Marys Medicine

Chin. Phys. B Vol. 24, No. 1 (2015) 014704 TOPICAL REVIEW — Magnetism, magnetic materials, and interdisciplinary research Surface modification of magnetic nanoparticles in Chu Xin(储 鑫), Yu Jing(余 靓), and Hou Yang-Long(侯仰龙 Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing 100871, China (Received 4 November 2014; published online 9 December 2014) Progress in surface modification of magnetic nanoparticles (MNPs) is summarized with regard to organic molecules, macromolecules and inorganic materials. Many researchers are now devoted to synthesizing new types of multi-functionalMNPs, which show great application potential in both diagnosis and treatment of disease. By employing an ever-greatervariety of surface modification techniques, MNPs can satisfy more and more of the demands of medical practice in areaslike magnetic resonance imaging (MRI), fluorescent marking, cell targeting, and drug delivery.
Keywords: magnetic nanoparticles, surface modification, functionalization, magnetic resonance imaging PACS:, 87.19.lf, 87.57.–s, 87.61.–c surface of MNPs is the interface of nanomaterials and patients' bodies, surface biocompatibility is a prerequisite to the medi- Magnetic nanoparticles (MNPs) have shown enormous cal application of nanomaterials.As a convenient and quick potential in disease diagnosis and therapy. Due to their su- approach to adjust the properties of MNPs, surface modifica- perior magnetic properties and high specific surface, MNPs tions have become a vital component of a great many medical are perceived as promising materials for magnetic resonance applications of MNPs, due to various requirements to add non- imaging (MRI) agents, biomedical drug carriers, magnetic hy- perthermia, etc.Based on the interaction between protons Cell phagocytosis of MNPs has expanded the applica- and surrounding molecules of tissues, MRI is already a key tions of contrast enhanced MRI beyond vascular and tissue tool for medical imaging diagnosis of cancer and is consid- morphology imaging, and enabled many novel applications of ered one of the most efficient imaging techniques in medical MNPs for MRI diagnosis of liver diseases, cancer metastasis practice. Colloidally stable MNPs, which display strong mag- to lymph nodes, and in vivo MRI tracking of implanted cells netization, now attract much attention for their great potential and grafts.The magnitude of contrast effects also needs to in MRI. In particular, they can be used as contrast agents in be improved for higher sensitivity to minimal changes in a dis- MRI, inducing hypo-intensities on T1/T2 and T1/T ∗-weighted ease and for biomarker-specific detection. Therefore, surface MRI maps. Drug delivery is another medical application for modifications of MNPs are developed to meet the increasing MNPs. Magnetic drug delivery is a method to target drugs interests in non-invasive in vivo imaging of the molecular and to the diseased area in the body. The drug is attached to an cellular activities that characterize a disease. Surface mod- MNP and injected into the blood flow. A magnetic field lo- ifications can inhibit MNPs' reactions and agglomeration in cated close to the diseased area is used to capture the MNPs aqueous phase, which is a precondition for medical applica- in the target area. Under the influence of the magnetic field, tions and endows MNPs with multifunctional properties such the MNPs move irregularly in the target area which acceler- as fluorescent marking, cell targeting, drug loading and so ates the release of drugs. Apart from pharmaceutical therapy, on.Furthermore, the addition of non-magnetic surfactants MNPs are also widely used in magnetic hyperthermia therapy.
can influence the magnetic performance of MNPs.
On account of excellent magnetic properties, metal carbide Surface modifications are accomplished mainly via two nanoparticles especially ferromagnetic NPs, can induce strong approaches, ligand exchange and ligand adsorption. In this attractive forces between the dipoles of neighboring NPs, and case, ligand exchange means changing a hydrophobic ligand aggregate under a static magnetic field.
into a hydrophilic one. Generally, these ligands consist of hy- While the efforts to develop new engineered MNPs and drophilic groups and linking groups. The linking groups can constructs continue to grow, with new chemistry and synthesis combine with the surface of the MNPs, whereupon the hy- approaches every year, the importance of specific functional- drophilic groups are exposed to the surrounding environment ization designs has been increasingly recognized. Because the and make the MNPs disperse in the aqueous solution. The key ∗Project supported by the National Natural Science Foundation of China (Grant Nos. 51125001 and 51172005), the Natural Science Foundation of Beijing, China (Grant No. 2122022), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (Grant No. 81421004), andthe Doctoral Program of the Education Ministry of China (Grant No. 20120001110078).
