Magnetic micro- and nano-particle-based targeting for drug and gene delivery

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    Jon DobsonKeele University, Institute for Science & Technology in Medicine, Thornburrow Drive, Hartshill, Stoke-on-Trent, ST4 7QB, UKTel.: +44 178 255 4253;Fax: +44 178 271 7079;E-mail: bea22@keele.ac.uk

    ill experi-rparamag- rare earthetic nano- both inalso high-n be usedlihood ofKeywords: drug delivery, gene therapy, magnetic targeting, magnetofection, nanoparticle

    are attached to magnetic nanoparticles, whichare then injected directly into the bloodstream.A strong, permanent (generally rare earth) mag-net is positioned above the target site outsidethe body. As the particles, carrying the thera-peutic agent, pass below the magnet, the mag-netic field captures them and pulls themtowards the field source. The particles may then

    field is homogeneous, the particle wence no force (provided it is supenetic). Because of this, high-gradient,magnets are generally used for magnparticle-based targeting applicationsvitro and in vivo. The equation above lights the variable parameters that cato increase the force and the likeMagnetic mtargeting fo10.2217/17435889.1.1.31 20In the late 1970s, researchers proposedattaching drugs to magnetic micro- and nano-particles and using these particles to transportthe therapeutic compounds to specific sites invivo in order to address these difficulties [13].The technique, now known as magnetic target-ing, is based upon the attraction of magneticparticles to a strong, high-gradient magneticfield. Therapeutic agents (either drugs or genes)

    magnetic particle, 1 is the volume magneticsusceptibility of the surrounding medium, o isthe magnetic permeability of free space, V isparticle volume, B is the magnetic flux densityin Tesla (T) and is field gradient, whichcan be reduced to B/x, B/y, B/z [5]. Itcan be seen from this equation that the mag-netic field must have a gradient in order to gen-erate a force on the magnetic particle. If the

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    icro- and nano-particle-based r drug and gene delivery

    The use of magnetic micro- and nano-particles as carriers for in vivo targeting of therapeutic compounds was first proposed over 25 years ago. Since then, a variety of animal studies have demonstrated the efficacy of the technique, however, only a handful of Phase I/II clinical trials have taken place. While the theoretical underpinnings have been lacking, recent advances in mathematical modeling of magnetic targeting, as well as the development of novel magnetic nanoparticle carriers and implantable magnets, show promise in progressing this technology from the laboratory to the clinic.

    Despite a myriad of advances in the develop-ment of therapeutic drugs and genes to fighthuman disease, delivering these agents to spe-cific targets within the body generally remains adifficult task. This problem is particularly rele-vant to the delivery of cytotoxic drugs for can-cer treatment chemotherapy where thesystemic distribution of these compounds leadsto serious and sometimes fatal side effects. Inaddition, with the recent sequencing of thehuman genome and the identification of spe-cific disease-related genes, the potential forgene therapy is being explored vigorously.However, one of the major drawbacks to thedevelopment of effective gene therapies is thedifficulty in delivering the therapeutic gene tothe target tissue where it must be expressed.Therefore, the goal of drug- and gene-targetingstrategies is to minimize systemic distributionof the administered therapeutic agents, while atthe same time ensuring that the correct dose isdelivered where it is needed.

    escape from the vasculature into the tissuewhere the agent is released, either via enzymaticcleavage or changes in the physiological envi-ronment, such as pH or osmolality [4]. Thedrug may also be released via magnetic field-induced heating of the particles.

    Magnetic targeting apparently offers a rela-tively simple and cost-effective mechanism fortargeting drugs and genes to specific sitesin vivo, thereby reducing systemic distribu-tion and allowing the administration of lowerdoses. However, in practice, the translation ofthis technique from animal studies to the clinichas been difficult.

    The physical principles of magnetic targetingare based on the attractive force exerted onmagnetic particles by a magnetic field source,according to the equation:

    where Fmag is the force on the magnetic particle,2 is the volume magnetic susceptibility of the

    Fmag 2 1( )V 10------B B( )=06 Future Medicine Ltd ISSN 1743-5889 Nanomedicine (2006) 1(1), 3137 31

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    32capture on the magnetic particle carrying thetherapeutic agent. These are the particle vol-ume (larger particles will result in more forcebut greater hydrodynamic drag), magnetic fieldstrength, magnetic field gradient and the mag-netic properties of the particles.

