Drug delivery and nanomedicine with nanomagnetic material
Drug Delivery and
Course: Nanomagnetic Materials and Device
2nd Year, M.Tech, NAST
Advantages and application of Magnetic material
Schematic illustration of MNP-based therapies.
Special Features of Magnetic Nanoparticles.
Synthesis and biofunctionalisation of magnetic nanoparticles.
Modified Nanoparticle and tissue interaction.
Size Dependence On Particle removal and particle delivery
Magnetic separation and drug carrier.
• Magnetism and magnetic materials have been used for many decades in many
modern medical applications.
• Magnetic materials - cell separation, immunoassay, magnetic resonance imaging
(MRI), drug and gene delivery, minimally invasive surgery, radionuclide therapy,
hyperthermia and artificial muscle applications.
• Physical properties which make magnetic materials attractive for biomedical
• first, that they can be manipulated by an external magnetic field – this feature is useful for
separation, immunoassay and drug targeting, and
• second, hysteresis and other losses occur in alternating magnetic fields – this is useful in
• In biology, bees and pigeons of magnetic materials as biological compasses for
navigation. Some magnetotactic bacteria are known to respond to a magnetic field.
• The earliest known biomedical use of naturally occurring magnetic materials involves
magnetite (Fe3O4) or lodestone which was used by the Indian surgeon Sucruta
around 2,600 years ago.
• Biomagnetism - In the human body, there is a constant movement of ions within and
outside the cells as well as across cellular membranes. This electrical activity is
responsible for magnetic fields, called biomagnetic fields, which we can measure
using sensitive instruments placed outside the body.
Fig. Schematic depicting the spin magnetic
moments for Fe3+ and Fe2+in Fe3O4
Magnetism and Magnetic Materials
Categories of Magnetic Materials
The Influence of Temperature
The main advantages of magnetic (organic or inorganic) NPs are that they
(i) visualized (superparamagnetic NPs are used in MRI);
(ii) guided or held in place by means of a magnetic field; and
(iii) heated in a magnetic field to trigger drug release or to produce
hyperthermia/ablation of tissue.
Fig: Schematic illustration
of MNP-based cancer
Magnetic properties of such materials
enable their applications in numerous
• Magnetically responsive nano- and microparticles and other relevant materials
can be selectively separated (removed) from the complex samples using an
external magnetic field (e.g. using an appropriate magnetic separator,
permanent magnet, or electromagnet) – Magnetic separation
• This process is very important for bioapplications due to the fact that absolute
majority of biological materials have diamagnetic properties which enable
efficient selective separation of magnetic materials.
• Magnetic particles can be targeted to the desired place and kept there using
an external magnetic field. These properties can be used e.g. for sealing the
rotating objects or in the course of magnetic drug targeting.
• Magnetic particles can generate heat when subjected to high frequency
alternating magnetic field; this phenomenon is employed especially during
magnetic fluid hyperthermia (e.g., for cancer treatment).
• Magnetic iron oxides nanoparticles generate a negative T2 contrast during magnetic
resonance imaging thus serving as efficient contrast agents.
• Magnetorheological fluids exhibit great increase of apparent viscosity when subjected to
a magnetic field.
• Magnetic nano- and microparticles can be used for magnetic modification of diamagnetic
biological materials (e.g. cells or plant-derived materials), organic polymers and inorganic
materials, and for magnetic labeling of biologically active compounds (e.g. antibodies,
enzymes, aptamers etc.).
• Magnetic Particles: Exhibiting magnétisation on exposure to magnetic Field.
• Magnetic Twisting: Twisting the magnetically tagging Biomolecules under magnetic field.
• Magnetic Tweezer: Fetching the magnetically tagged Biomelecules under magnetic field
• Magnetuc clustering: Clustering the Magnetically tagged Biomeolecule under Magnetic
Size Dependent Magnetism
Fig. Magnetic properties are affected by the particle size
(DM = diamagnetic, PM = paramagnetic, SPM =
superparamagnetic, FM = ferromagnetic)
Types of BioMagnetic Application
Special Features of Magnetic Nanoparticles
Figure 1. The different magnetic effects
occurring in magnetic nanoparticles. The
spin arrangement in a) a ferromagnet (FM)
and b) an antiferromagnet (AFM);
D=diameter, Dc=critical diameter. c) A
combination of two different ferromagnetic
phases (magenta arrows and black arrows
in (a)) may be used for the creation of
example, permanent magnets, which are
magnetization (Mr) and high coercivity
(HC), as shown schematically in the
magnetization curve (c), d) An illustration
of the magnetic moments in a
superparamagnet is defined as an
assembly of giant magnetic moments
which are not interacting, and which can
fluctuate when the thermal energy, kBT, is
larger than the anisotropy energy.