†Corresponding author. E-mail: 2015 Chinese Physical Society and IOP Publishing Ltd Chin. Phys. B Vol. 24, No. 1 (2015) 014704 to designing a successful ligand exchange is to select linking stable in aqueous phase, due to the reversibility of the co- groups that have the strongest combination with the surface of ordination process.
This problem is preferably solved by the application of polydentate ligands. Polydentate ligands "Ligand adsorption" in this case mainly means to adsorb have a plurality of coordinating groups that significantly en- amphiphilic molecules, which have a hydrophilic portion on hances the force of binding with the MNPs.
one side and hydrophobic part on another side. By means these surface-modified MNPs have high stability constant of hydrophobic forces, the hydrophobic portion can combine and exhibit favorable aqueous solubility.
firmly with a hydrophobic surfactant on the MNPs and the ligands are diphenols,polyacids,polyols and their hydrophilic portion is exposed so that the MNPs disperse in derivatives.For all of those, catechol and its deriva- aqueous phase. In addition, chemical reaction is a third ap- tives are most commonly used. With its benzene ring struc- proach to surface modification. In these three strategies, or- ture as electron-donor, catechol and its derivatives can be in- ganic molecules, macromolecules and inorganic materials are tensely coupled with metal ions.Hou et al. invented a usually used. In this review article, we will summarize the rapid ligand-exchange method to make hydrophobic Fe3O4 progress in surface modification of MNPs by considering the NPs water-soluble, employing dihydroxybenzoic acid as a lig- principal types of surface materials one by one.
and (Fig. Another common polydentate ligand is dimer- captosuccinic acid (DMSA). A small molecule, DMSA has 2. Surface modification with organic molecules notably superior hydrophilicity, biocompatibility and coordi- nation ability due its double sulfhydryl and double carboxyl For organic molecular agents, only a single approach (lig- and exchange or ligand adsorption) can be chosen for a given Recently, a new class of dual-modality imaging agents application because of the simple structure.
were reported, based on the conjugation of radiolabeled change, monodentate ligand is the simplest ligand. Due to bisphosphonates (BP) directly to the surface of superpara- ease of preparation, simple structure and other advantages, magnetic iron oxide (SPIO) nanoparticles.By linking monodentate ligands are widely used in ligand exchanges.
99mTc-dipicolylamine(DPA)-alendronate with SPIO, the dual- Since there is only one ligand, the binding force between modality imaging agents exhibit good performance in single monodentate ligands and MNPs is weak and the combina- photon emission computed tomography (SPECT) imaging and tion process is reversible.
To deal with this problem, re- magnetic resonance imaging (MRI).
searchers need to screen the ligands for strong coordination ability. Carboxyl,sulfydryl,silane,and some in- organic ionsare most commonly used in monodentate ligand exchange. Murray et al. used nitrosonium tetrafluo- roborate (NOBF4) to replace the organic ligands attached tonanocrystals' (NCs) surface (Fig. The replacement by inorganic BF− anions enabled NCs to be fully dispersible in polar, hydrophilic solvents without changing the particle size Fig. 2. Ligand exchange process with dihydroxybenzoic acid.Re- and shape. After surface modification, the NCs were read- produced with permission from Ref. Copyright 2013 Royal Soci- ily further functionalized by various capping molecules that ety of Chemistry.
greatly enrich the surface function of NCs.
Some organic molecules are amphipathic. Their struc- tures combine a hydrophilic portion with a hydrophobic por- tion that is able to attach to the surface of hydrophobic MNPs. The hydrophilic portion is usually long chains hy- drocarbons, but the hydrophobic portion has different struc- tures. In addition to enhancing the dispersibility of MNPs in aqueous solutions, optical dyes, targeting agents and thera- peutic agents, amphipathic compounds are useful in the lig- and adsorption process that helps endow some MNPs with multifunctionality.In combination with organic dyes, some MNPs have a dual-mode imaging property that contributes Fig. 1. Schematic illustration of surface modification of MNPs via theligand exchange process with NOBF to disease diagnosis (Fig. Among the organic dyes, 4.Reproduced with permission from Ref. Copyright 2011 American Chemical Society.
