Research Overview
Magnetic Nanoparticles for Drug Delivery
DDR
DRUG DEVELOPMENT RESEARCH 67:55–60 (2006)
Jon Dobson Institute for Science & Technology in Medicine, Keele University, Stoke-on-Trent, United Kingdom
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Targeting specific sites in vivo for the delivery of therapeutic compounds presents a major obstacle to the treatment of many diseases. One targeted delivery technique that has gained prominence in recent years is the use of magnetic nanoparticles. In these systems, therapeutic compounds are attached to biocompatible magnetic nanoparticles and magnetic fields generated outside the body are focused on specific targets in vivo. The fields capture the particle complex resulting in enhanced delivery to the target site. This review will focus on technical aspects of magnetic targeting as well as nanoparticle design and c 2006 Wiley-Liss, Inc. animal and clinical trials. Drug Dev. Res. 67:55–60, 2006. Key words: magnetic nanoparticles; drug targeting; drug delivery; cancer therapy
INTRODUCTION
Within the last two decades, the use of magnetic micro- and nanoparticles in biomedical applications has become relatively commonplace. Primarily, these particles are used as contrast agents in magnetic resonance imaging (MRI) and for magnetic cell sorting and immunoassay in pathology laboratories. However, experimental work is also underway that is aimed at the development of magnetic particle/fluid hyperthermia treatment for cancerous tumors and the controlled and directed transport of pharmaceuticals and therapeutic genes [Pankhurst et al., 2003]. Up to now, these latter two uses have met with more limited success. However, their potential is still very exciting, particularly with regard to the treatment of cancer through tumor targeting. The major disadvantage of most chemotherapeutic approaches to cancer treatment is that most are non-specific. Therapeutic (generally cytotoxic) drugs are administered intravenously leading to general systemic distribution. The non-specific nature of this technique results in the well-known side-effects of chemotherapy as the cytotoxic drug attacks normal, healthy cells in addition to its primary target, tumor c
2006 Wiley-Liss, Inc.
cells. The rationale for magnetic micro- and nanoparticle-based targeting lies in the potential to reduce or eliminate the side effects of chemotherapy drugs by reducing their systemic distribution as well as the possibility of administering lower but more accurately targeted doses of the cytotoxic compounds used in these treatments. The idea of using magnetic micro- and nanoparticles to act as therapeutic drug carriers in order to target specific sites in the body dates to the late 1970s [Widder et al., 1978; Senyei et al., 1978; Mosbach and Schro¨der, 1979]. Widder and others developed magnetic micro- and nanoparticles to which cytotoxic drugs could be attached. The drug/carrier complex is then injected into the subject either via intravenous or intraarterial injection. High-gradient, external magnetic fields generated by rare earth permanent magnets are Correspondence to: Jon Dobson, Institute for Science & Technology in Medicine, Keele University, Thornburrow Drive, Hartshill, Stoke-on-Trent, ST4 7QB UK. E-mail:
[email protected]
Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/ddr.20067
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Fig. 1. Schematic representation of a magnetic nanoparticle-based drug delivery system. Figure redrawn after Pankhurst et al. [2003].
