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Development of Superparamagnetic Iron Oxide. Nanoparticles (SPIONS) for Translation to. Clinical Applications. Meng Meng Lin, Do Kyung Kim, Alicia J. El Haj, ...

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Development of Superparamagnetic Iron Oxide Nanoparticles (SPIONS) for Translation to Clinical Applications Meng Meng Lin, Do Kyung Kim, Alicia J. El Haj, and Jon Dobson*

Abstract—Superparamagnetic iron oxide nanoparticles (SPIONs) have attract a great deal of interest in biomedical research and clinical applications over the past decades. Taking advantage the fact that SPIONs only exhibit magnetic properties in the presence of an applied magnetic field, they have been used in both in vitro magnetic separation and in vivo applications such as hyperthermia (HT), magnetic drug targeting (MDT), magnetic resonance imaging (MRI), gene delivery (GD) and nanomedicine. Successful applications of SPIONs rely on precise control of the particle’s shape, size, and size distribution and several synthetic routes for preparing SPIONs have been explored. Tailored surface properties specifically designed for cell targeting are often required, although the generic strategy involves creating biocompatible polymeric or non-polymeric coating and subsequent conjugation of bioactive molecules. In this review article, synthetic routes, surface modification and functionaliztion of SPIONs, as well as the major biomedical applications are summarized, with emphasis on in vivo applications. Index Terms—SPION, nanoparticles, biomagnetics, surface coatings, biomedical, gene therapy, MRI.

I. INTRODUCTION PPLICATIONS of superparamagnetic iron oxide nanoparticles (SPIONs) in biomedicine have been expanding over the last decade. There is enormous potential for utilising these nanoscale tagging and delivery strategies for applications in hyperthermia (HT), magnetic resonance imaging (MRI), gene delivery (GD), magnetic drug targeting (MDT), nanomedicine and regenerative medicine. SPIONs represent an elegant mechanism for controlling and interacting with cells and tissues. Key features of SPIONs include the fact they exhibit magnetization only in an applied magnetic field, that they can form stable colloidal suspensions which can be crucial for biomedical applications, especially in vivo, and that they can be directed to a desired site in the body, making them useful for controlled targeting in clinical applications. Successful application of SPIONs in healthcare is strongly dependant on the structural characteristics, specifically the ability to control the size and size distribution, a uniform shape, strong magnetic susceptibility and the desired surface chemistry. Tailored surface engineering of the particles can

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Manuscript received June 06, 2007; revised August 11, 2007. Current version published nulldate. This work was supported in part by the BBSRC and in part by the EPSRC. Asterisk indicates corresponding author. M. M. Lin, A. J. El Haj, and D. K. Kim are with the Institute for Science and Technology in Medicine, Keele University, ST4 7QB, UK. *J. Dobson is with the Institute for Science and Technology in Medicine, Keele University, ST4 7QB, UK (e-mail: [email protected]). Digital Object Identifier 10.1109/TNB.2008.2011864

be done through creating a polymeric or inorganic molecular shell surrounding the iron oxide cores, followed by the functionaliztion with specific biomolecules on the outer shell layer. In this review, various synthetic routes are explored, and the surface modification, including various coating materials and bio-functionaliztion with examples are also summarized. These examples are then presented in the context of biomedical applications specifically with a focus for moving this technology into the clinic. II. SYNTHESIS OF IRON OXIDE NANOPARTICLES A. Aqueous Coprecipitation Coprecipitation of Fe and Fe salts with alkaline in aqueous solution is the most common method to synthesize iron oxide nanoparticles, due to the low reaction temperature and the hydrophilic surface properties of the resulting particles. Conventionally, magnetite (Fe O ) is prepared by addition of ammonia to the aqueous mixture of Fe and Fe chloride at the ratio of 2:1 [1]. With alkaline coprecipitation in aqueous solution, the overall size, composition and even shape of the particles can be controlled to some extent, through the use of different types of salts (it is possible to adjust pH, ionic strength, and Fe /Fe ratio). But synthesis of nanometer-sized particles with narrow distribution in bulk solution remains a challenge. A modified method of coprecipitation can be used to produce particles with better size control, relying on the principle of particle formation in highly constrained domains. There are two routinely used methods to prepare polymer-coated iron oxide nanoparticles: one is called the step-wise method, which involves aqueous coprecipitation and subsequent coating process done in ultrasound. The other is one-pot coprecipitation in the polymer matrix, either polysaccharides or synthetic polymers, which restricts the growth of nanoparticles [2]. The latter is more popular now, due to its simplified procedure and reduced nanoparticles sizes. B. Microemulsion Microemulsion is defined as a thermodynamically stable, isotropic dispersion of two immiscible liquids, stabilized by a monolayer of surfactant at the interface of the two liquids. In water/oil microemulsion (w/o or inverse microemulsion) systems, small aqueous nanodroplets are dispersed in the organic phase, and vice versa. Homogenous SPIONs can be produced via w/o microemulsion, which are illustrated in Fig. 1. Compared to simple aqueous coprecipitation, microemulsion has certain advantages, due to the small size of the microemulsion