near-infrared fluorescent (NIRF) dyes may be the best choice, Although monodentate ligands have simple structure and due to their low interference and excellent deep penetration react fast with an MNP surface, the resulting MNPs are not of issues.Likewise, surface modification with a targeting Chin. Phys. B Vol. 24, No. 1 (2015) 014704 agent or therapeutic agent can strengthen the diagnostic capac- NPs.Due to the complex structures of polymers, there are ity of an MNP.Manuel et al. synthesized biocompatible, many aspects that affect the surface performance of MNPs multimodal, theranostic functional iron oxide nanoparticles (for example, the molecular weight, the properties of termi- that exhibit excellent properties for targeted cancer therapy nal groups and the conformation of the polymers).
and both optical and magnetic resonance imaging.Using Quite a few natural and synthetic polymers have been a novel water-based method, they finished the encapsulation demonstrated in polymer coating of MNPs.The gly- of both near-infrared dyes and anticancer drugs and realized cans such as dextran or chitosan are widely used in polymer successful theranostics.In recent research, a novel method coatings.Chitosan, a biodegradable natural polymer, is to synthesize Gd-NPs was reported wherein a Gd-based MR derived by deacetylation of chitin obtained from the shells contrast agent self-assembled into gadolinium NPs under the of crustaceans. It has many biological applications because action of furin proteins. These NPs can be used to locate the of its biological activities, biocompatibility, high charge den- right position for treatment.
sity, low toxicity toward mammalian cells and ability to im- prove dissolution. Weissleder and his group research dex- tran coated iron oxide nanoparticles and derivative magnetic Their work on monocrystalline iron oxide nanoparticles (MION)and cross-linked iron oxide (CLIO) nanoparticlesfound that dextran-coated superparamagnetic iron oxide nanoparticles were a very suitable platform for the synthesis of multifunctional imaging agents.Hyeon et al. developed chitosan oligosaccharide-stabilized ferrimag- netic iron oxide nanocubes (Chito-FIONs) as an effective heat nanomediator for cancer hyperthermia.The Chito-FIONs' magnetic heating ability is superior to that of commercial su- Fig. 3. Schematic of surface modification of MNPs via the ligand ab-sorption process with DMSA and fluorescent dye.DMSA is coupled perparamagnetic iron oxide nanoparticles, enabling eradica- to the particle and the fluorescent dye is coupled to DMSA. The cou- tion of cancer cells through caspase-mediated apoptosis.
pling between DMSA and the fluorescent dye can be made before or si-multaneously with the one between DMSA and the magnetic particles.
Another frequently-used polymer is polyethylene glycol Reproduced with permission from Ref. Copyright 2006 American (PEG).PEG is a flexible water-soluble polymer. The Chemical Society.
high hydrophilicity of PEG chains can render the MNP core soluble and stabilized in aqueous media.
3. Coating modification with macromolecules demonstrated to reduce uptake by macrophagessharply, so 3.1. Polymer coating as to increase the blood circulation time in vivo. By chang- For macromolecular agents, due to their complex struc- ing the molecular weight of PEG, the thickness of the coating ture with numerous functional groups, the two approaches, can be controlled.PEG-derivative modified MNPs were ligand exchange and ligand adsorption are usually applied prepared by post-synthesis coating. With increasing molec- together to form a more stable structure.
ular weight, the number of branched chains and functional- change or ligand adsorption, polymers with multiple func- ities, higher stability and better dispersion can be attained.
tional groups can be expediently combined with MNPs. Be- Sun et al. synthesized heterobifunctional PEG ligands using cause of the same reaction process, polymer coating usually 3-(3,4-dihydroxyphenyl) propanoic acid and PEG as reactants needs the help of active terminal groups. Various monomeric (Fig. They successfully modified porous hollow NPs species, such as bisphosphonates, DMSA and alkoxysilanes, (PHNPs) of Fe3O4 via this ligand and achieved targeted deliv- have been evaluated to facilitate attachment of polymer coat- ery and controlled release of the cancer chemotherapeutic drug ings on MNPs.In polymer coatings, polymers form a cisplatin. However, a PEG shell is unfavorable for uptake of barrier among MNPs to avoid agglomeration and provide va- MNPs by most cells. To solve this problem, these MNPs can rieties of surface properties. Most biocompatible MNPs de- be modified by hyaluronic acid (HA), a targeting moiety, for veloped for in vivo applications need to be stabilized and func- uptake by stem cells.A recent study reported that different tionalized with coating materials. The coating moieties can af- terminal groups partly affected the MRI images of MNPs.
