Blood Clearance and Activity of Erythrocyte-Coupled Fibrinolytics

Ganguly, Kumkum; Krasik, Tatiana; Medinilla, Sandra; Bdeir, Khalil; Cines, Douglas B.; Muzykantov, Vladimir R.; Murciano, Juan-Carlos

doi:10.1124/jpet.104.075770

Cited by 71 publications

(92 citation statements)

References 34 publications

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“…Results of previous studies have shown that coupling tPA to RBCs increased its intravascular life span compared with soluble tPA. 51 One possible explanation for this surprising result is that coupling to RBCs renders tPA less susceptible to plasma tPA inhibitors, 52 including the most physiologically relevant plasminogen activator inhibitor 1 (PAI-1). Further studies affirm the greater fibrinolytic potency of bound tPA compared with soluble tPA in mouse blood, and indicate that coupling to RBCs protects tPA against physiological and pathological concentrations of PAI-1, 53 and inhibition by other serpins (α 2 -macroglobulin and α 1 -antitrypsin).…”

Section: Activity Retention (%)mentioning

confidence: 99%

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Chen¹,

Yang²,

Ma³

et al. 2012

IJN

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Background and methods: Silica-coated magnetic nanoparticle (SiO 2 -MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO 2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO 2 surface, which provides abundant -NH 2 functional groups for conjugating with tPA. Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO 2 -MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO 2 -MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO 2 -MNP (SiO 2 -MNP-tPA) did not alter blood component concentrations. After conjugating to SiO 2 -MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO 2 -MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO 2 -MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis. Conclusion: Biocompatible SiO 2 -MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.

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Section: Activity Retention (%)mentioning

confidence: 99%

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Chen¹,

Yang²,

Ma³

et al. 2012

IJN

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“…Previous in vivo studies show that RBC carriage overrides differences in pharmacokinetics among soluble PAs (Ganguly et al, 2005). Thus, soluble tPA is cleared from the blood more rapidly than rPA (Retavase), a truncated tPA variant lacking the growth factor (G), finger (F), and first kringle (K1) domains (Kohnert et al, 1992).…”

mentioning

confidence: 99%

“…Thus, soluble tPA is cleared from the blood more rapidly than rPA (Retavase), a truncated tPA variant lacking the growth factor (G), finger (F), and first kringle (K1) domains (Kohnert et al, 1992). Yet, both RBC/tPA and RBC/rPA circulate for at least many hours in animals (Murciano et al, 2003;Ganguly et al, 2005). Previous studies also revealed that coupling to RBCs attenuates tPA inhibition by PAI-1 (Ganguly et al, 2005).…”

mentioning

confidence: 99%

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Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo

Ganguly

Goel²,

Krasik³

et al. 2005

J Pharmacol Exp Ther

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Plasminogen activators (PAs; e.g., tissue-type, tPA) coupled to red blood cells (RBCs) display in vivo features useful for thromboprophylaxis: prolonged circulation, minimal extravasation, and preferential lysis of nascent versus preexisting clots. Yet, factors controlling the activity of RBC-bound PAs in vivo are not defined and may not mirror the profile of soluble PAs. We tested the role of RBC/PA binding to fibrin in fibrinolysis. RBC/ tPA and RBC/tPA variant with low fibrin affinity (rPA) bound to and lysed plasminogen-containing fibrin clots in vitro comparably. In contrast, when coinjected in mice with fibrin emboli lodging in pulmonary vasculature, only RBC/tPA accumulated in lungs, which resulted in a more extensive fibrinolysis versus RBC/rPA (p Ͻ 0.01). Reconciling this apparent divergence between in vitro and in vivo behaviors, RBC/tPA, but not RBC/rPA perfused over fibrin in vitro at physiological shear stress bound to fibrin clots and caused greater fibrinolysis versus RBC/rPA (p Ͻ 0.001). These results indicate that because of high fibrin affinity, RBC/tPA binding to clots endures hemodynamic stress, which enhances fibrinolysis. Behavior of RBC/PAs under hemodynamic pressure is an important predictor of their performance in vivo.

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“…Reteplase (Retavase, PDL BioPharma) is a nonglycosylated recombinant plasminogen activator variant derived from human tissue-type plasminogen activator and having a 4-fold longer half-life than tPA, permitting bolus injection. 14,15 It is cleared from the plasma in a biphasic manner, with a half-life of about 1 minute in the ␣-phase (28% cleared) and 20 to 28 minutes in the ␤-phase (72% cleared). 16 The findings of the present study show that the addition of albumin to subthrombolytic doses of reteplase results in a robust improvement of microvascular hemodynamics distal to an arteriolar thrombosis.…”

mentioning

confidence: 99%

Albumin Therapy Augments the Effect of Thrombolysis on Local Vascular Dynamics in a Rat Model of Arteriolar Thrombosis

Park

Nimmagadda

DeFazio

et al. 2008

Stroke

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Background and Purpose-Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis. Methods-We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30-to 50-m cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control. Results-Baseline arteriolar flow velocity averaged 3.8Ϯ0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (Pϭnonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (Pϭ0.013 versus reteplaseϩsaline), which remained significantly higher than the reteplaseϩsaline group at multiple time-points over the subsequent hour. Conclusions-The

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Blood Clearance and Activity of Erythrocyte-Coupled Fibrinolytics

Cited by 71 publications

References 34 publications

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo

Albumin Therapy Augments the Effect of Thrombolysis on Local Vascular Dynamics in a Rat Model of Arteriolar Thrombosis

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