Magnetic nanoparticles in biomedicine Targeted delivery, hyperthermia and imaging

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Magnetic nanoparticles in biomedicine - Targeted
delivery, hyperthermia and imaging
Venkat S. Kalambur, John C. Bischof,
Ph.D Department of Mechanical Engineering,
University of Minnesota, Minneapolis, MN
Abstract Magnetic nanoparticles can be
potentially used in the targeted delivery of
therapeutic agents in vivo, in the hyperthermic
treatment of tumors, in magnetic resonance
imaging (MRI) as contrast agents and in the
biomagnetic separations of biomolecules. An
understanding of the movement, heating and
visualization of these nanoparticles in
physiological systems in vitro and in vivo is
required to tailor these nanoparticles for a few
of these applications. Secondly, a
characterization of the biodistribution and
injury in vitro and in vivo are required when
these nanoparticles are used as therapeutic
agents in hyperthermia and drug delivery.
Further, imaging protocols that allow for a
quantitative characterization of the distribution
of these nanoparticles in vivo are required to
monitor these nanoparticles during a particular
application. In this work, the movement, heating
and visualization of various magnetic
nanoparticles differing in their size and coating
will be studied in different physiological media.
Finally, suitable model systems will be used to
characterize the injury and biodistribution of
these nanoparticles in vitro and in vivo after a
therapeutic use.
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Background
Magnetic nanoparticles are superparamagnetic.
1. They have a strong (ferromagnet-like) and a
reversible (paramagnet-like) response to an
external magnetic field. 2. Due to their size
scale and hence the resultant Brownian motion
they do not settle down in a carrier fluid. 3.
They generate heat when exposed to a external
radio-frequency (RF) field.
Magnetic field
Magnetic nanoparticles are found as magnetosomes
in certain magnetotactic bacteria. Magnetite
(Fe3O4) nanocrystals produced by these bacteria
are used for alignment and movement in earths
magnetic field.
Frankel RB. Annu. Rev. Biophys. Bioeng.
19841385-102.
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Background
Magnetic nanoparticles can be used for a variety
of applications in biology and medicine.
Biomagnetic separations of DNA, proteins etc.
Targeted drug delivery in vivo
Magnetic hyperthermia for tumor treatment
Contrast agents in MRI
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Motivation
Understanding of movement, heating, visualization
and the biodistribution of these nanoparticles in
physiological systems in vitro and in vivo is
essential to tailor them for practical
applications.
How does the particle heat up the tumor?
- Heating
How does the drug-carrier move through blood and
the tumor interstitium in a given magnetic field
? - Movement
What happens to cells and tissue systems when
they interact with these Nanoparticles in vitro
and in vivo? Uptake and injury.
What is the distribution of the particles in the
tumor ? - Visualization
What happens to these nanoparticles in the
presence of blood flow and RES (immune system) in
vivo - Biodistribution
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Aim of the study
Improved understanding of movement, heating,
visualization and biodistribution of three
different types of magnetic nanoparticles and
interactions with cells and tissues in vitro and
in vivo.

• Movement In physiological systems in a known
  external magnetic field.
• Heating In physiological systems in a known RF
  field.
• Visualization Imaging protocols based on MRI
  and Infra-red (IR) imaging to track these
  nanoparticles in vitro and in vivo.

Summary of nanoparticles
Particle 1 Uncoated Fe3O4
Particle 2 Dextran-coated ?-Fe2O3
Particle 3 Polystrene-coated ?-Fe2O3 Fe3O4
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Movement studies
The movement of a collection of nanoparticles was
studied in glycerol and type-1 collagen to
simulate movement in the tissue interstitium in a
constant external magnetic field.
Figure 1. Magnetic field intensities of the NdFeB
magnet used
(a)
(b)
Figure 2. Set-up used to study movement in (a)
glycerol (b) collagen
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Movement studies
The movement is strongly dependent on the
suspending media, the size and the coating of the
nanoparticles.
(a)
(b)
Figure 3. Movement of different particles in (a)
glycerol (b) collagen
Particle 1 (uncoated, 10nm) and particle 3
(polystrene coated, 2.8µm do not move in
collagen. Particle 2 (dextran-coated, 50nm)
takes almost ten times longer to move 10mm in
collagen when compared to a distance of 5mm in
glycerol.
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Heating studies
The heating of magnetic nanoparticles is due to
the movement of the magnetic moment away from the
crystal axis called the Neel mode and the
oscillation of the whole nanoparticle called the
Brownian mode and is a strong function of the
size of the nanoparticles.
Rosensweig RE. J Mag. Mag. Mat. 2002252370-374.
The heating of the different nanoparticles were
studied in water, glycerol and collagen by
measuring the macroscopic temperature changes in
a known RF field.
Figure 4. Set-up to study heating of magnetic
nanoparticles
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Heating studies
The heating is strongly dependent on the
suspending media and the size of the
nanoparticles.
Particle 2 (50nm,dextran-coated) and particle 3
(2.8µm, polystrene-coated) do not heat up
(?Tlt2C). Only particle 1 (10nm) heats up in an
RF field of 175kHz, 14kA/m.
Figure 5. Change of temperature vs. time in (a)
water (b) glycerol (c) collagen
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Visualization studies
Infra-red (IR) and MR imaging can be used to
image magnetic nanoparticles.
IR imaging can be used to image an order of
magnitude higher concentration than MRI. However,
MRI is useful for 3-D imaging of internal organs
and lesions unlike IR which is limited to surface
applications in vivo.
Figure 5. IR imaging of magnetic nanoparticles.
Figure 6. MR imaging of magnetic nanoparticles.
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Quantification of iron in vitro
Colorimetric determination of iron based on
reaction of Fe2 with 2,2-bipyridine
For studies in vitro on cell culture systems and
tissue samples ex vivo, iron concentration
quantification can be done by using a
colorimetric assay. The amount of iron indirectly
will provide quantitative information on the
biodistribution and interaction of magnetic
nanoparticles with cells and tissues in vitro.
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In vivo studies
The biodistribution and the effect of these
nanoparticles after a therapeutic application
will be studied in a dorsal skin fold chamber
(DSFC) that allows for a intravital analysis of
the microcirculation.
Figure 7. Intravital microscopy using the DSFC
mouse model
Figure 8. Close-up of DSFC showing the
microvasculature to be studied.
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Future work

• Study the interaction of magnetic nanoparticles
  with cells in vitro and quantify the uptake and
  inflammation in cells after uptake.
• Quantify the biodistribution and effects on tumor
  microvasculature in vivo in a DSFC after magnetic
  nanoparticle injection.

References

• Pankhurst QA et al. Applications of magnetic
  nanoparticles in biomedicine. J Phys. D
  200336R167-R181.
• Kalambur VS et al. Characterization of movement,
  heating and visualization of magnetic
  nanoparticles for biomedical applications.
  Proceedings of ASME IMECE 2004.

Acknowledgements

• NSF Grant 0208564
• Dr. Thomas W Shield, Department of Aerospace
  Engineering and Mechanics, University of
  Minnesota
• Dr. Bruce Hammer, Department of Radiology,
  University of Minnesota
• Members of the bioheat and mass transfer lab,
  Department of Mechanical Engineering, University
  of Minnesota