New forms of superparamagnetic nanoparticles for biomedical applications

ADR-12413; No of Pages 12 Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

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New forms of superparamagnetic nanoparticles for biomedical applications☆ Chenjie Xu a, b,⁎, Shouheng Sun a,⁎ a b

Department of Chemistry, Brown University, Providence, RI 02912, USA Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore

a r t i c l e

i n f o

Article history: Received 10 July 2012 Accepted 3 October 2012 Available online xxxx Keywords: Magnetic nanoparticles Synthesis Modification Biomedical application Drug delivery Molecular imaging

a b s t r a c t Magnetic nanoparticles (MNPs) based on iron oxide, especially magnetite (Fe3O4), have been explored as sensitive probes for magnetic resonance imaging and therapeutic applications. Such application potentials plus the need to achieve high efficiency and sensitivity have motivated the search for new forms of superparamagnetic NPs with additional chemical and physical functionalities. This review summarizes the latest development of high moment MNPs, multifunctional MNPs, and porous hollow MNPs for biosensing, molecular imaging, and drug delivery applications. © 2012 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . Synthesis of MNPs . . . . . . . . . . . . . . . . 2.1. MNPs with high magnetic moment . . . . . 2.1.1. Structure controlled ferrite MNPs . . 2.1.2. Metallic MNPs . . . . . . . . . . . 2.2. Multifunctional MNPs . . . . . . . . . . . 2.2.1. Molecular functionalization of MNPs 2.2.2. Heterogeneous MNPs . . . . . . . 2.2.3. Core/shell MNPs . . . . . . . . . . 2.3. Hollow MNPs . . . . . . . . . . . . . . . 3. Modification and functionalization of MNPs . . . . . 4. Biomedical applications . . . . . . . . . . . . . . 4.1. High magnetic moment MNPs for biosensing . 4.2. Molecular imaging with multifunctional MNPs 4.2.1. Tumor imaging . . . . . . . . . . 4.2.2. Cell tracking . . . . . . . . . . . . 4.3. Drug delivery with hollow MNPs . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Inorganic nanoparticle platforms”. ⁎ Corresponding authors at: Department of Chemistry, Brown University, Providence, RI 02912, USA. E-mail addresses: [email protected] (C. Xu), [email protected] (S. Sun).

Nanomedicine is an emerging field that provides novel approaches to address the ever-increasing challenges in conventional medicine [1]. Magnetic nanoparticles (MNPs), due to their comparable sizes to biological molecules and their unique physical properties, have been explored extensively for medical applications. Among various functional MNPs

0169-409X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.addr.2012.10.008

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

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C. Xu, S. Sun / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

studied, superparamagnetic nanoparticles (NPs) are especially promising as contrast enhancement agents for magnetic resonance imaging (MRI) and also as a platform for drug delivery. These MNPs, represented by magnetite (Fe3O4) NPs, are often made in sizes smaller than 20 nm in diameter and their magnetization directions are subject to thermal fluctuation at room or biological temperatures. Therefore, without an external magnetic field, their overall magnetization value is randomized to zero. Such fluctuation in magnetization direction minimizes the magnetic interactions between any two NP in the dispersion, making the dispersion stable in physiological solutions and facilitating NP coupling with biological agents. Once exposed to an external magnetic field, these MNPs can align along the field direction, achieving magnetic saturation at a magnitude that far exceeds that from any of the known biological entities. This unique property of MNPs allows not only the detection of the MNPcontaining biological samples, but also the manipulation of these biological samples with an external magnetic field [2,3]. Conventional MNPs like iron oxide NPs have been demonstrated successfully in biomedical applications both in vitro (magnetic separation, magnetic sensing/detection, and magnetic transfection) and in vivo (MRI, targeted drug delivery, and tissue engineering). However, limitations exist including low magnetic moment [4], low sensitivity in MRI diagnosis [5], and low cargo capacity [6]. For example, one of the commercial iron oxide NP products, Feridex IV, has r2 relaxivity of 98.3 mM−1S −1 under normal MRI conditions, which requires ~35 mg iron for imaging liver of an adult with 60 kg of body weight [7]. Furthermore, due to the wide distribution of both size and magnetic moment, traditional MNPs tend to generate large magnetic field gradients that cause dephasing and signal loss in and around the MNP-concentrated regions. This makes it difficult to distinguish MNP-targeted area from other “field perturbers” such as air bubbles and blood clots [8]. When acting as drug carriers, traditional MNPs offer only one chemical surface for drug loading and targeting-molecular conjugation, lowering the capacity of either targeting agent or drug molecular (usually less than 10% by weight) as well as the targeting and therapeutic efficiency [9–11]. To overcome the limitations of mono-functional traditional MNPs, new forms of MNPs with high magnetic moment, multifunctionality, and high drug loading have been actively pursued [4,12–15]. Here, we summarize the recent developments in the synthesis of new MNPs for sensitive biomedical applications, including spinel structured ferrite NPs and metallic NPs with high magnetic moments, multifunctional MNPs for controlled coupling of different biological agents, and porous hollow MNPs with increased capacity for drug loading. 2. Synthesis of MNPs Traditional iron oxide based MNPs are synthesized by coprecipitation of ferrous and ferric ions in alkaline media in the presence of surfactants (e.g. Dextran). In the synthesis, other metal salts can be added to form ferrite MFe2O4. Despite the versatility of the synthesis, iron oxide NPs made from this method do not have the desired control on the morphology and magnetic moment. Monodisperse iron oxide NPs are now often produced by high-temperature reductive decomposition of metal salt or organometallic precursors in organic solutions [16,17]. In this method, a burst nucleation event first occurs when the concentration of metal precursors quickly increases to the critical saturation point without further formation of nuclei afterwards [18]. The remaining precursors deposit on the pre-formed nuclei, forming NPs with narrow size distribution. The method produces not only monodisperse ferrite NPs with high magnetic moment, but also a series of new MNPs with multifuctionalities. 2.1. MNPs with high magnetic moment 2.1.1. Structure controlled ferrite MNPs Ferrite MFe2O4 or MO·Fe2O3, with M being the common divalent transition metal cations (Mg 2+, Fe 2+, Co 2+, Ni 2+, Cu 2+, Zn 2+…) is