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Fig. 2. Schematic illustration of the two-step preparation of highly monodispersed iron oxide nanocrystals. (a) Synthesis of iron-oleate complexes; (b) synthesis of iron oxide nanocrystals via thermal decomposition. (Figure adapted from Park et al. [8]).

Fig. 1. Schematic illustration of coprecipitation of Fe O nanoparticles via a w/o microemulsion system.

(a few nanometres) which acts as a nano-reactors, confining the nanoparticles’ nucleation and growth. This method produces nanometer-sized, monodisperse iron oxide particles with better control of the size distribution. In addition, the size of the microemulsion can be adjusted by changing the ratio of water/surfactant/oil, thus the nanoparticles size can be controlled [3], [4]. However, there are also drawbacks to the microemulsion method. It is very difficult to scale up due to the huge amount of oil (organic phase) required and the surfactants which adhere to the particles are difficult to remove. Recently, Gupta et al. prepared highly monodispersed SPIONs less than 15 nm with uniform physical and chemical properties [3]. Microemulsion can produce not only iron oxide particles with uniform sizes, but also can be used in the polymerization of the shell coating, thus producing polymeric magnetic particles with controlled particle size and magnetic properties. Deng et al. prepared polymeric SPIONs via inverse microemulsion with controlled size (80–180 nm) by changing surfactant concentration and the amount of the cross-linkers [4]. C. Thermal Decomposition Thermal decomposition of various types of iron precursors, such as Fe(acac) [5], Fe(CO) [6] and Fe(oleate) complexes, [7], [8] under high temperature, has been recently developed to produce highly monodispersed iron oxide nanocrystals. The complete separation of nucleation and growth is a critical factor in achieving uniform-sized particles. Hyeon et al. succeed in the development of one-nanometerscale size-controlled synthesis of monodispersed magnetic iron oxides by thermal decomposition of iron oleate in 1-octadecene [7], [8]. The overall procedure to synthesise monodispersed oxide nanoparticles via thermal decomposition is shown in Fig. 2.

The thermal decomposition method can produce monodispersed SPIONs which is highly desirable in controlling particles’ physico-chemical properties, but the hydrophobic surface limits the biomedical applications that require water-dispersability and biocompatibility. The surface modification of such hydrophobic iron oxide particles remains a challenge. Zhen et al. produced water-dispersible SPIONs at high temperature using 2-pyrrolidone as both capping agents and media [9]. Woo et al. modified the hydrophobic SPIONs surface to hydrophilic via Fe-S covalent bond with bi-functional 3-mercaptopronic acid, and then the terminal carboxylic acid group was esterified with dextran to improve biocompatibility [10]. Another example of successful phase transfer from hydrophobic media to aqueous environment without significant aggregation is Qin’s work, which involves further coating the Pluronic polymer (composed of hydrophobic PPO middle part and hydrophilic PEO tails) to the hydrophobic oleic acid surrounded particles, and giving rise the hydrophilic surface properties [11]. III. SURFACE MODIFICATION OF SPIONS Bare SPIONs tend to aggregate and lose their intrinsic superparamagnetic properties in biological solution. Moreover, micrometer-sized aggregates may cause capillary blockage when injected into the body. Therefore, it is important to modify the surface of SPIONs with organic or inorganic substances which will stabilize the SPIONs either by electrostatic or steric repulsion, or both to form stable colloids. The coating is also essential for in vivo use of SPIONs to increase the biocompatibility. Current research had demonstrated that cells massively uptake bare SPIONs by endocytosis which may cause cell death, while particles coated with bovine serum albumin (BSA), dextran or pullulan showed reduced cytotoxicity [12], [13]. Functionaliztion of biomolecules (monoclonal antibodies (MAbs), peptides, oligonucleotides or enzymes) is also utilised as important strategy for targeting specific cells or tissues, and the attachment of these bioactive molecules can be done though the specific functional groups on a coating layer. In the following section, various coating materials, such as natural or synthetic polymers, surfactants and inorganic coating molecules are presented, and several functionalized particles are described as examples.