fect the relaxation of water molecules in various forms, such as Other polymers such as cellulose, poly (ethylene oxide) diffusion, hydration and hydrogen binding.In the research, (PEO), poly (vinyl alcohol) (PVA), poly(acrylic acid) (PAA) these coatings also serve to link MNPs with biomolecules and poly (lactide-co-glycolide) (PLGA) are also used for poly- or to change the surface charge or chemical environment.
mer coatings of MNPs. PLGA and cellulose are Food and Moreover, polymer coatings improve the colloidal stability of Drug Administration (FDA) approved for a variety of uses in Chin. Phys. B Vol. 24, No. 1 (2015) 014704 humans and commonly employed for drug delivery and oral and superparamagnetic iron oxide.These NPs show unusu- formulations. Xu et al. used a single emulsion method to ob- ally high MRI sensitivity, comparable to a conventional MRI tain oleic acid-stabilized iron oxide NPs (10 nm core size) contrast agent, despite their lower iron content. Lin et al. pre- encapsulated in PLGA.The PLGA coating gave the NPs pared PAA modified GdVO4 NPs by filling PAA hydrogel into a much higher r2relaxivity than normal SPIO nanoparticles.
GdVO4 hollow spheres. The PAA@ GdVO4 NPs can act as Hong et al. synthesized novel polymeric nanoparticles (YCC- a dual mode agent for MRI and up-conversion imaging and DOX) composed of poly (ethylene oxide)-trimellitic anhy- be applied for pH-dependent drug release due to their hollow dride chloride-folate (PEO-TMA-FA), doxorubicin (DOX) Fig. 4. Schematic of surface modification of hollow NPs with heterobifunctional PEG ligands.Reproduced with permission fromRef. Copyright 2009 American Chemical Society.
To gain specificity and reduce side effects and toxicity, layer by self-assembly;consequently polymer coatings can biomarker targeted functional proteins or peptide fragments, be formed by self-assembly on the surface of MNPs.
such as RGD targeting αvβ3 integrin, HER2/neu antibodies, Polymer coatings' effects on NP magnetic properties is also urokinase type plasminogen activator (uPA) amino-terminal a research field.Gao et al.
reported novel multi- fragments (ATF), and single chain anti-epidermal growth fac- functional polymeric micelles composed of a chemotherapeu- tor receptor (EGFR) antibodies, have been conjugated on the tic agent doxorubicin (DOXO) and a cRGD ligand.They surface of MNPs, so that the nanoprobes would be recognized demonstrated that each micelle loaded a cluster of superpara- and internalized by tumor cells expressing a specific receptor.
magnetic iron oxide (SPIO) nanoparticles inside, allowing the micelles to be tracked by ultrasensitive MRI detection of the 3.2. Liposome and micelle encapsulation As one of the earliest tools for drug delivery in nanomed- ical practice, liposome techniques have been developing for a long time. Liposome are composed of a lamellar phase lipid bilayer, so they are usually biocompatible. Having a bilayer structure, amphipathic liposomes can encapsulate MNPs and can have diameters ranging from 100 nm to 5 µm. Thus, an- Fig. 5. Schematic illustration of the encapsulation process for DOX- other advantage of liposome encapsulation is to gather a cer- SPIO.Reproduced with permission from Ref. Copyright 2008 tain number of MNPs for collective delivery to the target. For Elsevier Ltd.
these reasons, liposome complexes are an ideal platform for Other applications in polymer coatings are also benefi- delivery of contrast agents in MRI.
cial. To simplify the coating procedures, researchers have de- Polymeric micelles offer the advantage of multifunctional veloped "one-pot" methods, a series of copolymers can now be carriers that can serve as delivery vehicles carrying nanoparti- used to accomplish in situ coating of MNPs.Nevertheless, cles, hydrophobic chemotherapeutics and other functional ma- the growth of nanocrystals can be influenced as a result of the terials and molecules. Stimuli-responsive polymers are es- presence of polymers, leading to abnormal structures and sur- pecially attractive since their properties can be modulated in faces of MNPs (Fig. Polymers or macromolecules such a controlled manner. Due to its large encapsulation range, as peptides or PEG have the conformation to form a mono- molecules, proteins, DNA and MNPs can all be encapsulated Chin. Phys. B Vol. 24, No. 1 (2015) 014704 by liposome as one unit.
method(in aqueous phase) and sol-gel method(in both aqueous and oleic phase).