used to guide and concentrate the drugs at tumor locations (Fig. 1). Once the magnetic carrier is concentrated at the tumor or other target in vivo, the therapeutic agent is then released from the magnetic carrier, either via enzymatic activity or through changes in physiological conditions such as pH, osmolality, or temperature, leading to increased uptake of the drug by the tumor cells at the target sites [e.g., Alexiou et al., 2000]. Similar principles have recently been applied to the delivery of therapeutic genes to specific targets in vivo [e.g., Mah et al., 2002]. In theory, magnetic targeting offers some major advantages for drug delivery, in particular, the ability to target a specific site, such as a tumor, in vivo thereby reducing the systemic distribution of cytotoxic compounds, and enhancing uptake at the target site resulting in effective treatment at lower doses. In practice, however, there are difficulties in achieving these objectives. Many factors must be considered when designing a magnetic nanoparticle-based targeting system, including both physical parameters, such as magnetic properties and size of the carrier particles, field strength, field geometry, and drug/gene binding capacity, and physiological parameters such as the depth to target, the rate of blood flow, vascular supply, and body weight [Neuberger et al., 2005]. In most cases where magnetic drug targeting has been attempted, theoretical underpinning of these parameters has been lacking and there has been great difficulty in moving this technology from animal studies into successful clinical trials. Recent work on the development of a sound, theoretical basis for this technique, should lead to advances in experimental design [Grief and Richardson, 2005]. Drug. Dev. Res. DOI 10.1002/ddr
PHYSICAL PRINCIPLES
Magnetic targeting is based on the attraction of magnetic nanoparticles to an external magnetic field source. In the presence of a magnetic field gradient, a translational force will be exerted on the particle/drug complex, effectively trapping it in the field at the target site and pulling it towards the magnet [for a comprehensive review of the underlying physical principles, see Pankhurst et al., 2003; Grief and Richardson, 2005]. This magnetic force is governed by the equation: Fmag ¼ ðw2 w1 ÞV
1 BðrBÞ: m0
Where B is the magnetic field strength, rB is field gradient and can be reduced to qB/qx, qB/qy, qB/qz; w2 is the magnetic susceptibility of the magnetic particle; w1 is the magnetic susceptibility of the medium (which is very small in comparison to w2 and therefore can be disregarded in the case of biological systems). It is clear from this equation that the important parameters in regards to effective capture of the nanoparticles are the magnetic properties and volume of the particles, the magnetic field strength, and the magnetic field gradient. It is also clear that as the field strength decreases, the ability to capture the nanoparticles also decreases. This is one of the main reasons that scale-up of magnetic targeting from small animals to humans has been so difficult. Preliminary theoretical investigations of the hydrodynamic conditions of magnetic nanoparticle targeting and estimations from experimental work indicate that for most magnetic carriers field strength (flux density) at the target site should be on the order of
MAGNETIC NANOPARTICLES FOR DRUG DELIVERY
200–700 milliTesla (mT) with gradients along the z-axis of approximately 8–100 T/m depending on the flow rate (higher blood flow rates will require either stronger fields or higher gradients) [Voltairas et al., 2002; Ruuge and Rusetski, 1993]. These results indicate that magnetic targeting is likely to be more effective for targets that are near the surface and in regions of slower blood flow. However, this model is rather idealized and limited, and a more recent model has been developed in which particle capture has been modelled for a variety of field/particle configurations in a two-dimensional branching network [Grief and Richardson, 2005]. This newer model also incorporates the effects of sheer-induced diffusion due to the presence of cells within the blood plasma. The results indicate that it will not be possible to target a specific site in vivo without some degree of distribution to surrounding tissue. For this reason, Grief and Richardson [2005] also conclude that magnetic targeting is likely to be most effective for targets which are close to the surface of the body. MAGNETIC NANOPARTICLES/CARRIERS
There are several strategies for synthesis of magnetic nanoparticles for drug delivery. Particles may be produced that have a core-shell structure, where the core is a magnetic iron oxide (usually magnetite – [Fe3O4] or maghemite [gFe2O3]) and the shell is generally a polymer such as silica, dextran, or PVA, or metals such as gold to which functional groups can be attached via cross-linkers [e.g., Santra et al., 2001; Pardoe et al., 2001; Carpenter, 2001; Harris et al., 2003; Wilson et al., 2005]. This type of structure can be synthesised using both ionic and non-ionic surfactant techniques or encapsulated within a structure such as a carbon cage or ferritin protein [for example, see Meldrum et al., 1992; Sun et al., 2000; Santra et al., 2001]. These particles can then be functionalized by attaching carboxyl groups, amines, biotin, streptavidin, antibodies, and others. In addition to these polymers, a number of groups have developed techniques for the synthesis of magnetoliposomes [Shinkai et al., 1995; Gonzales and Krishnan, 2005]. These nanoparticles have a typical core-shell structure with a magnetic iron oxide core surrounded by an artificial liposome. These are generally used for magnetic hyperthermia but may also be useful in drug delivery. Particles may also be embedded within hydrogels, which can carry a therapeutic agent that is released upon heating, or the particles themselves may be used for hyperthermia applications [Kondo and Fukuda, 1997; Lao and Ramanujan, 2004; Chen et al., 2005].