a class of materials that has spinel structure with oxygen forming cubic close packing and Fe3+ and M2+ occupying the octahedral and tetrahedral interstitial sites. When Fe3+ takes octahedral sites and M2+ in tetrahedral sites, the structure is said to have a normal spinel structure. The MFe2O4 can also adopt an inverse spinel structure in which half of Fe3+ exchange sites with M 2+. In this inverse spinel structure, the spins in two Fe3+ located in tetrahedral and octahedral sites are anti-ferromagnetically coupled and cancel each other. Therefore, magnetic moments of the inverse spinel structured MFe2O4 are dependent on the un-paired d-electrons from M2+ and their overall values are reduced by anti-ferromagnetic coupling between Fe3+. When M is Fe 2+, Co2+, or Ni2+, MFe2O4 NPs have an inverse spinel structure [19]. As Fe2+ has larger magnetic moment (4 μB) than Co2+ (3 μB) and Ni2+ (2 μB), the mass magnetization of Fe3O4 (101 emu/g) is larger than that of CoFe2O4 (99 emu/g) and NiFe2O4 (85 emu/g) [20]. When M is Mn2+, however, nanostructured MnFe2O4 can adopt a normal spinel structure in which Fe3+ take octahedral sites and there has no anti-ferromagnetic coupling between Fe 3 +. The structure provides a higher mass magnetization than the inverse spinel structured MFe2O4 [20]. Furthermore, ZnFe2O4 NPs show a ferromagnetically mixed spinel state (Zn1 − xFexO4)A[Fe2 − xZnO4]B [21]. Addition of ZnFe2O4 into an inverse spinel structure (e.g. Fe3O4) can significantly increase the net magnetic moment [22]. This was demonstrated in the non-stoichiometric ZnxFe1−xO·Fe2O3 NPs (x= 0.14, 0.26, 0.34 and 0.76) that were synthesized by thermal decomposition of diethyl zinc and iron acetylacetonate (Fe(acac)3) [23]. When x was controlled from 0 to 0.34, r2 values increased systematically, achieving near 3 fold enhancement from 9.5 to 34.7 mM−1 s−1 (measured in a 0.55 T field). Recently the synthesis was further improved by replacing the unstable and pyrophoric diethyl zinc with zinc chloride, ZnCl2 and reacting ZnCl2 with Fe(acac)3 in the presence of oleic acid, oleylamine, and octyl ether to produce ZnxFe1 − xO·Fe2O3 [24]. When x in ZnxFe1 − xO·Fe2O3 NPs was from 0 to 0.1, 0.2, 0.3, and 0.4, r2 values reached from 276 to 397, 466, 568, and 687 mM − 1 s − 1 (measured in a 4.5 T field) respectively. The effect of Zn 2 + doping into MnFe2O4 NPs was also studied [24]. This led to the formation of Zn0.4Mn0.6Fe2O4 NPs with their relaxivity reaching 860 mM − 1 s − 1, the highest value ever reported. Table 1 summarizes some ferrite MNPs produced recently and their magnetic data for bio-imaging applications. 2.1.2. Metallic MNPs MNPs based on transition metals of Fe, Co and Ni have much high magnetic moments than their oxide counterparts [25]. They are normally prepared by thermal decomposition or reduction of organometallic precursors. For example, Fe NPs were synthesized by thermal decomposition of Fe(CO)5 at 180 °C in the presence of oleylamine in octadecene [26], or in the presence of oleylamine and hexadecylammonium chloride in octadecene [27], or at 170 °C in the presence of polyisobutene in decalin under N2 [28]. Similarly, Co NPs were prepared by thermal decomposition of Co2(CO)8 [29–32]. Reduction of Fe[N(SiMe3)2]2 with H2 in the presence of surfactants under 150 °C led to high moment Fe nanocubes [33]. Similarly, high-temperature reduction of [Co(η3-C8H13)(η4-C8H12)] and Ni(cycloocta-1,5-diene)2 gave Co and Ni nanorods respectively [34,35]. Magnetic alloy NPs can be produced by the combination of thermal decomposition and reduction of metal precursors. The key to the successful synthesis is to control the reaction condition so that two different metals can nucleate and grow into an alloy structure [36–38]. For example, FeCo NPs were synthesized by reduction of Fe(acac)3 and Co(acac)2 in the presence of oleic acid, oleylamine and 1,2-hexadecanediol under a gas mixture of 93% Ar+7% H2 at 300 °C or were made by sodium borohydride reduction of ferrous and cobalt salts [39,40]. FePt (or FeAu) NPs were synthesized by the thermal decomposition of Fe(CO)5 and the reduction of Pt(acac)2 (or AuAc3) by 1,2-hexadecanediol in the presence of oleic acid and oleylamine [41,42]. To stabilize high moment metallic NPs for biological applications, some robust coating strategies have

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

C. Xu, S. Sun / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

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Table 1 Survey of MNPs, their surface coating, magnetic moments and their relaxivities for MRI under a permanent magnetic field B0. MNPs

Core material

Core diameter (nm)

Surface coating

Feridex® Resovist® Combidex® Iron oxide

Fe3O4, γ-Fe2O3 Fe3O4 Fe3O4 Fe3O4

Dextran Carboxy-dextran Dextran DMSA

Mn–ferrite

MnFe2O4

Co–ferrite Ni–ferrite Zn–iron oxide

CoFe2O4 NiFe2O4 Zn0Fe1O·Fe2O3 Zn0.14Fe0.86O·Fe2O3 Zn0.26Fe0.74O·Fe2O3 Zn0.34Fe0.66O·Fe2O3 Zn0.76Fe0.24O·Fe2O3 Zn0Fe1Fe2O4 Zn0.1Fe0.9Fe2O4 Zn0.2Fe0.8Fe2O4 Zn0.3Fe0.7Fe2O4 Zn0.4Fe0.6Fe2O4 Zn0.8Fe0.2Fe2O4 Zn0Mn1Fe2O4 Zn0.1Mn0.9Fe2O4 Zn0.2Mn0.8Fe2O4 Zn0.3Fe0.7Fe2O4 Zn0.4Fe0.6Fe2O4 Zn0.8Fe0.2Fe2O4 Fe12Co88 Fe40Co60 α-Fe Amorphous Fe α-Fe