    In addition to the physical parametersrelated to the magnetic field and particles,there are also other factors that must be consid-ered in designing an effective magnetic nano-particle-based delivery system. These includephysiological parameters, such as depth to tar-get, rate of blood flow, vascular supply andbody weight [6]. With such a large number ofvariable parameters, it is important to developa theoretical underpinning to guide the devel-opment of magnetic targeting for specificcases. Until recently, this factor had not beenadequately addressed.

    Early theoretical analysis of magnetic target-ing was based on the development of relativelysimplistic mathematical models and did nottake into account several important physiologi-cal factors. This work was, however, an impor-tant first step. Work by Voltairas, Ruuge andothers provided an indication of the fieldstrengths and gradients required for particlecapture at the in vivo target [7,8]. They showedthat, in order to capture particles flowing in ablood vessel, field strength had to be of theorder of 200700 mT, with gradients along thez-axis of 8100 T/meter (T/m), depending onthe blood-flow rate. These results showed thatmagnetic targeting was likely to be more effec-tive at the surface of the body where fieldstrength from the magnet was highest.

    Although these early models providedimportant information to guide the design of apractical system, as previously mentioned, theydid not take into account important physiolog-ical parameters, such as the presence of bloodcells within the blood stream and the effects ofbranching networks of vessels. A more recentmodel has been developed by Grief and Rich-ardson, which examines a variety of magneticfield/particle configurations in a 2D branchingnetwork [9]. This model also incorporatessheer-induced diffusion, which would resultfrom the collision of cells in the bloodstreamwith the particles.

    All of this theoretical work has pointed to aninherent problem with magnetic targeting par-ticles flowing through the bloodstream near thesurface of the body will experience a stronger

    those deeper in the tissue (Figure 1). Both theoret-ical and experimental work indicate that it is eas-ier to target sites close to the surface of the body.Current work is aimed at addressing this prob-lem and will be discussed in a later section; how-ever, it is also clear from this work that thephysical and physiological conditions requiredfor magnetic targeting are achievable.

    Magnetic nanoparticle carriersMagnetic nanoparticles have already been inclinical use for several years primarily as con-trast agents for magnet resonance imaging andare used routinely for magnetic cell sorting andimmunoassay in pathology laboratories [5]. Parti-cles developed for drug and gene delivery gener-ally consist of a magnetic core (usually magnetite Fe3O4 or maghemite Fe2O3) with a poly-mer coating, such as silica, polyvinyl alcohol(PVA) or dextran, which can be functionalizedand to which drugs can be attached [10,11]. Parti-cles may also be composed of a porous polymeror block co-polymers in which the magneticnanoparticles are dispersed [1214]. For genedelivery, particles may be coated with molecules,such as polyethyleneimine, which encouragecondensation of DNA through charge inter-actions [6].

    A number of groups have developed tech-niques for the synthesis of magnetoliposomes[15,16]. These particles also have a core-shellstructure, but the core is precipitated within aspherical lipid membrane. The magnetic com-ponent may also be embedded within a hydro-gel along with the therapeutic drug or gene[1719]. The agent can then be released from thehydrogen by applying a radiofrequency field tothe particles in vivo, which results in heatingand melting of the hydrogel carrier.

    For in vitro gene transfection work, Cai andcolleagues have recently described a techniquethat they call nanotube spearing [20]. This isbased on coupling DNA to nickel-embedded car-bon nanotubes. The complex is then introducedinto cells in culture and, as they settle through theculture medium, the tubes align with the mag-netic flux lines, which have a component of orien-tation largely perpendicular to the cells surface.The attraction of the nanotubes along the mag-netic field gradient enables the particles to piercethe cell membrane in a manner similar to throw-ing a spear or shooting an arrow. While this tech-nique has only been demonstrated in vitro, thereis potential for in vivo nanotube spearing as theNanomedicine (2006) 1(1)

    attractive force due to the magnetic field than same principles would apply to nanotubes cap-

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    Magnetic targeting for drug and gene delivery REVIEWtured by a magnetic field as they flow through thebloodstream. However, before this can be trialedin humans, the toxicity effects of carbon nano-tubes will need to be evaluated.

    Recently, cobalt nanoparticles with a goldshell have been synthesized [21]. The gold shellcan be functionalized and the particles have a tai-lorable morphology and a size range of 525 nm.They are produced by the rapid decompositionof organometallic precursors in the presence ofsurfactants that control the size and shape. Ascobalt has a magnetic moment nearly twice thatof magnetite and maghemite, these particles maybe easier to capture at depth. Again, however, thetoxicity of the particles will need to beinvestigated thoroughly.

