Magnetically controlled release of recombinant tissue plasminogen activator from chitosan nanocomposites for targeted thrombolysis

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

doi:10.1039/c5tb02579f

Cited by 34 publications

(32 citation statements)

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“…(e) The inhibition of free rtPA, PMNP-rtPA, and pPMNP-rtPA by plasminogen activator inhibitor-1 (PAI-1) in vitro by measuring the residual amidolytic activity of rtPA after incubating with PAI-I at 37 °C for different times. We further used thromboelastometry to determine blood clots lysis induced by rtPA by measuring the lysis index, which was shown to be dosage-dependent on free rtPA concentration used for the assay, to evaluate the thrombolytic effects [38]. As shown in Figure 3d, there is no significant difference in lysis index among free rtPA, PMN-rtPA and pPMNP rtPA irrespective of assay time (30, 45, 60 and 120 min) at the same rtPA drug dosage, which is in accordance with those from agar plate assays ( Figure 3c).…”

Section: Preparation Of Peptide and Rtpa Conjugated Plga Magnetic Nanmentioning

confidence: 99%

“…We further used thromboelastometry to determine blood clots lysis induced by rtPA by measuring the lysis index, which was shown to be dosage-dependent on free rtPA concentration used for the assay, to evaluate the thrombolytic effects [38]. As shown in Figure 3d, there is no significant difference in lysis index among free rtPA , PMN-rtPA and pPMNP rtPA irrespective of assay time (30, 45, 60 and 120 min.)…”

Section: Characterization Of Physico-chemical Propertiesmentioning

confidence: 99%

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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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Section: Preparation Of Peptide and Rtpa Conjugated Plga Magnetic Nanmentioning

confidence: 99%

Section: Characterization Of Physico-chemical Propertiesmentioning

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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“…Lipid and/or PEGylated nanostructures encapsulating a thrombolytic drug were first reported and showed benefit from increasing the drug half-life [11][12][13][14]. More recently, this strategy was combined with active targeting approaches, mostly based on magnetic guidance [15][16][17][18][19]. Once accumulated on the thrombus, nanocarriers improve thrombolytic efficiency while reducing hemorrhagic complications, in preclinical models of thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

et al. 2018

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Injection of recombinant tissue plasminogen activator (rt-PA) is the standard drug treatment for thrombolysis. However, rt-PA shows risk of hemorrhages and limited efficiency even at high doses. Polysaccharide-poly(isobutylcyanoacrylate) nanoparticles functionalized with fucoidan and loaded with rt-PA were designed to accumulate on the thrombus. Fucoidan has a nanomolar affinity for the P-selectin expressed by activated platelets in the thrombus. Solid spherical fluorescent nanoparticles with a hydrodynamic diameter of 136 ± 4 nm were synthesized by redox radical emulsion polymerization. The clinical rt-PA formulation was successfully loaded by adsorption on aminated nanoparticles and able to be released in vitro. We validated the in vitro fibrinolytic activity and binding under flow to both recombinant P-selectin and activated platelet aggregates. The thrombolysis efficiency was demonstrated in a mouse model of venous thrombosis by monitoring the platelet density with intravital microscopy. This study supports the hypothesis that fucoidan-nanoparticles improve the rt-PA efficiency. This work establishes the proof-of-concept of fucoidan-based carriers for targeted thrombolysis.

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“…This concept has been further adapted by one research group that produced recombinant tissue plasminogen activator (rtPA) encapsulated magnetic chitosan nanoparticles. 82 They found that they could prevent the release of rtPA, a drug that induces thrombolysis, by applying a magnetic field to their nanoparticles in serum. Furthermore, they found that the removal of the magnetic field allowed for the release of the drug.…”

Section: Multimodal Imaging Of Atherosclerosis Using Iron Oxide Nanopmentioning

confidence: 99%

Iron Oxide Nanoparticles as Imaging and Therapeutic Agents for Atherosclerosis

Talev

Kanwar

2020

Semin Thromb Hemost

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Atherosclerosis is the major cause of cardiovascular diseases and is the leading cause of mortality worldwide. Iron oxide nanoparticles have emerged as potential diagnostic and therapeutic agents for a wide range of conditions. To date, the theranostic applications of iron oxide nanoparticles have been studied mainly in cancer, but atherosclerosis has not received the same attention. Therefore, it appears appropriate to review the current and future applications of iron oxide nanoparticles for the diagnosis and therapy of atherosclerosis. This review will first discuss current imaging techniques for the diagnosis of atherosclerosis as well as their limitations. It will then discuss the role of nanotechnology for molecular imaging of atherosclerosis and the benefits of this approach as well as reviewing current developments in the field including single, bi-, and tri-modal imaging. Next, it will discuss the role of nanotechnology for therapies of atherosclerosis with a focus on nanotheranostics, concluding with a look at the challenges faced by nanoparticle-based imaging and therapy of atherosclerosis as well as a look at future prospects.

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Magnetically controlled release of recombinant tissue plasminogen activator from chitosan nanocomposites for targeted thrombolysis

Abstract: Targeted delivery and triggered release of rtPA-encapsulated magnetic chitosan nanoparticles with the guidance of a magnet could be used for remote-controlled thrombolysis therapy.

Cited by 34 publications

References 50 publications

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

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

Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

Iron Oxide Nanoparticles as Imaging and Therapeutic Agents for Atherosclerosis

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