4.96 4 5.85 4 6 9 12 6 9 12 12 12 4.6 4.5 4.5 4.9 4.5 15 15 15 15 15 15 15 15 15 15 15 15 4 7 10 15 15

(ZnxFe1−x)Fe2O4

(ZnxMn1−x)Fe2O4

FeCo/C Fe Fe Fe

DMSA

DMSA DMSA DSPE-PEG

DMSA

DMSA

Phospholipid-PEG PEG OAm-PEG OAm-PEG

Magnetic moment (emu/g) 45 61 25 43 80 101 68 98 110 99 85 19.8 26.8 43.1 54.1 30.0 114 126 140 152 161 115 125 140 154 166 175 137 162 215 70 90.6 164

B0 (T)

Relaxivity r2 (mM−1 s−1)

Reference

1.5 1.5 1.5 1.5

120 186 65 78 106 130 218 208 265 358 172 152 9.5 14.5 22.4 34.7 7.4 276 397 466 568 687 307 422 516 637 754 860 388 185 644 129 67 220

[44] [45] [45] [20]

1.5

1.5 1.5 0.55

4.5

4.5

1.5 1.5 3 3

[23]

[24]

[43] [46] [27]

Notes: DSPE-PEG: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG, PEG MW = 5 kD); DMSA: 2,3-dimercaptosuccinic acid; OAm-PEG: oleylamine-α,ω-bis(2-carboxyethyl)poly(ethylene glycol).

been applied. For example, a layer of graphitic shell was coated onto FeCo NPs to protect their high magnetic moment from fast decay [36,43]. Crystalline Fe3O4 shell was also used to protect metallic Fe NPs as demonstrated in the Fe/Fe3O4 NPs through the controlled oxidation of the as-synthesized Fe NPs with (CH3)3NO [26]. Metallic NPs that have been studied as contrast agents for MRI are listed in Table 1. 2.2. Multifunctional MNPs Iron oxide MNPs are already multifunctional. Due to their response to external magnetic field, they have been studied as contrast agent for MRI and as magnetic heating element for magnetic fluid hyperthermia. However, such MNPs only have one kind of chemical surface. To couple these NPs with different biological agents and drug molecules, MNPs with different chemical surfaces are preferred [47]. This can be achieved through molecular functionalization of existing MNPs, design of multi-component MNPs (heterogeneous MNPs), or co-encapsulation of MNPs with other functional components in a matrix (core/shell MNPs). 2.2.1. Molecular functionalization of MNPs Conjugation of other functional molecules onto the surface of MNPs is an easy approach to achieve multifunctionality. This strategy is cost-effective, time-efficient, and easy to adapt for other circumstances. The conjugation can be realized by conventional coupling chemistry, “click” chemistry, and chelating coordination [48]. Conventional coupling chemistry uses the well-known reaction among \NH2, \SH, and \COOH to functionalize MNPs. For example, NH2-coated MNPs can be coupled with functional molecule containing \COOH via an amide bond formed through common

EDC/NHS or sulfo-NHS coupling chemistry. Molecule bearing \SH can be grafted onto the NH2-coated MNPs via a heterobifunctional linker such as succinimidyl iodoacetate, N-succinimidyl-3-(2-pyridyldithio) propionate, or succinimidyl-4-(N-meleiminomethyl)cyclohexane-1carboxylate. “Click” chemistry is a copper-catalyzed cyclo-addition of azide-alkyne and offers an alternative strategy for quick and robust coupling of NPs with other functional molecules [49]. The reaction can be performed in relatively mild conditions and is highly specific. A representative example is the functionalization of cross-linked iron oxide MNPs (CLIO) with 18F, in which CLIO functionalized with azide moiety were reacted with 3-(2-(2-(2-[ 18F]-Fluoroethoxy)ethoxy)ethoxy)prop-1-yne ( 18F-PEG3), producing 18F-CLIO with a decay-corrected yield of 58% [50]. Chelating coordination is often used to conjugate metal ions to MNPs. For example, 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOPA) pre-conjugated on Fe3O4 NPs through amide bond could bind 64Cu for additional positron emission tomography (PET) imaging capability [51]. Dithiocarbamate-bisphosphonate, (dtbp)2, was also studied as both surfactant for CLIO and chelating group for 64Cu [52]. Through chelating bond formation between \COO− and Pt, cisplatin could be conjugated onto the surface of Au–Fe3O4 dumbbell MNPs for controlled platin delivery and release [53]. 2.2.2. Heterogeneous MNPs Heterogeneous MNPs refer to those containing two or more different functional units within one nanostructure, such as Au–Fe3O4, FePt–CdS, and Fe2O3–carbon nanotube MNPs. In such a heterogeneous NP structure, each NP unit exhibits its unique magnetic, optical, or electronic properties and provides its distinct surface for selective chemical modification [54–56].

