Liposomal nanocarriers for plasminogen activators

Koudelka, Štěpán; Mikulík, Robert; Mašek, Josef; Raška, Milan; Knotigová, Pavlína Turánek; Miller, Andrew D.; Tuřánek, Jaroslav

doi:10.1016/j.jconrel.2016.02.019

Cited by 61 publications

(41 citation statements)

References 100 publications

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“…Further modification by including an extrusion method might allow us to improve the encapsulation ratio of OFP-tELIP. Recently, Koudelka et al (2016) used an extrusion step before lyophilization and obtained a rt-PA encapsulation ratio of 18%. Our group has also recently reported that monodisperse (5 μ m diameter) octaflurocyclobutane and rt-PA-loaded liposomes ( μ t-ELIP) can be manufactured using a microfluidic device (Kandadai et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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 μg 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 μg ml−1 and 3.15 μg ml−1 (p< 0.05). These results indicate that OFP t-ELIP can nucleate sustained stable cavitation activity and enhance the efficacy of thrombolysis.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…However, it was proved that the lipid environment showed no effects on the binding of tPA to fibrin 26 . Nevertheless, we should avoid utilizing negatively charged components (such as sulphatide or phosphatidylserine) to formulate liposomal tPA, because these components were proved to impair the activation of plasminogen by tPA 27 . In addition, high intensive sonication and organic solvents should also be avoided to alleviate the degradation and loss of activity of tPA during preparation of liposomal tPA.…”

Section: Nanocarriers For Tpamentioning

confidence: 99%

“…Moreover, when preparing liposomal tPA via lipid film hydration method, pH and ionic strength can also influence the loading efficiency of liposomal tPA. Because the conformation of tPA may be altered at certain pH and by high ionic strength, moreover, high ionic strength may promote non-specific tPA/liposome interactions, thus impeding the efficient encapsulation of tPA 27 . Freeze-thawing can promote tPA encapsulation after hydration.…”

Section: Nanocarriers For Tpamentioning

confidence: 99%

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

Liu

Feng

Jin

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA. Areas covered We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed. Expert opinion Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.

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“…Furthermore, the liposomal encapsulated plasminogen activators may be targeted to the sites of thrombi via the intravenous route preventing their degradation by plasma components due to their limited exposure. 184 The liposomally entrapped streptokinase when used in a rabbit model of thrombolysis showed a 47.4 C/¡ 1.4% of clot lysis against 36.3 C/¡ 3.4% for free streptokinase. The streptokinase immunized rabbits containing anti-SK antibodies also showed a slightly reduced thrombolytic activity of 33.8 § 1.5%.…”

Section: Liposome-based Plasminogen Activatorsmentioning

confidence: 94%

The evolution of recombinant thrombolytics: Current status and future directions

Adivitiya

Khasa

2016

Bioengineered

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Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

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Liposomal nanocarriers for plasminogen activators

Cited by 61 publications

References 100 publications

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

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

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

The evolution of recombinant thrombolytics: Current status and future directions

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