Functionalisation of Magnetic Nanoparticles For Applications in Biomedicine
Functionalisation of Magnetic Nanoparticles For Applications in Biomedicine
Functionalisation of Magnetic Nanoparticles For Applications in Biomedicine
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TOPICAL REVIEW
Functionalisation of magnetic
nanoparticles for applications in
biomedicine
Catherine C Berry1 and Adam S G Curtis
Centre for Cell Engineering, Institute of Biomedical and Life Sciences,
Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
E-mail: catherine.berry@bio.gla.ac.uk
Abstract
Magnetic nanoparticles have been proposed for use as biomedical purposes
to a large extent for several years. In recent years, nanotechnology has
developed to a stage that makes it possible to produce, characterize and
specifically tailor the functional properties of nanoparticles for clinical
applications. This has led to various opportunities such as improving the
quality of magnetic resonance imaging, hyperthermic treatment for
malignant cells, site-specific drug delivery and the manipulation of cell
membranes. To this end a variety of iron oxide particles have been
synthesized. A common failure in targeted systems is due to the
opsonization of the particles on entry into the bloodstream, rendering the
particles recognizable by the bodys major defence system, the
reticulo-endothelial system. This review discusses each of the above
bio-applications of such magnetic nanoparticles and details some of the
main recent advances in biological research.
the region of interest for treatment. Alternatively in many renders the particles recognizable by the bodys major defence
cases the particles suspension would be injected directly into system, the reticulo-endothelial system (RES). The RES is
the general area when treatment was desired. Either of these a diffuse system of specialized cells that are phagocytic
routes has the requirement that the particles do not aggregate (i.e. engulf inert material) associated with the connective tissue
and block their own spread. This leads to questions about the framework of the liver, spleen and lymph nodes (Kreuter
best way to produce a suspension that is stable. 1994, Araujo et al 1999). The macrophage (Kupffer) cells
Fortunately there is appreciable intracellular space in the of the liver, and to a lesser extent the macrophages of the
body through which nanoparticles can diffuse out of flow. spleen and circulation, therefore play a critical role in the
A large proportion of this space is between cells. Brightman removal of opsonized particles. As a result, the application
found that 9 nm diameter ferritin particles would diffuse of nanoparticles in vivo or ex vivo would require surface
rapidly through intercellular spaces to achieve a near uniform modification that would ensure particles were non-toxic,
distribution in a few minutes (Brightman 1965). Two tissues biocompatible and stable to the RES.
were not accessible by this route; those that are beyond the Particles that have a largely hydrophobic surface are
blood brain barrier, and those inside spaces of the kidney efficiently coated with plasma components and thus rapidly
tubules. These regions have special types of cell to cell contacts removed from the circulation, whereas particles that are more
called the zonulae occludentes, which have contacts less than hydrophilic can resist this coating process and are cleared more
1 nm wide. slowly (Gaur et al 2000). This has been used to the advantage
The diffusion to the general mass of tissues was when attempting to synthesize RES evading particles by
presumably aided by pressure gradients from the blood vessels sterically stabilizing the particles with a layer of hydrophilic
(chiefly microcapillaries) to the tissue spaces. Larger particles polymer chains (Allemann et al 1993). In the literature the
of 50100 nm diameter did not transport in this way and most common coatings are derivatives of dextran, polyethylene
remained in circulation or attached to the walls of the vascular glycol (PEG), polyethylene oxide (PEO), poloxamers and
system. Attaching particles to the vascular walls may be a polyoxamines (Lacava et al 2001). The role of the dense
method of therapy in some instances, but carries the risk of brushes of polymers is to inhibit opsonization, thereby
thromboses. permitting longer circulation times (Shen et al 1996, Portlet
These considerations suggest that nanoparticles of about et al 2001, Briggar et al 2002). A further strategy in avoiding
510 nm diameter should form the ideal particles for most the RES is by reducing the particle size (Gref et al 1994,
forms of therapy but that there will also be problems of Moghimi et al 2001). Despite all efforts, however, complete
formulating the particle concentrations and suspending media evasion of the RES by these coated nanoparticles has not yet
to obtain best distributions. been possible (Gaur et al 2000).