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

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Au–Fe3O4 dumbbell-like MNPs were prepared through seedmediated growth in which Au NPs were used as seeds and Fe3O4 MNPs were grown on Au by decomposition of Fe(CO)5 followed by oxidation of Fe [53,57]. These dumbbell-like MNPs preserve the optical property of Au NPs (plasmonic absorption at ~530 nm) and magnetic property of Fe3O4 MNPs (saturation magnetic moment at 80 emu/g). The synthesis has been extended to prepare noble metal–metal oxide dumbbell MNPs with Fe3O4 MNPs grown over the noble metal (Au, Ag, Pt, or AuAg) NPs (Fig. 1A) [58]. In these dumbbell MNPs, the size of noble metal NPs was controlled in pre-synthesis and the size of Fe3O4 MNPs was tuned through the concentration of Fe(CO)5 during the reaction. Alternatively, noble metal could be grown on the pre-synthesized MNPs [59–61]. For example, Ag–Fe3O4 MNPs or Ag-hollow Fe3O4 MNPs were made by controlled nucleation of Ag on the pre-formed Fe3O4 MNPs or hollow Fe3O4 MNPs [59,62]. In the synthesis, the as-prepared MNPs dispersed in organic solution and AgNO3 dissolved in water were mixed and agitated by ultrasonication. The sonication provided the energy required for the formation of a micro emulsion with Fe3O4 MNPs assembling at the liquid/liquid interface (Fig. 1B). Fe(II) ions on MNPs acted as a catalytic center for the reduction of Ag + and nucleation/growth of Ag NPs. The partial exposure of MNPs to the aqueous phase caused the formation of Ag–Fe3O4 MNPs, which showed the typical plasmonic absorption of Ag NPs and magnetic behavior of Fe3O4 MNPs. Slightly different from this two-phase reaction, hollow Fe3O4–Ag MNPs were prepared (Fig. 1C) [60]. The synthesis started from Fe MNPs coated with amorphous iron oxide, followed by the reduction of Ag on the shell by oleylamine. As iron oxide shell was amorphous, the mechanical stress caused by the lattice mismatch between iron oxide and Ag was minimized, which led to a low interfacial energy between iron oxide and Ag. Following the Ag deposition, Fe MNPs were oxidized to the hollow Fe3O4 MNPs through the Kirkendall effect [63]. In addition to the noble metal–metal oxide heterogeneous MNPs, semiconductor–metal alloy, semiconductor–metal oxide MNPs, and carbon nanotube–metal oxide complex have also been reported [47,64,65].

For example, FePt–CdS and FePt–CdSe MNPs were fabricated through two-stage reaction (Fig. 1D) [66,67]. First, an amorphous CdS or CdSe layer was grown on the surface of FePt at a low reaction temperature to achieve a core/shell structure. Subsequently, the temperature was raised to crystallize the CdS/CdSe phase. Because of the difference in phase transition temperatures between FePt and CdS/CdSe, the CdS/CdSe components melt and induced their dewetting from FePt cores, resulting in the heterodimeric MNPs. In the case of carbon nanotube–iron oxide (CNT–IO), the CNT nucleated from CO catalytically on iron clusters [68]. The resulted CNT–Fe was oxidized in air to CNT–IO. We should note that the presence of heterojunction between different components modifies the material properties at both sides. This is caused by many factors including surface reconstruction around the junction, lattice mismatch-induced crystal strain, and electron interaction/transfer across the interface, which are still under intensive investigation. In some cases, the original properties are affected negatively. For example, the quantum yield of Fe3O4–CdSe MNPs was only 38% compared with their single-core counterparts (CdSe) [69]. In Au–Fe3O4 MNPs, along the increase of Au core's size (0 to 3 to 8 nm), the r2 relaxivity of the Fe3O4 core deteriorates (121 to 114 to 105 s−1 mM−1) [70]. In another hand, the original properties could be enhanced. For example, the incorporation of Ag core (13.5 nm) onto Fe3O4 MNPs (7–10 nm) increased the coercivity of the MNPs from 300 Oe (Fe3O4) to 500 Oe (Ag–Fe3O4), and also changed their magnetic properties from superparamagnetic (Fe3O4) to ferromagnetic (Ag–Fe3O4) at room temperature [71]. In Ag–CoFe2O4 MNPs, their magneto-optical Faraday rotation was enhanced by nearly an order of magnitude at 633 nm compared to the monomer (CoFe2O4 MNPs) [61]. Table 2 lists some common heterogeneous MNPs studied for biomedical applications. 2.2.3. Core/shell MNPs Multifunctional MNPs can be further prepared by encapsulating MNPs into a robust matrix to form a core/shell structure. There have been a number of examples reporting on the synthesis of core/shell MNPs using gold, silica, zinc oxide [75], polymer [76], or liposomes

Fig. 1. A) Schematic illustration of the growth of metal-oxides dumbbell MNPs on pre-made noble metal NPs and high-resolution transmission electron microscope (HRTEM) images of a) Au–Fe3O4, b) Ag–Fe3O4, and c) AuAg–Fe3O4 MNPs. Reproduced with permission from reference [58]. B) Schematic illustration of the growth of Ag-hollow Fe3O4 dumbbell MNPs in aqueous phase. Reproduced with permission from reference [62]. C) Schematic illustration of the growth of Ag-hollow Fe3O4 dumbbell MNPs in organic phase. Reproduced with permission from reference [60]. D) Schematic illustration of the growth of FePt–CdS dumbbell MNPs. Reproduced with permission from reference [66].