Superparamagnetic particles exhibit no
remanence or coercivity, that is, there is no
hysteresis in the magnetization curve (d).
e) The interaction (exchange coupling; linked red dots) at the interface between a ferromagnet and an antiferromagnet produces
the exchange bias effect. In an exchange-biased system, the hysteresis is shifted along the field axis (exchange bias field
(Heb))and the coercivity increases substantially. f) Pure antiferromagnetic nanoparticles could exhibit superparamagnetic relaxation
as well as a net magnetization arising from uncompensated surface spins (blue arrows in (b)). This Figure, is a rather simplistic
view of some phenomena present in small magnetic particles. In reality, a competition between the various effects will establish the
overall magnetic behavior.
Examples and Property Requirements of Magnetic
• Magnetite is found in many biological entities, from bacteria to people. It is an
example of cubic ferrites which have an inverse spinel structure. It is
ferrimagnetic with a Curie temperatureof 578 ◦C and a saturation
magnetization of 4.76 × 105 A/m.
• Another example is maghemite (gamma Fe2O3), which is formed when
magnetite is oxidized. It has a structure similar to that of magnetite, the
difference being that all or most of the iron is trivalent, the saturation
magnetization is 4.26 × 105 A/m.
• Ferritin is a protein that stores iron in humans. It contains typically 4,500 iron
atoms in an approximately spherical 12 nm diameter molecule. It has a 12
subunit protein shell containing a ferrihydrite core and an antiferromagnetic
• Gadolinium(III) chelates are commonly used in MRI applications.
• Iron coated with activated carbon has recently been tried for magnetic drug
targeting for the treatment of hepatocellular carcinomas.
• The magnetic biomaterial can, in principle, also be Ni, Co, b.c.c. Fe, magnetic
alloys of Fe, Co, Ni, Nd–Fe–B or samarium–cobalt materials.
• In all cases, however, issues of biocompatibility and toxicity limit the choice of
materials; however, the use of coatings may make the use of these materials
• The hard magnetic materials Nd–Fe–B and samarium–cobalt have the
disadvantage that large external fields are required to influence these
• Materials with high magnetization and high susceptibility are preferred for
applications such as drug targeting and magnetic separation.
• Most of the examples of useful magnetic biomaterials are in powder form, and
usually the particles are suitably coated before use.
• Ideally, the magnetic material should be non-toxic and non-immunogenic.
• In the case of drug delivery, the particle sizes should be small enough to be
injected into the bloodstream and then to pass through the required capillary
• In many cases, it is required to coat the magnetic particles; this is usually done
by coating with a biocompatible polymer or with other coatings such as gold,
activated carbon or silica.
• The coating reduces aggregation and prevents the magnetic particle from
being exposed directly to the body.
• In addition, the polymer can be used as a matrix in which drugs, radionuclides
or genetic material can be dissolved or as a site for binding of drugs; thus the
magnet-coating system can act as “carrier” to deliver useful material to the
• Some examples of common coatings are derivatives of dextran, polyethylene
glycol (PEG) and polyethylene oxide (PEO), phospholipids and polyvinyl alcohol
carrier for drug
Size Dependence On Particle removal and particle delivery
• Cell labelling and magnetic separation- It is a
two-step process, involving
(i) the tagging or labelling of the desired
biological entity with magnetic material, and
(ii) the separating out of these tagged
entities via a fluid-based magnetic separation
• Tagging is made possible through chemical modification of the surface of the magnetic
nanoparticles, usually by coating with biocompatible molecules such as dextran, polyvinyl
alcohol (PVA) and phosopholipids—all of which have been used on iron oxide nanoparticles.
• As well as providing a link between the particle and the target site on a cell or molecule,
coating has the advantage of increasing the colloidal stability of the magnetic fluid.
• Specific binding sites on the surface of cells are targeted by antibodies or other biological
macromolecules such as hormones or folic acid.
• As antibodies specifically bind to their matching antigen this provides a highly accurate way
to label cells.