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Fig. 3. Chemical structures of (a) dextran; (b) chitosan.

A. Natural Polysaccharides The main source of dextran is Leuconostoc mesenteroides B512F. Dextran is composed of -D-1,6-glucose-linked repeating glucan units, sometimes with side-chains 1–3 linked to the backbone units. The degree of branching is approximately 5%. [14] (Fig. 3.) Dextran is a biocompatible, neutral polymer, thus it is commonly used as coating material for SPIONs. Dextran-SPIONs based on physical adsorption are unstable as dextran tends to dissociate from SPION cores. Covalent bonding between the particle and the dextran coating is, therefore desirable. Sonvico et al. modified SPION surfaces with aminopropylsilane, followed by covalent conjugation of partially oxidized dextran by secondary amine bond [15]. Alternatively, crosslinked iron oxides (CLIOs) can be prepared through “physical adsorption”, followed by cross-linking of dextran, which makes tighter association with SPIONs. Although without covalent bonding between the iron oxide core and dextran shell, CLIOs showed excellent colloidal stability and biocompatibility. Further functionaliztion of dextran-coated particles has been performed through conjugation of desired molecules to the dextran layer. Hydroxyl groups on the dextran serve as functional groups for further attachment of bioactive molecules. The multivalent nature of dextran allows molecules to be attached at numerous sites along the polymer chain. Activated dextran containing functional groups such as carboxylate, amine, and aldehyde, has been coupled with proteins and other biomolecules. The dextran can be oxidized by sodium periodate to cleave the associated carbon between the two adjacent diols resulting in an aldehyde. The oxidized dextran is a highly reactive, multifunctional polymer which can be coupled to numerous amine containing molecules. Chen et al. modified the oxidized dextran coating to generate amine groups for conjugation of folate and fluorescein isothiocyanate (FITC) [16]. Weissleder et al. prepared aminated CLIOs by simply soaking CLIOs in ammonia overnight, and the same authors attached Tat peptides to aminated dextran through -succinimidyl3-(2-pyridyldithio) propionate (SPDP) [17]. Chitosan is a linear polysaccharide consisting of repeating units of N-acetyl-D-glucosamine and D-glucosamine, formed by partial deacylation of the naturally occurring polysaccharide chitin at the N-position. (see Fig. 3.) [18] Cost-effective chitosan, with its bioadhesive and biocompatible properties, has enormous applications in the pharmaceutical industry, such as drug carrier, absorption enhancement, gene delivery, metal chelating agent, etc., Lee et al. synthesized chitosan-SPIONs by sonochemical methods and demonstrated their use as MR

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contrast agents in a New Zealand white rabbit model [19]. Other authors had demonstrated that chitosan coating can guide spatial electrodepostion of SPIONs to construct Fe O films due to its positive charge under neutral pH [20]. Natural starch, a long chain of D-glucose, which provides good biocompatibility and biodegradability, is another coating substance for SPIONs. Kim et al. synthesized starch-coated SPIONs via alkaline coprecipitation of iron salts in the starch matrix, which prevents the particles’ agglomeration. Afterward, H O treatment was applied to cleave the glucosidic bond to reduce the agglomeration size. In vivo MRI after direct injection of these SPIONs into rat brains demonstrated the feasibility of these starch coated iron oxide particles as MR contrast agents for brain scans [21]–[23]. Gupta et al. prepared and characterized pullulan-coated mag– nm). Due to pulnetic particles (Pn-SPIONs; diameter lulan’s high affinity for asialoglycoprotein, the Pn-SPIONs may prove useful for magnetic resonance angiography, imaging of lymph nodes, perfusion imaging, receptor imaging and target specific imaging [24]. B. Synthetic Polymers Polyethylene glycol (PEG) has been used as a coating substance to stabilize SPIONs. The surface coverage of PEG minimizes or eliminates protein absorption onto the particle surface resulting in the particles evading the reticuloendothelial system (RES). To immobilize PEG onto the SPION surface, silane coupling agents are commonly used, such as 3-aminopropyltrimethoxysilane [25]. PEG molecules have only one hydroxyl group at the end, resulting in limited further functionaliztion. Kolher et al. had demonstrated that synthesized trifluoroethylester (TEFE)-terminal PEG silane not only self-assembled onto SPIONs to form a stable layer, but also carboxylic and amine groups were generated for further fixation of targeting ligands [26]. Poly (ethylene oxide) (PEO) is a well-known biocompatible, and non-biodegradable polymer. PEO-containing copolymers are used as coating materials in stabilizing SPIONs, taking advantage of its hydrophilicity and resistance to protein absorption to increase the blood circulation time. Harris et al. synthesized triblock copolymer (containing two PEO tails and a central polyurethane segment) coated SPIONs that are stable at physiological pH [27]. Thunemann et al. coated SPIONs with a layer of positively charged poly (ethylene imine) (PEI), followed by absorption of poly (ethylene oxide)-poly (glutamic acid) (PEG-PGA) copolymer on maghemite nanoparticles, resulting in 46 nm particles, suitable for use as an MR contrast agent, as tested in rats [28]. Polyvinyl alcohol (PVA) is also a good synthetic polymer that prevents coagulation and results in monodispersed particles [29]–[31]. Fetri-Fink et al. functionalized PVA-coated SPIONs with amino, carboxylate and thiol groups and compared the cellular uptake of theses functionalized SPIONs with human melanoma cells. It was shown that the amino-PVA coated particles were taken up by human melanoma cells [30]. In addition, the in vitro and in vivo test of PVA-SPIONs showed the potential use of PVA-SPIONs in MDT in joint inflammatory diseases [31].