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More recently, gold/cobalt nanoparticles with a core-shell structure and tailorable morphology have been synthesized in the size range of 5–25 nm [Bao and Krishnan, 2005]. These particles have been produced via the rapid decomposition of organometallic precursors in the presence of surfactants that control the size and shape of the particles. One of the major advantages of these particles is that cobalt has a magnetic moment nearly twice that of magnetite or maghemite. Another strategy for the synthesis of magnetic/ polymer nanoparticles involves the precipitation of magnetic iron oxide nanoparticles within a porous polymer micro- or nanoparticle scaffold [Hans and Lowman, 2002]. One advantage of this technique is that it is often possible to produce particles with a relatively tight size distribution as well as a welldefined, spherical morphology. Again, as with coreshell structures, the particles can be functionalized so that drugs or genes may be attached or therapeutic compounds can be embedded within a degradable polymer matrix [for a comprehensive review, see Neuberger et al., 2005]. OBSTACLES TO CLINICAL APPLICATIONS
In order to retain the magnetic nanoparticle/drug complex at a particular location, the externally applied field must have a relatively strong gradient, as discussed previously. In the absence of this gradient, no translational forces will act on the particles and they will be affected only by rotational torque if they are magnetically blocked. Additionally, once the drug is released from the magnetic complex, it no longer responds to the applied magnetic field. It is then free to resume its normal distribution patterns in the body. Therefore, if the drug or gene is released while the carrier particles are still within the vasculature, even if they are held at the target site, there will still be some degree of systemic distribution. Another problem with these systems is the potential for embolization as the particles accumulate within the bloodstream, blocking blood flow. The particles also can become concentrated in the liver where cytotoxicity may be an unwelcome side-effect. However, both of these problems potentially may be turned to good advantage as it may be possible to enhance targeting of tumors in the liver and block the blood supply to the tumor mass [Lu¨bbe et al., 1999]. Further and more difficult problems with magnetic targeting arise due to constraints on the spatial geometry of the magnetic field with respect to the target site. The problem of the depth to which magnetic guidance systems may function has been demonstrated theoretically by Grief and Richardson Drug. Dev. Res. DOI 10.1002/ddr
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[2005] as discussed above, but it is also clearly shown by the difficulties encountered in scaling-up these techniques from small animals with near-surface targets to large animals and humans. As most magnetic targeting systems rely on external, rare-earth permanent magnets (generally NdFeB magnets with a maximum surface flux density of a little over one Tesla), there is a limit to the strength of field and field gradient that can be achieved at any site within the tissue. In addition, magnetic carriers will also tend to accumulate in the intervening tissue between the magnet and the target where the fields and gradients are higher. This point was also illustrated in the work of Grief and Richardson [2005]. Though these difficulties are not easy to overcome, there has been some limited success with magnetic micro- and nanoparticle-based targeting systems in larger animals, and even in early clinical trials. Further work on overcoming these difficulties is continuing. APPLICATIONS
Since the work of Widder and others [1978], other groups have developed and refined magnetic micro- and nanoparticle-based drug and gene delivery systems with varying results. The method has been successful in several animal studies, including the first study by Widder and others [1983] in which (doxorubicin) was coupled to magnetic particles and targeted to sarcoma tumors implanted in rat tails. Total remission was achieved in the magnetic-targeting group whereas there was no evidence of remission in the control group, which was administered 10 times the dosage but without magnetic targeting. Tumor remission has been achieved in a variety of other animal studies including not only small animals such as rabbits and rats [e.g., Alexiou