Magnetically targeted thrombolysis with recombinant tissue plasminogen activator bound to polyacrylic acid-coated nanoparticles

Ma, Yunn‐Hwa; Wu, Shih-Chung; Wu, Tony; Chang, Yeu-Jhy; Hua, Mu-Yi; Chen, Jyh‐Ping

doi:10.1016/j.biomaterials.2009.02.034

Cited by 166 publications

(133 citation statements)

References 39 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…SPIO proved effective both as an image indicator (to identify distribution of chemotherapeutic drugs after BBB disruption) and as a means of increasing treatment efficacy when used in conjunction with magnetic targeting. Similar approaches have potential thrombolytic applications: One recent study used magnetic targeting of recombinant tissue plasminogen activator agents conjugated to SPIO nanoparticles to strengthen the thrombolytic efficacy of the drugs (36).…”

Section: Discussionmentioning

confidence: 99%

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

Liu

Chen

Yang

et al. 2011

Magnetic Resonance Imaging

Self Cite

View full text Add to dashboard Cite

Purpose: To verify that low-frequency planar ultrasound can be used to disrupt the BBB in large animals, and the usefulness of MRI to quantitatively monitor the delivery of superparamagnetic iron oxide (SPIO) nanoparticles into the disrupted regions.Materials and Methods: Two groups of swine subjected to craniotomy were sonicated with burst lengths of 30 or 100 ms, and one group of experiment was also performed to confirm the ability of 28-kHz sonication to open the BBB transcranially. SPIO nanoparticles were administered to the animals after BBB disruption. Procedures were monitored by MRI; SPIO concentrations were estimated by relaxivity mapping.Results: Sonication for 30 ms created shallow disruptions near the probe tip; 100-ms sonications after craniotomy can create larger and more penetrating openings, increasing SPIO leakage $3.6-fold than 30-ms sonications. However, this was accompanied by off-target effects possibly caused by ultrasonic wave reflection. SPIO concentrations estimated from transverse relaxation rate maps correlated well with direct measurements of SPIO concentration by optical emission spectrometry. We have also shown that transcranial low-frequency 28-kHz sonication can induce secure BBB opening from longitudinal MR image follow up to 7 days. Conclusion:This study provides valuable information regarding the use low-frequency ultrasound for BBB disruption and suggest that SPIO nanoparticles has the potential to serve as a thernostic agent in MRI-guided ultrasound-enhanced brain drug delivery.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

Liu

Chen

Yang

et al. 2011

Magnetic Resonance Imaging

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously, tPA was immobilized to polyacrylic acid-coated MNP by using carbodiimide-mediated amide bond formation between carboxylic acid groups of polyacrylic acid and amine groups of tPA. 31 For amine-derived SiO 2 -MNP, imide bond formation between tPA and SiO 2 -MNP could be achieved with GA or genipin. Although genipin may be preferable to reduce the associated toxicity of GA, it may not equate to GA's ability to immobilize and promote the formation of imide bonds between the aldehyde groups of GA and amine groups of SiO 2 -MNP or tPA.…”

Section: Preparation and Properties Of Tpa Immobilized To Silica-coatmentioning

confidence: 99%

“…28 It will therefore be highly desirable to deliver tPA under guidance for targeted thrombolysis, which will allow tPA to be localized to the target site and reduce its hemorrhagic side effects. [29][30][31] Target delivery of tPA using MNP as a drug carrier could meet this need by retaining the drug under magnetic guidance. 32 Thus, delivery of tPA by binding the thrombolytic drug to SiO 2 -MNP will ensure that the drug is delivered under magnetic guidance and retained in a local area in circulation, which is potentially useful for targeting fibrin clot in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Yang²,

Ma³

et al. 2012

IJN

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…New drug-delivery systems have been developed to reduce the side effects of fibrinolytic agents and enhance their stability during storage and in blood circulation. Such systems may utilize liposomes, 7 polymeric nanoparticles, 8 or magnetic carriers [9][10][11][12] for delivery of fibrinolytic drugs to increase the efficiency of thrombolytic therapy.…”

Section: Introductionmentioning

confidence: 99%

“…The polymer shell may provide high-capacity functionalized surfaces that are capable of binding enzymes, 13 inhibiting aggregation, and increasing the stability of drugs. 14,15 MNCs can also be used for various biomedical applications, such as contrastenhancing agents for magnetic resonance imaging, 16,17 magnetically guided drug targeting, 9,18 enhancing enzyme stability for repeated use, 13,19,20 and magnetic diagnosis. 21 MNCs also exhibit high drug-loading capacity and good stability in aqueous solutions as well as excellent biocompatibility with cells and tissues when used for drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Bioconjugation of recombinant tissue plasminogen activator to magnetic nanocarriers for targeted thrombolysis

Ma¹,

Yang²,

Hua³

et al. 2012

IJN

Self Cite

View full text Add to dashboard Cite

Low-toxicity magnetic nanocarriers (MNCs) composed of a shell of poly [aniline-co-N-(1-one-butyric acid) aniline] over a Fe 3 O 4 magnetic nanoparticle core were developed to carry recombinant tissue plasminogen activator (rtPA) in MNC-rtPA for targeted thrombolysis.With an average diameter of 14.8 nm, the MNCs exerted superparamagnetic properties. Up to 276 µg of active rtPA was immobilized per mg of MNCs, and the stability of the immobilized rtPA was greatly improved during storage at 4°C and 25°C. In vitro thrombolysis testing with a tubing system demonstrated that magnet-guided MNC-rtPA showed significantly improved thrombolysis compared with free rtPA and reduced the clot lysis time from 39.2 ± 3.2 minutes to 10.8 ± 4.2 minutes. In addition, magnet-guided MNC-rtPA at 20% of the regular rtPA dose restored blood flow within 15-25 minutes of treatment in a rat embolism model without triggering hematological toxicity. In conclusion, this improved system is based on magnetic targeting accelerated thrombolysis and is potentially amenable to therapeutic applications in thromboembolic diseases.

show abstract

Magnetically targeted thrombolysis with recombinant tissue plasminogen activator bound to polyacrylic acid-coated nanoparticles

Cited by 166 publications

References 39 publications

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

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

Bioconjugation of recombinant tissue plasminogen activator to magnetic nanocarriers for targeted thrombolysis

Contact Info

Product

Resources

About