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C. Inorganic Molecules The main advantage of silica coating is the presence of surface silanol groups. These groups react with alcohol or silane coupling agents through which further attachment of bioactive molecules can be achieved [32]–[34]. For example, Lu et al. chemically incorporated two fluorescent dyes into silica-coated SPIONs using 3-aminopropyltriethoxysilane coupling agent [33]. Silica coating can stabilize the colloid regardless of changes in pH and electrolyte concentration. In addition, due to their anionic nature, they promote non-specific endocytosis of the particles. Dormer showed the silica-coated particles were internalized by epithelial tissues in a pig model via endocytosis, enhanced by magnetic force [34]. Recently, preparation of core-shell iron oxide/Au nanoparticles has been reported by several authors. Au coating can not only provide high stability and prevent corrosion and oxidation of the iron oxide cores, but also exhibits very good biocompatibility. The main advantage of Au coating is that the Au shell can easily react with thiol-terminated molecules, forming Au-SR covalent bonds, opening the possibility of chemical functionaliztion. Several attempt had been made to reduce Au on the surface of pre-synthesized iron oxide cores. Lyon et al. synthesized nm diameter SPIONs/Au nanoparticles by reduction of Au onto pre-synthesized iron oxide particle surfaces ( nm) via iterative hydroxylamine seeding in aqueous solution [35]. Seino et al. directly reduced HAuCl4 on SPIONs surfaces via ultrasound or -ray treatment. In this work, PEG monostearate and PVA were physically absorbed onto the SPION surface to inhibit the growth of Au particles [36]. To improve monodispersibility, the SPIONs/Au was prepared in the organic phase. Fe O core was first prepared by thermal decomposition of Fe(acac) in phenyl ether as seeds, and the gold acetate was reduced in the presence of capping agents in phenyl ether at high temperature. But such nanoparticles are capped with an organic shell, which limits their biomedical application [37]. It is also worth mentioning that another group attached 2–3 nm Au nanograins onto nm Fe O particles thorough a simple two-step chemically controlled procedure [38]. However, with all the abovementioned methods, the continuity of the metallic coating, the coating thickness and the monodispersibility still remain the major challenges.

IV. SURFACE FUNCTIONALIZATION OF SPIONS The general strategy of bio-functionaliztion of SPIONs and particle-cell interactions are illustrated in Fig. 4. Surface modification involves two steps: creating a polymeric or non-polymeric shell and conjugation of bioactive molecules onto this coating. Various biomolecules such as antibodies, proteins and peptides can be conjugated to SPIONs as targeting ligands to facilitate the recognition of specific cells/tissue. Targeting cell surface receptors are of particular interest in targeted drug/gene delivery or localized hyperthermia treatment. Due to their different natures and functions, protein-functionalized magnetic particles can be potentially used in either passive or active targeting.

Fig. 4. Schematic illustration of (a) tailored surface engineering of SPIONs; (b) ligand tagged SPIONs selective binding to specific receptors on cells.

