p=0.001). Interestingly, a positively correlation between the activity of PAI-1 and the lysis time of the formed clot (r=0.7015, p=0.0006) was observed. Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Future clinical studies should address the contribution of the fibrinolysis system to the procoagulatory state in blood of COVID-19 patients and investigate potential therapeutic targets in this system.

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