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Magnetic Nanoparticles and Neurotoxins for Treating Atrial Fibrillation

2010; Lippincott Williams & Wilkins; Volume: 122; Issue: 25 Linguagem: Inglês

10.1161/circulationaha.110.000166

1524-4539

Dara L. Kraitchman, Jeff W. M. Bulte,

Cardiac electrophysiology and arrhythmias

HomeCirculationVol. 122, No. 25Magnetic Nanoparticles and Neurotoxins for Treating Atrial Fibrillation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMagnetic Nanoparticles and Neurotoxins for Treating Atrial FibrillationA New Way to Get Burned? Dara L. Kraitchman, VMD, PhD, FACC and Jeff W.M. Bulte, PhD Dara L. KraitchmanDara L. Kraitchman From the Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research (D.L.K., J.W.M.B.), Department of Molecular and Comparative Pathobiology (D.L.K.), Institute for NanoBioTechnology (D.L.K., J.W.M.B.), Department of Biomedical Engineering (D.L.K., J.W.M.B.), Department of Chemical & Biomolecular Engineering (J.W.M.B.), Cellular Imaging Section, Institute for Cellular Engineering (J.W.M.B.), Johns Hopkins University School of Medicine, Baltimore, MD. and Jeff W.M. BulteJeff W.M. Bulte From the Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research (D.L.K., J.W.M.B.), Department of Molecular and Comparative Pathobiology (D.L.K.), Institute for NanoBioTechnology (D.L.K., J.W.M.B.), Department of Biomedical Engineering (D.L.K., J.W.M.B.), Department of Chemical & Biomolecular Engineering (J.W.M.B.), Cellular Imaging Section, Institute for Cellular Engineering (J.W.M.B.), Johns Hopkins University School of Medicine, Baltimore, MD. Originally published6 Dec 2010https://doi.org/10.1161/CIRCULATIONAHA.110.000166Circulation. 2010;122:2642–2644Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2010: Previous Version 1 Atrial fibrillation (AF) is the most common cardiac dysrhythmia,1with over 2.6 million Americans affected. Partly due to the high risk of stroke in these patients, AF is associated with significant morbidity and mortality.2 The number of individuals affected with AF is expected to rise ≈6-fold over the next 40 years. Catheter-based ablation may offer a more effective means of treating AF than conventional medical therapy.3–5 Ablation techniques have been adopted after limited clinical trials with a relatively small number of patients.4–7 In an effort to guide the best treatment strategies, a registry has been established to follow the increasing numbers of AF patients who are being treated with ablation.8 Although the generally accepted initial ablation strategy is isolation of the pulmonary veins, which are often the source of ectopic beats that initiate AF, animal models have shown that the cardiac ganglionated plexi play a role in inducing and maintaining AF.9 Initial clinical studies indicate that ablation of the ganglionated plexi, in addition to pulmonary vein isolation, may improve ablation outcome.10 Indeed, fortuitous ablation of the ganglionated plexi during pulmonary vein isolation may contribute to procedure success. However, targeting the ganglionated plexi for selective ablation requires their localization, presently achieved by additional mapping to detect sites where high-frequency stimulation elicits heart rate slowing and then ablation at that site, which, for endocardial catheter techniques, includes the surrounding atrial myocardium. Better methods to identify and ablate these focal neural networks are desirable for potential use as adjunct treatments to conventional cryoablation or radiofrequency ablation.Article see p 2653Interestingly, Yu et al11 have proposed a technique using injected iron-core nanoparticles to target the ganglionated plexi for ablation. The use of magnetic particles has a long history in medicine. Ultrasmall superparamagnetic iron oxide particles have been widely used in magnetic resonance angiography applications in cardiovascular magnetic resonance imaging (MRI) due to their ability to remain in the blood pool for long periods of time. The toxicity of these particles is low due their biocompatibility with recycling of iron into the normal body iron pool, similar to hemoglobin. Clearance of these particles by activated macrophages has also been used as a method by which to identify the potentially vulnerable atherosclerotic plaque.12,13 The ability of these particles to remain intravascular for long periods of time makes them ideal candidates to attach ligands for active targeting to specific cells. Yu et al used a superparamagentic nanoparticle, which is larger than commonly used ultrasmall superparamagnetic iron oxide particles, and was coated with a heat-sensitive polymer to enable the release of a neurotoxin at body temperature.11 They employed the simple approach of surgically placing a permanent magnet adjacent to the plexus to trap the nanoparticle after intracoronary delivery. Unfortunately, this straightforward approach eliminated the ability to image the nanoparticle directly with MRI. In a less invasive manner, Wilson et al used a permanent magnet placed outside the body to localize magnetic particles that contained a chemotherapeutic drug injected under conventional fluoroscopic