A. Protein Derivatization The chemical conjugation of proteins to SPIONs needs to be handled with care. Monoclonal antibodies (MAbs) as targeting agents with SPIONs have been widely investigated, due to the specific and strong interaction of the antibody and antigen. However, the use of MAbs can be potentially problematic, because MAbs are large and elicit immune responses in the body. Natural proteins are often attached to SPIONs for various purposes, such as generically reducing the cytotoxicity of the particles, [23] and giving rise to specific targeting ability. Berry et al. synthesized superparamagnetic particles, derivatized with transferrin, lactoferrin and ceruloplasmin, and characterized these particles in vitro and tested their influence on human dermal fibroblasts. Such derivatized particles attached to the cell membrane, most likely to the cell-expressed surface receptor and were not endocytosed [39]. Some cancer cells also over-express certain hormonal receptors, thus natural hormones or derivatives may be tagged onto SPIONs for cancer targeting. It has been shown that luteinising hormone releasing hormone (LHRH) tagged SPIONs were accumulated in primary and metastatic lung and breast cancer cells [40]. B. Peptide Derivatization Due to their small size, peptides are another important targeting agent that can be conjugated to SPIONs. RGD (ArgGly-Asp) is a commonly used peptide for SPIONs. The main receptor that is receptor of RGD motif is the integrin over-expressed in some melanoma cells and tumor blood vessels [41]. Some peptide attachments can even target subcellular compartments, for example, the nuclear localization signal (NLS) peptide isolated from the SV-40 virus can direct particles to enter the nucleus by interacting with nuclear transport proteins [42]. Tat peptide, found in the HIV virus, plays an important role in internalization as a membrane translocating signal peptide [43]. C. Vitamin Derivatization Folic acid (FA) is the most classic example of a vitamin-mediated targeting agent. The folate receptor is a high affinity, folate-binding protein over-expressed in various types of human tumors, while non-proliferating normal cells only express folate receptors at very low level. Thus, FA receptors provide a highly selective site that differentiates tumor cells from normal cells. Some authors have shown FA-SPIONs are massively taken up

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by human epithelial mouth carcinoma, breast adenocarcinoma and cerviex adenocarcinoma [15], [16], [26]. V. BIOMEDICAL APPLICATIONS A. Magnetic Fluid Hyperthermia (MFH) Hyperthermia is a very promising treatment for cancer in both ancient and modern medicine, and based on the fact that cancerous cells are more sensitive to temperature than normal cells. Hyperthermia heating devices include ultrasound, microwaves, laser fibers and other relatively non-specific techniques. By loading tumors with SPIONs, they can act as transducers, converting AC electromagnetic energy into heat which targets only the SPION-loaded cells [44]. The key features of SPIONs as a mediator of hyperthermia are: (i) Nano-sized particles have a higher specific absorption rate (SAR) than micrometer-sized particles, (ii) Magnetic Fluid Hyperthermia (MFH) can achieve localized, controlled heating in deep tissue and (iii) SPIONs can achieve high cellular selectivity via tailored surface modification [15]. More importantly, due to their magnetic properties, the in vivo particle distribution can be determined by MRI prior to heating. It is also possible to combine MFH and antibody therapy together to achieve maximum tumor targeting [45]. Work on various types of cancers in vivo have been reported to have promising tumor responses via MFH in mouse models [46]. B. Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (MRI) is currently a very popular imaging technique that differentiates pathological and normal tissues, based on the relaxation properties of hydrogen atoms in water. Gadolinium (Gd) complexes are routinely distributed into intravascular and interstitial space to enhance contrast in fluid compartments or lesions. But the risk of leaking of toxic Gd ions, the low relaxivity and short half-lives of the compounds limit somewhat the application of Gd-based agents [47]. SPIONs are proved to be a good replacement for Gd contrast agents due to their superparamagnetic complex as properties and high relaxivity. There are a few commercially available iron oxide contrast agents, such as Endorem and Sinerem. The imaging applications depend on particle size. For partinm, they are mainly captured by the cles with diameters RES once injected into the body, which makes them suitable for nm have liver or spleen imaging. Particles with diameter hours) and stay in blood circulaa long plasma half-life ( tion long enough to be used as blood pool agent in magnetic resonance angiography (MRA) [1]. They may also leak into the intersitium and subsequently be captured by macrophages and accumulated in lymph nodes, which makes them useful for detecting lymphatic tumors. Metastatic and normal lymph nodes have been differentiated using MRI and SPIONs in a murine model [48]. The efficacy and efficiency of using MR lymphography to detect lymph node metastasis by a commercial USPIO Sinerem is currently under investigation in stage III clinical trials [49].