Magnetic nanoparticles are physiologically well tolerated, An interesting possibility in the attachment of particles
for example dextran-magnetite has no measurable toxicity to cells may be the presentation of topographical cues to
index LD50 (Babincova et al 2000). However the fate other cells. It was proposed in 1964 that cells reacted to
of nanoparticles following intravenous administration, as the topography of their environment (Curtis and Varde 1964),
indicated in figure 1, represents the diverse biological events and recent studies have demonstrated that cells can respond
that need to be considered. After particles are injected into to nanometric cues in vitro (Curtis and Riehle 2001, Curtis
the bloodstream they are rapidly coated by components of the and Wilkinson 2001). It is further postulated that cells
circulation, such as plasma proteins. This process is known respond to topographies presented in vivo by proteins such
as opsonization, and is critical in dictating the circumstance as collagen (with the 64 nm repeat banding) and that cells
of the injected particles (Davis 1997). Normally opsonization may also respond to nanotopography present by neighbouring
cells (Curtis and Wilkinson 1999). Particles attached to cells
would most likely present nano-spheres or nano-bumps to
Intravenous Injection neighbouring cells. Studies by Chen et al (1997) showed that
cells reacted to micropatterned surfaces exhibiting differently
sized extracellular matrix covered islands or bumps. The
Opsonization
endothelial cells tested were encouraged to switch from growth
to apoptosis with decreasing island size. This phenomenon was
attributed to the patterned island influence on cell spreading,
Inflammation Sites Bone Marrow
which in turn influenced cell shape, feeding back to govern cell
viability status. More recent studies have also shown that cells
alter their spreading on nano-sized island topographies (Dalby
Circulation et al 2002). In this case three island heights were investigated
Tumour Spleen (13, 35 and 95 nm), with the largest cell response to the 13 nm
islands, resulting in increased cell spreading and cytoskeletal
formation. This importance of topography supporting cell
Lymphatics
extension and subsequent spreading may be relevant when
Liver
considering particle attachment to the cell surface, as this may
Figure 1. The fate of nanoparticles following intravenous injection. in turn influence attachment of neighbouring cells.
Particles are conditioned immediately on injection by plasma Nanotechnology has reached a stage that makes it possible
proteins (opsonization). to produce, characterize and specifically tailor the functional
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properties of nanoparticles for clinical applications. This short PARTICLE CLATHRIN DYNAMIN
review will detail the main areas of biomedical applications and COATED PIT
current research using such magnetic nanoparticles including
as MRI contrast agents, for use as potential hyperthermia
treatment of malignant cells, targeted drug delivery and also
as laboratory tools to manipulate cell membranes. ACTIN
CYTOSKELETON CLATHRIN
INVOVLEMENT COATED
2. MRI VESICLE
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approaches. The first is called magnetic hyperthermia and selectively deliver drug molecules to the diseased site, without
involves the generation of temperatures up to 4547C by the a concurrent increase in its level in healthy tissues, is currently
particles. This treatment is currently adopted in conjunction one of the most active areas of cancer research. The first
with chemotherapy or radiotherapy, as it also renders the cells clinical trials in humans with a magnetic drug targeting
more sensitive (Hilger et al 2002). The second technique worldwide were reported by Lubbe et al (1997), who used
is called magnetic thermoblation, and uses temperatures of a ferrofluid (particle size 100 nm) to which the drug epirubicin
4355C that have strong cytotoxic effects on both tumour and was chemically bound. Epirubicin is a well-known antibiotic
normal cells (Jordan et al 1996, Hilger et al 2001). The reason antracylin that has a wide range of application for the treatment
for this use of increased temperatures is due to the fact that of solid tumours (Bonadonna et al 1993). In brief, special
about 50% of tumours regress temporarily after hyperthermic starch polymers coat the magnetic particles together with
treatment with temperatures of up to 44C, therefore authors anionic phosphate groups so that a cationic binding to the
prefer to use temperatures up to 55C (Hilger et al 2001). The positively charged amino sugars of epirubicin was possible.