guidance to hepatocellular carcinoma.14 Other methods–perhaps adding magnets to ablation catheters–might be envisioned as means to enjoy the simplicity of magnets for targeting combined with the advantages of MRI's high spatial resolution and serial imaging capabilities for anatomic imaging of particle delivery.Polymer hydrogels have also been an area of great interest for controlled drug release. Unlike liposomes, polymer-based coatings offer superior stability characteristics and can be engineered to decompose at a specific pH or temperature.15 Poly-N-isopropylacrylamide-coacrylamide, the polymer used by Yu et al, is hydrophilic and thus hydrated at temperatures below body temperature.11 However, the polymer is hydrophobic at body temperature, so the structure collapses once injected and can release any incorporated drugs for a localized therapeutic effect. The critical temperature for disintegration of poly-N-isopropylacrylamide-coacrylamide can be altered by the addition of residues. Potentially, this would offer the ability to combine radiofrequency ablation for the release of the incorporated drugs at a higher temperature trigger. Unfortunately poly-N-isopropylacrylamide-coacrylamide is not biodegradable, which means that it would permanently remain within the body. Consequently, other hydrogels with similar heat-sensitive properties, but with enhanced breakdown properties, are being explored for drug delivery and in combination with iron oxides for imaging.16,17An appealing secondary mechanism by which to realize the benefits of the targeted agent may be microvascular plugging of the nanoparticle in the tissue. While this was not explored in detail by Yu et al, histopathology demonstrated the embolization of the particle.11 Clearly, if this was not a desirable effect, there are many polymer-coated iron oxide agents of much smaller size (eg, ultrasmall superparamagnetic iron oxide particles) that exhibit less clumping, which could provide a viable alternative approach.Iron-based nanoparticles have also shown promise for hyperthermia-based treatments for cancer.18,19 While heating of devices in MRI is a concern, in magnetic hyperthermia treatments, the deposition of thermal energy occurs as superparamagentic nanoparticles are exposed to rapidly alternating positive and negative magnetic fields and relax toward an equilibrium state. This heating is exploited for tumor cell destruction. Particle conformation, including overall particle size, size distribution, and core size, is important in determining the efficiency of heating. Fortuitously, superparamagnetic nanoparticles appear not only to be good for imaging, but also for the enhancement of the heating effect through surface modification of the nanoparticles. Targeting of these iron nanoparticles to the tumor is critical to avoid killing normal cells. For example, Ito et al have shown antibody targeting to Her2-positive breast cancer cells of magnetic liposomes in combination with hyperthermia treatment.20 The success of nanoparticle delivery was further confirmed by MRI. One can imagine that the nanoparticle developed by Yu et al11 could be extended to provide not only tracking with MRI, but also ganglionated plexi ablation using hyperthermia as an adjunct to radiofrequency ablation. If hyperthermic heating of cells was insufficient, the polymer coating could be designed to have a higher critical temperature that would release only the endotoxin with the use of alternating magnetic field hyperthermia, providing additional targeting of the drug delivery.Yu et al11 have provided an interesting first step toward targeted drug-based treatment of atrial fibrillation. As the population ages, increasing procedural risk, minimally invasive treatments that can provide complementary means to monitor therapeutic response will become increasingly sought as alternatives to conventional medical or surgical therapies. The combination of catheter ablation techniques with magnetically targeted nanoparticles for ablation of autonomic ganglia involved in initiating and perpetuating AF can be envisioned. Yu et al11 have just scratched the surface of a new approach to ablation for treatment of arrhythmias.DisclosuresDrs. Kraitchman and Bulte receive grant support from Siemens Medical Systems.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Dara L. Kraitchman, VMD, PhD, Johns Hopkins University School of Medicine, 600 N. Wolfe St., 314 Park Building, Baltimore, MD 21287. E-mail [email protected]eduReferences1. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. 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Cancer Lett. 2004; 212:167–175.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 21, 2010Vol 122, Issue 25 Advertisement Article InformationMetrics © 2010 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.000166PMID: 21135362 Originally publishedDecember 6, 2010 Keywordsiron oxide labelingcardiovascular magnetic resonance imagingatrial fibrillationEditorialsautonomic functionelectrophysiologyPDF download Advertisement SubjectsArrhythmiasCatheter Ablation and Implantable Cardioverter-DefibrillatorComputerized Tomography (CT)ElectrophysiologyImaging