C. Magnetic Drug Targeting (MDT) Chemotherapy and radiotherapy are the current treatment options for most cancers; however, side effects are a common consequence of the systematic nature of tese treatments. Targeted drug delivery systems (DDS), which target cancerous cells, offers a promising solution to maximize the efficiency of chemotherapy and radiotherapy and reduce side-effects, dosage and cost [50]. In MDT, magnetic carriers loaded with anti-cancer agents, are intravenously or intra-arterially administrated, and randomly circulated in the blood stream. When applying an external high-gradient magnetic field at the desired site, for example solid tumor site, the drug/carrier complexes is accumulated at that site. Afterward, the drug can be released via either enzymatic cleavage or changes in physiological conditions, such as pH, osmolality or temperatures [51]. In MDT cytotoxic drugs are concentrated in specific organs and may be combined with cellular and subcellular targeting by tailored surface engineering of the magnetic carriers. Another advantage of using magnetic drug carriers in targeting is that MRI can be used to trace the distribution and capture of these particles and thus the success of MDT. A prospective phase I trial was carried out, in which 11 patients were examined by MRI before and after MDT [52]. The criteria of the magnetic particles as carriers in MDT includes: sizes within the range of 10–100 nm to avoid both RES extravasation and renal clearance, hydrophilic surfaces to reduce the plasma protein absorption and maximize blood circulation, and a strong magnetic force to counteract the drag forces from blood flow [50]. Alexiou et al. treated squamous cells carcinoma in rabbits with ferrofluids loaded with mitoxantrone that was concentrated with an external magnetic field [51]. Although some successful animal studies prove the MDT concept, the human trial is still a challenge. Recently, a novel MDT technology composed of two steps had been proposed. First, intravenous injection of magnetic nanocarriers encapsulated with a drug and second, focal concentration of the drug at the target site utilizing an implanted, magnetisable intraluminal stent or seed. Such technology can be performed on demand (acutely or chronically), and also allows changes in drug choices [53]. For comprehensive, recent reviews of the physics and applications of this technology, the reader is referred to [43], [54], [55]. D. Magnetofection and Gene Delivery (MF) Gene therapy is a promising medical treatment for genetic disorders, cancers, cardiovascular disease and neuro-degenerative diseases. The mechanism of gene therapy is to correct the genetic disorder or produce exogenous proteins/peptides which boost the immune system, by insertion of exogenous DNA. The true value of gene therapy cannot be realized until efficient gene deliver vectors are developed. Currently, the transfection/transduction efficiency of both viral and non-viral vectors is limited. Magnetic micro- and nanoparticle-based techniques show great potential for high-efficiency transfection both in vitro and in vivo [56]. This technique, in which DNA, or viral vectors containing DNA, is attached to a magnetic micro- or nanoparticle carrier, was first developed by Mah et al. [57], [58] It has since been further developed, primarily for in vitro, non-vrial applications

LIN et al.: DEVELOPMENT OF SPIONS FOR TRANSLATION TO CLINICAL APPLICATIONS

[59]. There are several advantages of magnetic nanoparticlebased transfection—the potential to use both viral and non-viral vectors; the low vector dose to yield saturation level transfection; the extraordinarily short incubation time to achieve high transfection/transduction efficiency and the possibility of gene delivery to otherwise non-permissive cells and the potential for in vivo targeting [56], [60]. In one example, the gene vector was attached to PEI coated SPIONs (tranMAG ), by electrostatic interaction and salt-induced colloid aggregation. The tranMAG /vector complexes were tested in vitro, in which a strong permanent magnet was positioned beneath the cell monolayer. Peak transfection levels were achieved with 10-min incubation of cells, compared with 2 to 4 hrs required for other non-viral agents, such as cationic lipids. The strongly increased concentration of vectors at the cell surface leads to a dramatically improved dose-response profile [61].