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

C. Xu, S. Sun / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

[77] as the matrix. The robust shell not only protects the magnetic cores, but also prevents the direct contact of magnetic core with other sensitive biological agents. Here, we focus on the gold and silica encapsulation. Gold (Au) encapsulation is advantageous in term of their stability, biocompatibility, and convenience for further functionalization [78]. The Au shell could be deposited on Fe3O4 MNPs through gradually reducing HAuCl4 on Fe3O4 MNPs by oleylamine [79]. After initial coating, the surface of MNPs was treated with sodium citrate and cetyltrimethylammonium bromide (CTAB) for the dispersion in aqueous solution. Such aqueous-soluble MNPs then served as seeds to grow multiple layers of Au or Ag on the surface. The change of shell thickness allowed the tuning of plasmonic properties of the core/shell MNPs to be either red-shifted (to 560 nm with more Au coating) or blue-shifted (to 501 nm with more Ag coating). Au shell could also be formed over MNPs by simultaneously activating MNPs and Au NPs in a hot solution [80]. Specifically, Au NPs (2 nm) coated with alkanethiolate were mixed with MNPs protected with oleylamine/oleate. At an elevated temperature (149 °C), alkanethiolate bonding to Au was weakened and small Au attached to MNPs, forming a core/shell structure with thiolate re-capturing the enlarged Au surface. Compared with the direct deposition of Au shell on MNPs, this thermally-driven procedure is time-efficient, cost-effective, and easy to apply to control the shell thickness. More recently, Au shell was grown on poly-L-histidine coated iron oxide NPs in an aqueous phase [81]. The core/shell structure showed both strong absorption in near infra-red spectrum and sensitive MRI response, allowing for multimodality imaging. Silica coating is another popular choice to make MNPs stable and multifunctional. By simply hydrolyzing silica precursors (e.g. tetraethylorthosilicate (TEOS)) under the basic solution, a uniform and thickness-controllable silica shell can be obtained. Silica formed through this approach (Sol–gel approach) is usually amorphous and has strong affinity to MNPs [82–84]. For example, quantum dots (QDs) and iron oxide NPs had been co-encapsulated inside the silica NPs to preserve magnetic property of iron oxide NPs and optical property of QDs [85], enabling the magnetic manipulation with real-time fluorescence microscope imaging [86]. This silica shell can also act as a carrier for

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anticancer drugs (e.g. paclitaxel) and fluorescent molecules (e.g. fluorescein isothiocyanate (FITC)) [87]. By simply mixing FITC modified aminopropyltriethyoxysilane with silica precursor (TEOS) during the encapsulation step, FITC was incorporated onto the surface of MNPs. The anticancer drugs were inserted into the porous silica matrix through soaking MNPs in a concentrated drug solution in dimethylsulfoxide (DMSO). These modifications as discussed above can allow MNPs to have exotic properties such as plasmonic resonance and enhanced chemostability. However, it should be noted that these are achieved at the price of increased distance between the superparamagnetic core and biological environment (water molecules mostly), which might subsequently result in reduced sensitivity in MRI. The issues have been discussed more thoroughly in a recent review by Hyeon et al. [88]. 2.3. Hollow MNPs As a potential drug-delivery tool, MNPs offer the possibility of being directed toward a specific target and eventually remaining localized by means of an applied magnetic field. Research on the synthesis and modification of MNPs has enabled the further studies on MNP biocompatibility, chemical stability, uniformity, and controllable circulation in vivo. And emerging reports also provide solid evidence for the effectiveness of the MNP-based delivery system. However, limited by the high density of the inorganic core and the necessary coating for MNP stabilization, a drug in the conjugates can only occupy a very small mass percentage [6]. One solution is to use hollow MNPs that have a magnetic shell and void core. In this case, drugs can be loaded both outside and inside of the MNPs. Considering the biocompatibility requirements, the ideal candidates are Fe3O4 hollow MNPs (HMNPs) [63,89], Fe hollow nanoframe [90], MnxFe3 − xO4 hollow nanotube [91], Fe3O4/ZnS HMNPs [92], and porous Fe3O4 or Fe3O4–SiO2 double layer hollow nanorods [93,94]. Fe3O4 HMNPs were synthesized through controlled oxidation of core/shell structured Fe/Fe3O4 MNPs by an oxygen transfer agent (CH3)3NO (Fig. 2A) [63]. Core/shell Fe/Fe3O4 MNPs were obtained by high-temperature solution-phase decomposition of Fe(CO)5 and air oxidation of the amorphous Fe MNPs at room temperature [26].

Table 2 Heterogeneous MNPs studied for potential biomedical applications. Name

Functional components

Size of components (nm)

Biomedical applications

Reference

Au–Fe3O4

Au Fe3O4 Ag Fe3O4 AuAg Fe3O4 Ag CoFe2O4 Ag Hollow Fe3O4 Cu Hollow Fe3O4 TiO2

3, 5, 6, 8 12, 18, 20, 25 2–15, 13.5 9, 12, 13 6 10 6 14 4–8, 4 5–10, 12 17 17 Length: 50–70; 18 Thickness: 5–6 5.6, 11.3–8.1 2–4 4 4.6 8 Diameter: 1 2–5 10 6 3 5 3 6–8

Optical imaging, MRI, magnetic manipulation, and platin delivery

[53,58,70]

Two photon fluorescence imaging, and magnetic manipulation

[58,71,72]

Ag–Fe3O4 AuAg–Fe3O4 Ag–CoFe2O4 Ag-hollow Fe3O4 Cu-hollow Fe3O4 TiO2–γ-Fe2O3

CdSe–Fe3O4 XS (X=Zn, Cd, Hg)–γ-Fe2O3 Carbon nanotube–Fe2O3 FePt–Au FePt–CdS FePt–CdSe

γ-Fe2O3 CdSe Fe3O4 XS (X = Zn, Cd, Hg) γ-Fe2O3 Carbon nanotube Fe2O3 Au FePt FePt CdS FePt CdSe

[58] [61] [60,62] [60] Magnetically induced hyperthermia; magnetic induced targeting; and photodynamic therapy

[64,73]

Fluorescent imaging and magnetic manipulation

[69] [65]

MRI and near infra-red mapping

[68]

Biological detection, MRI, and optical signal enhancing

[74] [67]