problem of deleterious effects on normal cells is reduced by Preliminary successful animal trials lead to these human trials,
intratumoural injection of the particles. where for the first time documented tolerance and efficacy
The heating power of the particles is quantified as the was observed in mice and rats, in which no LD50 could be
specific absorption rate (SAR) and describes the energy amount found for the ferrofluid. The treatment protocol consisted of
converted into heat per time and mass (Moroz et al 2002). the intravenous infusion of the chemically bound drug and
Apart from the particle size and shape influencing their one course of conventional chemotherapy. During infusion,
magnetic properties, thus consequently their heating power, and for 45 min after, a magnetic field was built up as close to
there is also a dependency between temperature elevation the advanced and unsuccessfully pretreated tumour as possible
and magnetic field amplitude which must be considered (distance assured to be less than 0.5 cm). It was shown that the
when comparing experiments with different tissue parameters. ferrofluid could be successfully directed to the tumours in about
On the basis of recent studies, tumours with volumes of half of the patients. However it was also concluded, based
approximately 300 mm3 can be heated and no potential on MRI techniques, pharmacokinetics and clinical detection
problems were expected with larger tissue volumes (e.g. that although the treatment seemed safe, improvements were
>1000 mm3 ) if there is proper regulation of the magnetic mass needed to make it more effective (Lubbe et al 1997).
used and the intra-tumoural particle distribution (Hilgar et al To understand this new form of pharmacological
2001). The frequency should be greater than that sufficient to application as well as the mechanism of action, there are
cause any neuromuscular response, and less than that capable many considerations, which may be subdivided into several
of causing any detrimental heating of healthy tissue, ideally categories. In the first instance there is the ferrofluids
in the range of 1001000 kHz (Babincova et al 2000). If parameters, which include particle size, surface characteristics,
suitable frequencies and field strength combinations are used, concentration, volume and strength of drugparticle binding.
Secondly there is access to the organism, where considerations
no interaction is observed between the human body and the
involve the infusion route, such as the duration and rate of
field.
the injection. Finally there are the physiological parameters
to consider, ranging from the organisms weight, blood
4. Targeted drug delivery volume, cardiac output, circulation time through to tumour
volume/location/blood flow (Lubbe et al 2001). Therefore the
The main problems currently associated with systemic drug step from animal trials to human trials is not straightforward
administration include even biodistribution of pharmaceuticals (Lubbe et al 1999).
throughout the body, the lack of drug specificity towards a There are, however, fundamental problems associated
pathological site, the necessity of a large dose to achieve high with the use of magnetic directed drug targeting. Targeting,
local concentration, non-specific toxicity and other adverse for example, to a specific cell type, may be possible with
side effects due to high drug doses. Drug targeting aims to directed coatings, but retaining the particles localized at the cell
resolve many of these problems (Torchilin 2000). Amongst membrane for any length of time is difficult as the cell tends
the current principle schemes of drug targeting is magnetic to automatically instigate receptor-mediated endocytosis, as
targeting, i.e. the targeting of a drug immobilized on magnetic was described in figure 3. In addition, the ability of magnetic
materials under the action of an external magnetic field. particles to concentrate will depend on both the blood flow rate
To enhance target specificity the drug is associated with and the intensity of the magnetic field. The success therefore
another molecule capable of specific recognition and binding depends to a large extent on the construction of strong magnets,
to the target site. Target recognition can occur at different able to produce high magnetic field gradients at the target sites.
levels: on the level of the whole organ, the level of certain It has been shown that most of the available fields are only
specific cell types for a given organ, or on the level of individual strong enough for the manipulation of particles against the
components characteristic for these cells such as cell surface diffusion and bloodstream velocities found in living systems
antigens. The most common type of associated molecules are over a distance of a few centimetres from the sharp end of a
antibodies (and their fragments), lectins, proteins, hormones, magnet pole (Lubbe et al 2001). This means that it is difficult
charged molecules and some low molecular weight ligands to build up and sustain a field strength sufficient to counteract
such as folate (Sudimack et al 2000). the linear blood flow rates in tissues so as to effectively retain
A highly publicized example of magnetic drug delivery is the drug carrier at a specific location.
as a replacement or to augment chemotherapy/radiotherapy A further research interest in the use of targeted magnetic
treatments. The development of techniques that could nanoparticles is in the field of gene therapy. Gene therapy
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Topical Review
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