• For example, magnetic particles coated with immunospecific agents have been successfully
bound to red blood cells, lung cancer cells, bacteria, urological cancer cells and Golgi
• For larger entities such as the cells, both magnetic nanoparticles and larger particles can be
used: for example, some applications use magnetic ‘microspheres’— micron sized
agglomerations of sub-micron sized magnetic particles incorporated in a polymeric binder
• This force needs to overcome the hydrodynamic drag force acting on the magnetic particle in
the flowing solution,
Fd = 6πηRm ∆v,
where η is the viscosity of the medium surrounding the cell (e.g. water), Rm is the radius of the magnetic particle, and
v = vm −vw is the difference in velocities of the cell and the water
• The major disadvantage of
most chemotherapies is that
they are relatively non-specific.
• The therapeutic drugs are
leading to general systemic
deleterious side-effects as the
drug attacks normal, healthy
cells in addition to the target
• The objectives are two-fold:
(i) to reduce the amount
of systemic distribution of the
cytotoxic drug, thus reducing the
associated side-effects; and
(ii) to reduce the dosage
required by more efficient,
localized targeting of the drug
ia of heat generated per unit volume is
• The amount
given by the frequency multiplied by the area of
the hysteresis loop:
PFM = μ0f ∫H dM.
• Advancements in our ability to fabricate MNPs with greater control over physicochemical
and bioactive properties have led to new NP candidates for imaging and therapeutic use.
• These formulations offer
• (1) disease diagnosis at their earliest stages and improved preoperative staging,
• (2) delivery of therapeutics specifically to diseased tissue, limiting unwanted side effects, and
• (3) non-invasive monitoring capabilities of new therapeutics. Size, shape, and surface chemistry dictate in
vivo behavior, including biodistribution, biocompatibility, and pharmacokinetics.
• As such, these parameters can be tuned to achieve enhanced targeting via passive, active,
and magnetic targeting mechanisms.
• Active targeting, in particular, offers high sensitivity due to the ability to direct MNP
localization, but requires added attention be paid to the targeting agent used, and the
method of MNP attachment employed.
• A number of bioconjugation strategies including physical methods, covalent strategies, and
click chemistries are available, each having distinct advantages.
• In addition to assisting in disease imaging, cell targeting by MNPs can also assist in disease
treatment if a therapeutic payload is integrated into the MNP.
• This requires additional design considerations, though, including type of therapeutic,
method of release, and intracellular activity.
• Chapter 17, Magnetic Particles for Biomedical Applications by Raju V. Ramanujan.
• O. Veiseh, et al., Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging,
Advanced Drug Delivery Reviews (2009).
• Q A Pankhurst et al., Applications of magnetic nanoparticles in biomedicine, J. Phys. D: Appl. Phys. 36 (2003)
• T.K Indira and P.K Lakshmi, Magnetic Nanoparticle- A review, International Journal of Pharmaceutical science
and nanotechnology, 3, 3 (2010).
• F. Schth et al., Magnetic Nanoparticles: Synthesis, Protection, Functionalization, and Application, Angew.
Chem. Int. Ed. 2007, 46, 1222 – 1244.
• Akbarzadeh et al., Magnetic nanoparticles: preparation, physical properties, and applications in biomedicine,
Nanoscale Research Letters 2012, 7:144
• Nhiem Trana and Thomas J. Webster, Magnetic nanoparticles: biomedical applications and challenges, J.
Mater. Chem., 2010, 20, 8760–8767.
• Jaromir Hubaleket al., Magnetic nanoparticles and targeted drug delivering, Pharmacological Research 62
• Gao Songet al., Magnetic nanoparticle-based cancer therapy, Chin. Phys. B Vol. 22, No. 2 (2013) 027506.
• Sheng Tonget al., Multifunctional Nanoparticles for Drug Delivery and Molecular Imaging, Annu. Rev.
Biomed. Eng. 2013. 15:253–82.
• Kuo-Chen Wei et al., Potential of magnetic nanoparticles for targeted drug delivery, Nanotechnology,
Science and Applications 2012:5 73–86
• Akira Yoshiasa et al., Synthesis of novel CoCx@C nanoparticles, Nanotechnology 24 (2013) 045602.
• Carlos J Serna et al., The preparation of magnetic nanoparticles for applications in biomedicine, J. Phys. D:
Appl. Phys. 36 (2003) R182–R197.
• Chapter 7, Magnetic Nanoparticles: Synthesis, Surface Modifications and Application in Drug Delivery by
Seyda Bucak, Banu Yavuztürk and Ali Demir Sezer.
• Article in Nanotoday, Magnetic nanoparticles for drug delivery, JUNE 2007 | VOLUME 2 | NUMBER 3