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During the controlled oxidation process, Fe diffuses outward at a faster rate than oxygen from (CH3)3NO does inward, which produces the Fe3O4 at the metal–oxide interface rather than the interior of the core (Kirkendall effect). With different mechanism (acid etching vs. Kirkendall effect), Fe3O4 NPs can evolve from solid MNPs to uniform HMNPs under the continuous heating in the presence of trioctylphosphine oxide (TOPO) and alkylphosphonic acid (Fig. 2B) [89]. In the heating process, alkylphosphonic acid coordinated to the metal cations on the surface of MNPs and formed iron–phosphonate complexes. The Fe hollow nanoframes were produced from the thermal decomposition of Fe(II)–stearate complex in the presence of sodium oleate and oleic acid (Fig. 2C) [90]. Recently, corrosion-aided Ostwald Ripening was used to prepare two-component HMNPs, Fe3O4/ZnS HMNPs (Fig. 2D) [92]. In this synthesis, FeS NPs were prepared first and then dispersed in the aqueous mixture containing Zn(acac)2, poly(vinylpyrrolidone), ammonium nitrate, and glycol. After reacting at 150 °C for 10 h, the superparamagnetic fluorescent Fe3O4/ZnS HMNPs were obtained. Porous Fe3O4 hollow nanorods were prepared a wrap–bake–peel process from akagenite (beta-FeOOH) nanorods (Fig. 2E) [93]. In this synthesis, β-FeOOH nanorods were prepared as a template to deposit a layer of silica precursor, followed by calcinations in air and reduction under the hydrogen/argon flow to transform the inner iron oxide to Fe3O4. The silica removal provided porous hollow Fe3O4 nanorods [93]. Without silica removal, it became Fe3O4–SiO2 double layer hollow nanorods [94].

3. Modification and functionalization of MNPs For MNPs, the main forces affecting their stability in solution are attractive van der Waals forces, repulsive double layer, and steric interactions [95]. Such forces have been extensively discussed in the literature [96,97] and are out of scope of this review. There are various kinds of materials that can act as dispersants for MNPs. The commonly chosen ones include 2,3-dimercaptosuccinic acids, catechol derivatives, dendrimers, polysaccharides, cellulose, chitosan, PEG, and PVP (more details could be found in a recent review by Reimhult et al. [98]). They can be grafted onto the surface of MNPs through either ligand addition or ligand exchange [2]. Ligand addition does not need to remove the original protecting ligands and usually generates core/shell or layer-by-layer structure [99]. MNPs modified in this strategy usually have better dispersibility and chemical stability, as demonstrated in FePt NP stabilization and dispersion by using surfactant addition with DSPE-PEG as dispersants [100]. The second method, surfactant exchange replaces the original surfactants with the dispersants (e.g. catechol derivatives [101]) that have stronger affinity to the surface of iron oxide MNPs. This has been shown in the functionalization of Fe MNPs [26], Fe3O4 HMNPs [13], and Au–Fe3O4 MNPs [70] with a catechol derivative, dopamine. The strong coordination bond between Fe and catechol enables the replacement of the original surfactants, producing stable MNP dispersions in water.

Fig. 2. Transmission electron microscope (TEM) image of A) 13 nm Fe3O4 HMNPs. Reproduced with permission from reference [63]. B) 21 nm sized Fe nanoframe. Reproduced with permission from reference [90]. C) Cubic α-Fe2O3. Reproduced with permission from reference [89]. D) Fe3O4/ZnS HMNPs. Reproduced with permission from reference [92]. E) Wrap–bake–peel process to obtain nanocapsules from akagenite. Reproduced with permission from reference [93].

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

C. Xu, S. Sun / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

After modification, hydrodynamic diameter and surface charge (zeta potential) of the MNPs need to be characterized because the size and charge of MNPs can impact their uptake by cells and their distribution in organs [102,103]. Previous studies have indicated that when MNPs with a hydrodynamic diameter larger than 200 nm are delivered into the circulation through systematic administration, they are easily sequestered by the reticuloendothelial system (RES) of the spleen and liver. But if the size is less than 10 nm, they are subject to rapid renal clearance [104]. Therefore, to ensure maximal NP circulation, the optimum hydrodynamic diameter is believed to be between 10 and 200 nm. Villanueva et al. showed that the charge and nature of surface functionalizing molecules on MNPs affected their response to cancer cells [105]. In four different charged carbohydrates including dextran (neutral), aminodextran (positive), heparin (negative), and dimercaptosuccinic acid or DMSA (negative), cells had effective uptake of aminodextran-MNPs, minimal uptake of neutralcharged dextran coated MNPs, low uptake of DMSA-coated MNPs, and concentration dependent uptake of heparin coated MNPs. In addition, the surface charge also influenced the location of MNPs after cellular internalization. Schweiger et al. found that negatively charged MNPs were firstly in endosomes and lately in lysosomes whereas positively charged MNPs were exclusively inside lysosomes [106]. As early as 1996, Chouly et al. have demonstrated that surface charge influenced the capacity of MNPs to be opsonized right after injection and so changed their phagocytosis. They found that the negatively charged MNPs enhanced liver uptake greater than neutral MNPs [107]. 4. Biomedical applications 4.1. High magnetic moment MNPs for biosensing Rapid and sensitive measurement of clinically relevant biomarkers, pathogens, and cells in biological samples (e.g. blood or urine) is priceless for early detection/screening of disease like cancer, and for real-time monitoring of personal responses to treatments [108]. Diagnostic magnetic resonance (DMR) based on MNPs has recently received considerable attention because of its low magnetic background from biological samples, which enables the sensitive identification of small percentage of biomarkers from the ocean of background entities [109]. One important parameter in these assays is signal-to-noise ratio or sensitivity, which relates directly to magnetic properties of MNPs. MNPs with high magnetic moment are ideal candidates to meet this need. DMR measures the transverse relaxation rate (R2) of water molecules in biological samples in which target molecules or cells of interest are labeled with MNPs [110]. There are two forms of DMR assays depending on the size of the targets [108]. For molecule targets smaller than that of MNPs, molecular targets are used as cross-linking agents to assemble MNPs into clusters, thus effecting a corresponding decrease in T2. Alternatively, enzymatic cleavage or competitive binding of molecular targets disassembles pre-formed clusters to cause an increase in T2, which is called reverse switching. For large biological structures like cancer cells or bacteria, targeted MNPs tag the surface markers to impact their magnetic moment. The change of 1/T2 is proportional to the number of cells/bacteria MNPs bind, and also indicative of the abundance of relevant surface biomarkers. Lee and Weissleder et al. utilized MnFe2O4 MNPs to label cancer cells from fine-needle-aspirates (FNA) to allow the quantification and profiling of cancer cells with DMR-2 system developed in their group [111]. Thanks for the high magnetic moment of MnFe2O4 MNPs, they could detect as less as 2 HER2/neu positive cancer cells with only 1 μL sample and 15 min frames (Fig. 3A and B). While with traditional iron oxide MNPs, the sensitivity is 1000 cells with the requirement of 10 μL sample. With the same DMR device, the same group demonstrated that another type of MNPs with high magnetic moment, Fe MNPs could be conjugated with antibodies for tuberculosis detection [112]. In the assay, the biological samples were incubated with Fe MNPs and then separated from the unbound Fe MNPs before DMR diagnosis. With these