    Here at Keele University (UK), we are devel-oping mesoporous silica nanoparticles, whichmay contain up to 80% iron oxide [22,23]. In this

    case, the magnetic component (magnetite ormaghemite) is precipitated within long, narrowpores in silica nanoparticles. As magnetite hasstrong shape anisotropy, these particles will havethe advantages of a strong magnetic moment aswell as the potential for orientation in anapplied magnetic field.

    For virtually all of these particles, the mag-netic component of the carrier particles is gen-erally less than a few tens of nanometers in size.At this small scale, the particles are superpara-magnetic. Superparamagnetic materials arestrongly magnetic but lose their magnetizationupon removal of the applied field. The majoradvantage of this behavior, particularly forin vivo applications, is that in the absence of afield, the particles will have less tendency toaggregate within the vasculature. Such aggrega-tion can potentially cause problems, such as

    Figure 1. Schematic of a magnetic-targeting system showing a target at depth.

    Magnetic nanoparticle carriers traveling in the blood vessels between the target and the magnet will also be captured as shown.Fmag, Magnetic force vector; MTC, Magnetically targeted carrier.

    Magnet

    Fmag

    Body surface

    Tissue Target

    Blood vessel

    Fmag

    MTCs

    MTCs

    Magnet33

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    34embolization, if the aggregates are trapped bythe magnetic field and block blood flowthrough the vessel.

    Experimental & clinical resultsAlthough magnetic targeting has been tested ina large number of in vitro and animal modelexperiments, only a few clinical trials have beenreported to date. Animal studies began shortlyafter the introduction of the method and, in1983, Widder and colleagues demonstrated tar-geting of doxorubicin to sarcoma tumorsimplanted in rat tails [24]. In this study, totalremission was achieved in the magnetic target-ing group compared with controls, who wereadministered ten-times the dose.

    Since these studies, several other groups havealso demonstrated the efficacy of magnetic tar-geting in a variety of small animal models, suchas rats and rabbits [4,25,26]. In one study, targetingdepth in a swine liver was extended to approxi-mately 10 cm, however, the group used relativelylarge particles with a size range of 500 nm to5 m [27]. Quantification of magnetic-targetingefficiency has been demonstrated recently byAlexiou and colleagues [28]. This group usedHPLC analysis of mitoxantrone coupled to mag-netic nanoparticles in a rabbit model and alsolight microscopy for direct observation of uptakeinto HeLa cells in vitro.

    As mentioned in the introduction, targetingto depth can be a problem for two reasons: themagnetic field strength decays rapidly with dis-tance and magnetic nanoparticle carrierstraveling in the blood vessels within tissue,which lies between the magnet on the bodys sur-face and the target at some depth, will experiencea stronger field. This leads to particle capturewithin this intervening tissue region, as shownin Figure 1. One potential technique for overcom-ing both of these obstacles is to surgicallyimplant magnets near the target site.

    This principle has been demonstrated byKubo and colleagues. This group implanted per-manent magnets near solid osteosarcoma sites inhamsters. After implantation and recovery fromsurgery, the hamsters were injected with cyto-toxic compounds carried by magnetoliposomes.This strategy resulted in a fourfold increase indrug delivery to the osteosarcoma site in com-parison with intravenous delivery of the samecompounds without magnetic carriers [29]. A sig-nificant increase in antitumor activity as well asa reduction in weight-loss side effects was also

    targeting of transforming growth factor1 viamagnetic liposome targeting to cartilage defectsin a rabbit model. Again, permanent magnetswere implanted near the cartilage defect, result-ing in accelerated cartilage repair [30]. In a varia-tion on the implantation of permanent magnets,Yellen and colleagues have proposed and dem-onstrated the use of implanted magnetic gridsfor targeting heart muscle [31].

    Although in vitro magnetic targeting for genedelivery was demonstrated several yearsago [32,33], in vivo studies have only begun rela-tively recently. For example, Morishita and col-leagues have demonstrated the concept by usingmagnetic nanoparticles to enhance transfectionin BALB/c mice. In this study, heparin-coatedmagnetite particles were associated with thehemagglutinating virus of Japan envelope, whichimproved gene transfection in the liver [34].Krtz and others have also used the technique todeliver antisense oligodesoxynucleotides totargeted sites in mice [35].

    Magnetic targeting has been successful in avariety of animal m...