E. Magnetic Stem Cell Imaging (MS) MRI has emerged as potentially powerful tool in the investigation of cell migration and differentiation. The non-invasive MRI tracking of stem cells in vivo has significant implications in stem cell therapy research. A new protocol under development in our and other laboratories is magnetic labelling by surface attachment of SPIONs or via endocytosis and phagocytosis. MRI tracking will then depend on magnetic particle labelling efficiency and a low body clearance rate. Weissleder et al. have developed Tat-CLIOs, which can be efficiently internalized by haemopoetic and neural progenitor cells [18]. There are an increasing number of MRI tracking studies for stem cell transplantation particularly for brain and spinal cord repair. The MRI results can be verified by fluorescent imaging of the animal, thus one approach is to use bifunctional magnetic-fluorescent nanoparticles to label the cells in vitro. Neural precursor cell (NPC) transplantation is a promising strategy for treatment of neurodegenerative disorders because of the potential for precursor cell replacement. An important element in future clinical application is the development of a non-invasive procedure to follow NPC fate. Frank et al. have demonstrated how neuronal-restricted precursors (NRPs) and glial-restricted precursors (GRPs) can be labeled in vitro with the superparamagnetic iron oxide contrast agent, Feridex. Following engraftment into intact the adult spinal cord, labeled cells robustly survived in white and gray matter and migrated selectively along white matter tracts up to 5 mm. Localization of cells was reliably established using ex vivo MRI of spinal cords combined with histological detection of iron and the human alkaline phosphatase transgene in most grafting sites. Following transplantation, magnetically labeled cells exhibited mature morphologies and differentiated into neurons, astrocytes, and oligodendrocytes, similar to grafts of unlabeled NRPs and GRPs [62]. These studies demonstrate the potential for these protocols but there are remaining challenges for localization at depth within the body using magnetic nanoparticle techniques which remain to be solved.

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F. Magnetic Nanoparticle Applications in Tissue Engineering (MTE) Strategies for combining magnetic fields and nanoparticles for tissue engineering applications have been in development since the early 2000s [63]. The work has focused on two applications-control of cell behaviour through magnetic force targeting and cell orientation and mobilisation strategies for in vitro generation of tissues [64]–[66]. The former work describes how specific mechano-responsive receptors can be tagged on cells from a variety of sources and lineages. Magnetic fields can then be applied to apply a localised force onto the receptor which results in activation and downstream changes in cell signalling and ultimately phenotype. This technique is being explored both in vivo and in vitro for stem cell conditioning and new methods for applying mechanical strain to 2-D and 3-D cultures in vitro using a magnetic force bioreactor. The latter strategy is to use magnetic fields to orientate cells within tissues. Using nanoparticle-labelled calls in scaffolds, magnetic fields can then be used to draw the cells through 3-D systems and form orientated sheets in multilayer. Multiple tissue examples have now been considered for endothelial, bone and other tissue applications [67], [68]. G. Conclusion In the past few years, numerous work has been done on synthesis and surface modification of SPIONs to yield desirable properties for biomedical applications. Monodispersed iron oxide particles with uniform size and shape, and high magnetization properties are of particular interest. Tailored surface modification for specific applications is another active area which can be summarized in two major steps: firstly, producing polymer-coated particles with the appropriate size, shape, surface hydrophilicity and functional groups as a backbone; secondly, conjugation of specific targeting ligands onto the coating layers. The biomedical applications of SPIONs, especially in vivo applications such as MFH, MRI, MDT, MF, MS and MTE are expanding. The concept of using SPIONs in such applications is now widely accepted, but most in vivo applications are still under development and optimization. A few SPION-based MRI contrast agents are commercially available and clinical trials on MDT are underway. In conclusion, the potential of SPIONs in biomedicine is large, but to realize the true benefit of SPION-based biomedical applications, the production of SPIONs with the desired properties is required REFERENCES [1] T. Neuberger, B. Schopf, H. Hofmann, M. Hofmann, and B. von Rechenberg, “Superparamagnetic nanoparticle for biomedical applications: Possibility and limitations of a new drug delivery system,” J. Magn. Magn. Mater., vol. 293, pp. 483–496, 2005. [2] H. Lin, Y. Watanabe, M. Kimura, Y. Hanabusa, and H. Shirai, “Preparation of magnetic poly(vinyl alcohol) (PVA) materials by in situ synthesis of magnetite in a PVA matrix,” J. Appl. Polym. Sci., vol. 87, pp. 1239–1247, 2003. [3] A. K. Gupta and S. Wells, “Surface-modified superparamagnetic nanoparticles for drug delivery: Preparation, characterization, and cytotoxicity studies,” IEEE Trans. Nanobiosci., vol. 3, pp. 66–73, 2004. [4] Y. Deng, L. Wang, W. Yang, S. Fu, and A. Elaissari, “Preparation of magnetic polymeric particles via inverse microemulsion polymerization process,” J. Magn. Magn. Mater., vol. 257, pp. 69–78, 2003.