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high magnetic moment MNPs, as few as 20 CFUs (colony-forming units) could be detected in 1 mL of sputum sample in less than 30 min (Fig. 3C and D). 4.2. Molecular imaging with multifunctional MNPs Molecular imaging is a biomedical research discipline dealing with visualization, characterization, and quantification of biological processes at the cellular and sub-cellular levels. The images produced through molecular imaging (usually non-invasive) would help reflect cellular and molecular pathways and mechanism of disease in the subjects. Existing imaging techniques include MRI, PET/SPECT, optical imaging (fluorescence, bioluminescence, and optical coherence), CT, ultrasound etc., and each of them has their own advantages and disadvantages. For example, MNP based MRI is advantageous for the higher spatial resolution (10–100 μm), but suffers from the lower sensitivity, the high background coming from “field disturber”, and long acquisition time/high cost [113,114]. On the other side, PET are super sensitive (10 −11–10 −12 M) with low background, and optical imaging is time/cost efficient which facilitates rapid testing of biologic hypotheses and proofs-of-principle in living experimental models. Therefore, using multifunctional MNPs that combine the advantages of two or more imaging modalities is becoming an attractive strategy in molecular imaging. Here we will describe some representative examples in tumor imaging and cell tracking. 4.2.1. Tumor imaging To diagnose tumor malignancy early and accurately in clinics, it is necessary to apply two or more imaging modalities [115]. The emergence of multifunctional MNPs fulfills this need and would minimize the cost in clinical practices. Au–Fe3O4 dumbbell MNPs (Fig. 4A) have been studied for both MRI and optical imaging of EGFR-positive breast cancer cells (Fig. 4B and C). Au NPs are optically active and have been used in a variety of optical imaging based on light-scattering, two-photo luminescence and surfaceenhanced Raman scattering [116]. Au NPs also present enhanced light reflection between 500 nm and 800 nm [70]. The combination of Au and Fe3O4 in the dumbbell MNPs allows the integration of reflection imaging and MRI, which could potentially be used as dual contrast agents for MRI diagnosis before surgery and metastasis mapping during surgery. Recently, Chen et al. reported a triple functional imaging probe for PET/NIFR/MRI [117]. They modified Fe3O4 MNPs with human serum albumin (HSA) and functionalized HAS–Fe3O4-NPs with 64Cu-DOTA and Cy5.5 (Fig. 4D). In this case, they obtained a novel reporter that had a high spatial resolution (MRI), good signal-to-noise ratio (PET), and convenience for both in vivo and ex vivo analysis (near infrared fluorescence (NIRF)). In a subcutaneous U87MG xenograft mouse model, Chen demonstrated the triple-imaging-capabilities of this contrast agent through examining the preferred accumulation in tumor after 18 h circulation time (Fig. 4E–G). 4.2.2. Cell tracking Another exciting application of multifunctional MNPs is to qualitatively and quantitatively monitor transplanted cells in the exogenous cell therapy, which utilizes transplanted cells, in particular stem and progenitor cells, to replace or regenerate damaged or diseased tissue [118]. The understanding of cell distribution and engraftment tracking in cell therapy will facilitate prediction of treatment efficacy, reveal optimal transplantation conditions including cell dose, delivery route, and timing of injections, and ultimately improve patient treatment [119,120]. Stelter et al. showed that an aminosilane coated MNPs could be functionalized with the fluorescent dye (fluorescein) and the positronemitting radioisotope (gallium-68) [121]. Hepatogenic HuH7 cells labeled with these MNPs were intravenously administered and could be followed through the sensitive γ-ray measurements. Their results

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Fig. 3. A) TEM and HRTEM (insert) images of 16 nm MnFe2O4 MNPs. B) Human breast cancer cells (BT474) were labeled with anti-Her2 CLIO and MnFe2O4 MNPs. The change in R2 (R2 = 1/T2) varied linearly with cell counts, and the detection sensitivity was 10× better using the more magnetic MnFe2O4 MNPs. Reproduced with permission from reference [111]. C) Fe MNPs or Cannonballs (CBs) that have an iron core (11 nm) passivated with a thin ferrite shell (2.5 nm). D) Comparison of detection sensitivity. First, a microfluidic chip without a membrane filter was used to determine the intrinsic mass-detection limits. The bacteria were targeted either with CB–BCG (MNPs conjugated with monocolonal antibody of bacillus Calmette–Guerin, a surrogate for tuberculosis) or CLIO–BCG. With CB–BCG, they achieved a mass-detection limit of approximate 6 CFU (1 μL detection volume), much lower than that of approximate 100 CFU for CLIO–BCG. When CB–BCG-targeted samples (100 μL) were filtered, the concentration limit was further reduced to approximate 60 CFU/mL. Reproduced with permission from reference [112].

revealed the predominant localization of the labeled cells in the lungs 2 h after injection and the even distribution throughout the animals' body 48 h later. Nahrendorf et al. designed a PET-MRI-fluorescence trimodality contrast agent through chelating 64Cu onto the dextranated and DTPA-modified magnetofluorescent MNPs [122]. This platform was used to image the macrophages and to identify the atherosclerotic lesions in an Apolipoprotein E deficiency (apoE−/−) mouse model. The combination of PET, MRI and fluorescence combined the individual advantages of each imaging modality. After in vivo distribution of MNPs, all imaged apoE−/− mice showed a robust PET signal in the aortic root and arch, which showed significant differences between accumulated dose in excised aortas and carotids in apoE−/− versus wild-type mice.