4. Coating modification with inorganic materi- The functionalization of silica shells is similar to ligand adsorption. This inevitably makes the diameter of the modi- fied MNPs too large, which affects the biocompatibility, fluid- 4.1. Silica coating ity, stability and magnetic performance of the MNPs. To con- Coating MNPs with inorganic agents is generally accom- trol the thickness of the silica shell, researchers have utilized plished by chemical reaction. Silica is most widely used for tetraethoxysilane (TEOS) as the source of silica, controlled re- surface modification via an inorganic coating. Silica-coated action conditions very carefully, and finally obtained diame- MNPs always form core-shell structures.
ters from 10 nm to 1 µm.Zhang et al. studied the reg- advantages over organic coatings. Silica-coated NPs are ro- ulation of the controlled synthesis of Fe3O4@SiO2 core-shell bust, water-soluble, colloidally stable and photostable.
nanoparticles via a reverse microemulsion method.They Serving as protective coatings, silica shells are easy to syn- found that the thickness of the silica shell increased with the thesize with controlled size. The general method to produce size of the aqueous domain. This result can guide us to avoid silica coating can be divided into two types: classical Stober the formation of core-free silica particles (Fig. Fig. 6. The coating mechanism of SiO2 on the surface of Fe3O4 NPs.Reproduced with permission from Ref. Copyright 2012American Chemical Society.
With controlled size, silica shells are appropriate for en- ica shells with foamed or porous structures have received capsulation of NPs and organic molecules like dyes or drugs.
more attention do to the convenience of loading and releasing Salgueirino-Maceira et al. encapsulated Fe3O4 NPs and CdTe quantum dots within composite silica spheres.These sil- ica spheres can serve as both luminescent and magnetic nano- accomplished the same function by embedding a dye molecule inside the silica shell.Re- searchers also focus on the synthesis of various other core- shell structures. Deng et al. synthesized superparamagnetic microspheres with an Fe Synthesis route of Fe 3O4@SiO2 core and a perpendicu- with permission from Ref. Copyright 2008 American Chemical larly aligned mesoporous SiO2 shell (Fig. The micro- spheres possess very high magnetization, large surface area, large pore volume, and uniform, accessible mesopores. Wu A robust core-shell structure, silica coated MNPs can be et al. reported a silica nanoshuttle as a drug delivery system functionalized with various biomolecules.
with a nanoscale PEGylated-phospholipid coating and a 13- tends to adsorb molecules, but silane coupling agents can sig- nificantly inhibit this process.These agents always con- silica NP.The therapeutic and imaging agents were trapped sist of siloxy (linking with silica shells) at one side and bio- and ligand-assisted targeted delivery was achieved through compatible groups like amino, sulfydryl and so on (linking surface functionalization of the phospholipids. Recently, sil- with biomolecules) or even biomolecules themselves that al-

Chin. Phys. B Vol. 24, No. 1 (2015) 014704 ready incorporate a silane group at another side. Biomolecules the carbon and silver on its surface, this nanoprobe, syner- can easily be added to the outer shells by using alkoxysilanes gistically combining NIR-controlled drug release and the two with active groups, such as aminopropylsilane (APS) or mer- imaging modes of MRI and two-photon fluorescence (TPF) imaging, could lead to a multifunctional system for medical diagnosis and therapy. Sometimes researchers utilize gold and 4.2. Metal element coating silver together, looking for better biomedical properties.
The metallic elements used for surface modification are Some rare earth elements can be also be used in surface relatively inert in order to act as a protective layer. The coat- modification via the formation of core-shell structures. For ing metal and MNPs are tightly coupled through a chemi- example, an Fe3O4@NaLuF4:Yb,Er/Tm core-shell nanostruc- cal reaction process. The metal coating is more easily bio- ture with multifunctional properties was developed by step- functionalized than the bare surface of MNPs.
wise synthesis (Fig. Comprising an Fe3O4 core and a Gold is the major element among noble metal coatings.