et al., 2000; Lu¨bbe et al., 1999; Pulfer et al., 1999], but also larger swine [Goodwin et al., 1999, 2001], and targeting depth had been extended in one study to approximately 10 cm [Scott et al., 1999]. Recently, Alexiou and others [2005] have had success in quantifying the distribution of magnetically targeted carriers in a rabbit model using HPLC analysis of mitoxantrone bound to ferrofluids and have demonstrated, via light microscopy, uptake of magnetically targeted carriers in HeLa cells in vitro. In an effort to overcome problems with the spatial configuration of these delivery systems, Kubo and others [2000] implanted permanent magnets at solid osteosarcoma sites in hamsters followed by delivery of cytotoxic compounds via magnetoliposomes. This resulted in a fourfold increase in drug delivery to the tumor site in comparison with normal intravenous (non-magnetic) delivery. In addition, the group reDrug. Dev. Res. DOI 10.1002/ddr
ported a significant increase in anti-tumor activity and a reduction of weight-loss side effects. Theoretical and experimental analysis of implanted magnetic grids for targeting to the heart muscle point to another potential solution to the geometry problem [Yellen et al., 2005]. To date, application of magnetic targeting in humans has not reached the marketplace although there have been two Phase I/II clinical trials. A Phase I clinical trial was conducted by Lu¨bbe and others on 14 patients [Lu¨bbe et al., 1999]. This was primarily aimed at evaluating the potential toxicity of the particle carrier complex and, though targeting was not examined in detail, particle accumulation was observed in the tumor masses of six of the patients. Though the particles accumulated in the liver, the study demonstrated that magnetic carriers are generally well tolerated. A more recent Phase I/II trial was conducted on four patients using technology developed by FeRx Corporation. This study was aimed at evaluating the potential for magnetic nanoparticle-based targeting of hepatocellular carcinomas [Wilson et al., 2004]. The magnetic carrier was bound to doxorubicin and targeted to the liver via transcatheter delivery through the hepatic artery under concurrent MR imaging. The study demonstrated that the final fraction of treated tumor volume ranged from 0.64 to 0.91 while the fraction of affected normal liver volume ranged from 0.07 to 0.30. This result provides an indication that the combination of MR imaging and angiography could be used in some cases to optimize magnetic targeting. The principles described thus far can be applied not only to drug targeting but also to magnetic nanoparticle-based hyperthermia and gene delivery. Magnetic hyperthermia involves the delivery of magnetic nanoparticles to target sites following the techniques outlined above. Once the particles have been take up by a tumor, for instance, an alternating field is applied that couples to the particles, resulting in efficient heating. If the tumor cell is heated to 40–421C for 30 min., apoptosis may be induced, effectively killing the tumor. Again, this technique has been demonstrated effectively in animal models but translation to the clinic has been slow [for review see Pankhurst et al., 2003]. Magnetic targeting for gene delivery has been demonstrated in vitro and, in conjunction with associated viral vectors, in vivo in animal models [Mah et al., 2002; Schillinger et al., 2005]. CONCLUSIONS
Though many obstacles remain to be overcome before magnetic nanoparticle-based drug and gene delivery can achieve clinical success and reach the
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marketplace, recent advances are promising. New materials are being used to design nanoparticles with higher magnetic moments that will be easier to capture. There are continuing advances in permanent magnet technology and novel, implantable materials capable of generating high magnetic fields and high gradients look set to greatly enhance the ability to target sites deeper in the tissue. Patients with tumor sites near the body’s surface and in the liver are likely to be the first to benefit from this technique. But the potential for clinical application of magnetic targeting to a range of tumors and other diseases makes this an extremely fertile field of applied research.
Lao LL, Ramaujan RV. 2004. Magnetic and hydrogel composite materials for hyperthermia applications. J Mater Sci Mater Med 15:1061–1064.
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