4.3. Drug delivery with hollow MNPs Targeted drug delivery is a Holy Grail in chemotherapy. In an ideal targeted drug delivery, the drug carrier selectively delivers drug molecules to the diseased site without a concurrent increase in their intensity in healthy tissues. In the late 1970s, Widder and Senyi proposed the idea of using MNPs to carry drugs to specific sites such as solid tumor, where high-field magnets were positioned [123,124]. Following their early studies, the efficacy of this approach was demonstrated in numerous small animal studies and even resulted in a small number of clinical trials [125]. However, despite these efforts and achievements, this technique has yet to develop into a workable clinical application. One of the reasons is the low payload capacity of existing MNPs [6] because payload (i.e. drugs) can only be attached on the surface or embedded in the double-layer coating around MNPs. To address this issue, one of the solutions is to utilize hollow MNPs discussed in Section 2.3, in

which drugs could be loaded both inside their hollow core and on the surface. Our group investigated this hypothesis through utilizing Fe3O4 HMNPs to deliver cisplatin (one of traditional chemotherapeutics) to HER2/neu positive cancer cells [13]. We noticed the shell of Fe3O4 HMNPs (Figs. 2A and 5A) was polycrystalline and its crystallinity could be further improved by prolonged heating in solution containing oleic acid. With the crystal domain growing larger in the shell structure, the crystal boundaries in the polycrystalline structure opened up, resulting in the porous shell with 3 nm pore size (Fig. 5B). The open pores facilitated the diffusion of cisplatin into the cavity of Fe3O4 HMNPs during the ligand exchange process (Fig. 5C). More specifically, we carried out the loading by mixing oleylamine/oleate-coated Fe3O4 HMNPs with cisplatin and replacing surfactant (i.e. dopamine-PEG) in chloroform/DMF followed by solvent evaporation to maximize cisplatin loading. Through this method, we could improve the cisplatin percentage on the final conjugate from 4.82% of Fe3O4 MNPs to 24.8% of Fe3O4 HMNPs. This high payload capacity of hollow MNPs has also been confirmed by other groups. With porous Mn3O4 HMNPs, Lee et al. improved the loading amount of a hydrophobic anticancer agent (doxorubicin), where they mixed the water-dispersible porous Mn3O4 HMNPs with doxorubicin in CH3OH/CH3Cl and evaporated the organic solvent [126]. They found that the amount of doxorubicin incorporated into the porous Mn3O4 HMNPs was 3.5 times higher than that on the solid Mn3O4 MNPs under the same NP concentration. The final doxorubicin percentage in Mn3O4 HMNPs was approximately 14% while that in Mn3O4 MNPs was approximately 4%. Shi et al. tested the hollow core, magnetic, and mesoporous double-shell MNPs (Fe3O4/SiO2 in Fig. 2E) as carriers for water-insoluble anticancer drugs (docetaxel or camptothecin) [94]. The drugs were

Please cite this article as: C. Xu, S. Sun, New forms of superparamagnetic nanoparticles for biomedical applications, Adv. Drug Deliv. Rev. (2012), http://dx.doi.org/10.1016/j.addr.2012.10.008

C. Xu, S. Sun / Advanced Drug Delivery Reviews xxx (2012) xxx–xxx

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Fig. 4. A) TEM image of 8–20 nm Au–Fe3O4 dumbbell MNPs. Scale bar is 20 nm. B) T2-weighted MRI images of i) 20-nm Fe3O4, ii) 3–20-nm Au–Fe3O4, iii) 8–20-nm Au–Fe3O4 MNPs, and iv) A 431 cells labeled with 8–20-nm Au–Fe3O4 MNPs. Reproduced with permission from reference [70]. C) Reflection images of the A431 cells labeled with 8–20-nm Au–Fe3O4 MNPs. D) Schematic illustration of the multi-functional HSA–Fe3O4-NPs. E) Representative in vivo NIRF images of mouse injected with HSA–Fe3O4-NPs. Images were acquired 1 h, 4 h and 18 h post injection. F) In vivo PET imaging results of mouse injected with HSA–Fe3O4-NPs. Images were acquired 1 h, 4 h and 18 h post injection. G) MRI images acquired before and 18 h post injection. Reproduced with permission from reference [117].

loaded through soaking the MNPs in a concentrated drug/DMSO solution. After purification, the drugs represented 15–14% (mass percentage) of the final products. In comparison, for solid silica encapsulated Fe3O4 MNPs, the drug percentage was only 1–3% [87].

5. Conclusion In this paper, we have summarized recent efforts in designing new platforms of MNPs to address the problems met in the biomedical

Fig. 5. HRTEM images of A) Fe3O4 HMNP and B) Fe3O4 porous HMNP. C) Schematic illustration of simultaneous surfactant exchange and cisplatin loading into a Fe3O4 porous HMNP and functionalization with Herceptin. Reproduced with permission from reference [13].

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application of traditional MNPs. To improve the magnetic moment, other metal ions are chosen to dope into the spinel structure of ferrite. High magnetic moment metallic MNPs are further synthesized and stabilized. To improve the sensitivity and accuracy of MRI, other NP components responsible for different imaging modalities are also combined into one MNP unit. To improve therapeutic efficacy, hollow MNPs are designed so that more drug can be loaded both inside and outside the NPs. These multifunctional MNPs have shown great advantages over the traditional MNPs in disease diagnosis, cancer imaging, cell tracking and drug delivery. Once their biodistribution and metabolism are better understood, these new forms of MNPs will serve as sensitive probes and platforms for highly efficient diagnostic and therapeutic applications. Acknowledgments This work was supported in part by Nanyang Technological University Start-Up Grant to XCJ and Brown Imaging Fund to SS. References [1] O.C. 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