NaLuF4shell, this class of nanoprobes combines the merits of Due to strong conjugation with sulfur, gold offers remarkable three imaging modes, upconversion luminescence (UCL), MR advantages in sulfydryl-containing surface coatings.Be- and computed tomography (CT), and is suitable for various cause of the chemical inertness of gold, forming gold shells is applications requiring different spatial resolutions and imag- difficult, so gold coated MNPs are completely stable. Zhong et al. produced gold-coated iron oxide nanoparticles via a reduc- tion of gold precursors on iron oxide nanoparticles of selected sizes as seeds.Williams et al. synthesized gold-coated iron oxide NPs via iterative hydroxylamine seeding. The gold- coated particles exhibit a surface plasmon resonance peak that blue-shifts from 570 to 525 nm with increasing Au deposition and the magnetic properties of NPs are largely independent of Au addition. In addition to core-shell structures, Au-coated MNPs with heterostructures are widely used in medical prac- tice (Fig. Gold also has a good photothermal prop- erty. Kim et al. fabricated a new gold nanorod (GNR) con- jugated with MNP composite.The GNR-MNP performed very efficiently as a photothermal agent for repeated cycles of photothermal ablation of bacteria.
Fig. 9. Synthesis process of Fe3O4@NaLuF4 nanoparticles.Re-produced with permission from Ref. Copyright 2012 ElsevierLtd.
5. Conclusions and outlook This review presents the surface modification of MNPs by discussing separately three groups of surface modifica- tion agents and investigating the processes of applying them.
With regard to ligand exchange and ligand absorption, two key modes of surface modification, an enormous variety of MNPs are discussed. Moreover, MNPs can be a multifunction plat- form for medical practice, in both diagnosis and therapy, after modifying the particles' surface with optical dyes, targeting Fig. 8. Synthesis process of Au-Fe3O4 nanoparticles.Gold nanopar-ticles are attached to the surface of Fe agents, therapeutic drugs or other functional molecules.
3O4 nanoparticles. Reproduced with permission from Ref. Copyright 2007 American Chemical Presently, the study of MNPs is developing rapidly. Re- searchers expect to attain MNPs that combine multiple func- Silver is another element among noble metal coatings.
tions that are much needed in clinical practice. It seems that Silver coating makes MNPs germicidal,because silver has functionality is the number on requirement for future MNPs.
very strong sterilization ability. The study of silver coating is However, in research, we must think comprehensively of all very similar to that of gold. Silver can also form both core- the properties of MNPs, like stability, safety, economy and ef- shell structures and heterostructures.Chen et al. syn- ficiency, rather than only multifunctionality, so that the MNPs thesized Fe3O4@C@Ag hybrid nanoparticles.Owing to can indeed be applied in medical practice. Accordingly, as- Chin. Phys. B Vol. 24, No. 1 (2015) 014704 pects such as biocompatibility, toxicity, in vivo and in vitro tar- [29] Xie J, Chen K, Huang J, Lee S, Wang J H, Gao J, Li X G and Chen X geting efficiency, and long-term stability of the functionalized [30] Bertorelle F, Wilhelm C, Roger J, Gazeau F, Menager C and Cabuil V MNPs must receive more attention. Meanwhile, there is an im- mense requirement for surface-modification materials that are [31] Zhang Y, Kohler N and Zhang M Q [32] Chekina N, Horak D, Jendelova P, Trchova M, Benes M J, Hruby M, convenient, efficient, biocompatible and stabilized. In the fu- Herynek V, Turnovcova K and Sykova E ture, further development of surface modification is expected [33] Hilderbrand S A and Weissleder R [34] Veiseh O, Gunn J W and Zhang M Q to realize the union of diagnosis and therapy at nanoscale, and with ever-improving techniques of surface-modification engi- [35] Santra S, Kaittanis C, Grimm J and Perez J M neering, research in multifunctional MNPs is sure to remain a [36] Xie J, Lee S and Chen X Y [37] Cao C Y, Shen Y Y, Wang J D, Li L and Liang G L frontier of biomedical science.
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