Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation

Liu, Chih-Hsin; Hsu, Heng-Jung; Chen, Jyh‐Ping; Wu, Tony; Ma, Yunn‐Hwa

doi:10.1016/j.nano.2019.03.014

Cited by 35 publications

(28 citation statements)

References 35 publications

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“…For instance, echogenic liposomes was prepared by incorporating gas bubbles and rtPA in the aqueous compartment of the lipid-bilayer structure of liposomes, allowing rtPA release controlled by ultrasound [10]. By incorporating MNPs and rtPA into thermal sensitive liposomes, the magnetoliposomes can be magnetically guided in vivo with rtPA release controlled by elevated temperature at the target site [11].…”

Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

“…Activity of immobilized PAs may be compromised due to steric hindrance; whereas for protected PAs, the local concentration at the target is greatly dependent on the release kinetics or the strategy of controlled release. There have been liposomal preparations [11,16,17,18,19,20] and polymeric nanocomposite [21,22] developed and achieved target thrombolysis in vivo , as shown in Figure 2. The protection may extend its half-life [20], allowing PAs to be administered from a remote site in circulation such as vein [11,16,17,18].…”

Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

“…One useful strategy is to use targeting ligand that allows presumably better association of the liposome with fibrin [16] or activated platelets [17,20] in the thrombus, resulting in higher PA concentration at the target for longer time. In the case of thermosensitive magnetoliposome encapsulating rtPA, focal hyperthermia may induce release of rtPA at the site of thrombus and induce restore of blood flow [11]; whereas ultrasound may trigger release of rtPA from an echogenic liposome preparation to enhance thrombolysis [19]. Pawlowski et al designed liposomal nanocomposites that respond to secreted phospholipase A2 from activated platelets and unload the encapsulated PA; such nanocomposites allows release of the thrombolytic drug without additional intervention after reaching the target site [23].…”

Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

“…Activity retention after immobilization can be defined as the percentage of activity of immobilized PA compared with that of PA added initially. This method is simple with good reproducibility, and thus often used in optimization of the nanocomposites during preparation [11,12,14,21,22,26,30,34]. However, plasminogen is a much bigger molecule in structure, and therefore, interaction of plasminogen and PAs may not be as free as the small substrate.…”

Section: Assessment Of In Vitro Thrombolysismentioning

confidence: 99%

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Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation

Liu

Liang

et al. 2019

Molecules

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In thrombolytic therapy, plasminogen activators (PAs) are still the only group of drug approved to induce thrombolysis, and therefore, critical for treatment of arterial thromboembolism, such as stroke, in the acute phase. Functionalized nanocomposites have attracted great attention in achieving target thrombolysis due to favorable characteristics associated with the size, surface properties and targeting effects. Many PA-conjugated nanocomposites have been prepared and characterized, and some of them has been demonstrated with therapeutic efficacy in animal models. To facilitate future translation, this paper reviews recent progress of this area, especially focus on how to achieve reproducible thrombolysis efficacy in vivo.

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Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

Section: Design and Preparation Of Rtpa Nanocompositesmentioning

confidence: 99%

Section: Assessment Of In Vitro Thrombolysismentioning

confidence: 99%

See 2 more Smart Citations

Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation

Liu

Liang

et al. 2019

Molecules

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“…We have extensively studied different MNP-based polymeric nano-carrier for magnetically targeted delivery of rtPA, being prepared either by immobilization of rtPA on the particle surface or by encapsulation within the polymeric matrix, and demonstrated the improved thrombolytic efficacy both in vitro and in vivo [13][14][15]. Recently, we also pioneered the use of thermosensitive magnetic liposomes for targeted delivery and temperature-sensitive release of rtPA [16,17]. Other groups used different ligands for targeting fibrin in a blood clot or different moieties that are associated with the blood clot.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Hsu

et al. 2020

IJMS

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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.

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Smart Delivery of Plasminogen Activators for Efficient Thrombolysis; Recent Trends and Future Perspectives

Refaat

Rosal

Palasubramaniam

et al. 2021

Advanced Therapeutics

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Fibrinolytic drugs have been successfully used to manage acute thrombotic and thromboembolic conditions. However, their narrow administration time window, rapid clearance, and possible inactivation limit their efficient and wider application. Most importantly, they present a substantial risk of fatal bleeding complications, which are a major cause of mortality and morbidity. Improving the therapeutic outcomes of pharmacological thrombolysis, including alleviating associated side effects, is an urgent challenge. In this context, nano‐drug delivery systems have attracted major interest. State‐of‐the‐art nanodelivery systems have achieved reduced immunogenicity and a significant prolongation of the biological half‐life of drugs, the latter allowing their application as boli instead of infusions. Recent research focuses on theranostic systems capable of image‐guided thrombolysis, clot targeting strategies, and stimuli‐responsive systems. The latter are designed so that an external or internal stimulus triggers the drug release, offering unique spatiotemporal control over the treatment and potentially minimizing side effects. In this review, the authors discuss the different nanodelivery platforms and focus on stimuli‐responsive systems, highlighting their therapeutic advantages and the challenges for their clinical translation.

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Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation

Cited by 35 publications

References 35 publications

Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation

Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation

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

Smart Delivery of Plasminogen Activators for Efficient Thrombolysis; Recent Trends and Future Perspectives

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