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LIN et al.: DEVELOPMENT OF SPIONS FOR TRANSLATION TO CLINICAL APPLICATIONS

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[65] J. Dobson, S. H. Cartmell, A. Keramane, and A. J. El Haj, “Principles and design of a novel magnetic force mechanical conditioning Bioreactor for tissue engineering, stem cell conditioning, and dynamic in vitro screening,” IEEE Trans. NanoBiosci., vol. 5, pp. 173–177, Sep. 2006. [66] S. Hughes, S. McBain, J. Dobson, and A. J. El Haj, “Selective activation of mechanosensitive ion channels using magnetic particles,” J. Roy. Soc. Interface, vol. 5, pp. 855–863, 2008. [67] A. Ito, Y. Takizawa, H. Honda, K. I. Hata, H. Kagami, M. Ueda, and T. Kobayashi, “Tissue engineering using magnetite nanoparticles and magnetic force: Heterotypic layers of cocultured hepatocytes and endothelial cells,” Tissue Eng., vol. 10, pp. 833–840, May 2004. [68] A. Ito, K. Ino, M. Hayashida, T. Kobayashi, H. Matsunuma, H. Kagami, M. Ueda, and H. Honda, “Novel methodology for fabrication of tissue-engineered tubular constructs using magnetite nanoparticles and magnetic force,” Tissue Eng., vol. 11, pp. 1553–1561, Sep. 2005. Meng Meng Lin received the B.Sc. degree in animal and plant biotechnology at the University of Hong Kong, China in 2004 and the M.Sc. degree in biomedical nanotechnology at Newcastle University, U.K. in 2005. She is currently working towards Ph.D. degree in Institute of Science and Technology in Medicine, Keele University, U.K. She was a visiting student in the Royal Institute of Technology, Sweden in 2006. Her research interests include nanoparticles preparation, interaction between nanoparticles and cells, and cancer oriented drug delivery.

Do Kyung Kim received the Ph.D. degree in materials chemistry (nano-bio) from the Royal Institute of Technology (KTH) in Sweden, 2002. He was a Postdoctoral Fellow in the Department Electrical Engineering and Computer Science, Massachusetts Institute of Technology (MIT), in 2003. He is currently lecture in the Institute of Science and Technology in Medicine (ISTM, rated 5 A in the 2001 RAE exercise), Keele University, U.K. His research interests include target oriented drug delivery system, nanocomposites, quantum dots, and bulk production of nanomaterials for energy applications.

Alicia El Haj holds a personal chair in Cell Engineering and is currently Research Director at the Institute of Science and Technology in Medicine which underpins the development of a New Medical Scholl between Manchester and Keele University, U.K. She is the cofounder and Director of the spin-off company in regenerative medicine, Magnecell Ltd. Her research has helped to define our understanding how the physical environment interfaces the biological environment and how we can use this knowledge in the clinical environment. The research programs in the 5 rated institute, located on hospital sites, is at the clinical interface with extensive programs in developing new tissue engineering strategies for regenerative medicine. Alicia is well recognized in the field of connective tissue engineering and regenerative medicine funded by the BBSRC, EPSRC, Welcome and EU with extensive publications in the field. She is the President of U.K. Cell and Tissue Engineering Society.

Jon Dobson was born in Columbus, OH, in 1960. He received the B.Sc. and the M.Sc. degree in geological science/geophysics (iron biomineralization/mineral magnetics), from the University of Florida, Gainesville and the Ph.D. degree in natural sciences (mineral magnetics) from the Swiss Federal Institute of Technology (ETH-Zurich) in 1991. He did his postdoctoral research in the Department of Physics, Institute of Geophysics, ETH-Zurich (1991–1995), before taking the fellowship/lectureship in the Biophysics Programme in the Department of Physics at the University of Western Australia (1995–1998). He is currently a Professor in Biophysics and Biomedical Engineering at Keele University, Stoke-on-Trent, U.K. and Eminent Scholar/Visiting Professor at the University of Florida. He has published more than 140 peer-reviewed papers, is a Fellow of the Institute of Nanotechnology and the Royal Society of Medicine, and is Royal Society Wolfson Research Merit Fellow.

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