Documente Academic
Documente Profesional
Documente Cultură
By
N.H.K.S.Senathilake.
August 2009
ACKNOWLEDGEMENTS
I am grateful and express my heartiest thanks to my supervisor Dr. W.R.M. De Silva for
her valuable guidance, encouragement and support throughout the study.
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ABSTRACT
When it comes to biomedical applications Iron oxide nano particles is the major interest
as they are less toxic and bio-compatible magnetic particles with shorter relaxation times
allowing a good magnetic manipulation in biological systems. This study covers the
current synthetic methods and biomedical applications of magnetic ion oxide nano
particles in brief.
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Table of contents
Acknowledgement ii
Abstract iii
Table of contents iv
List of abbreviations v
Referances 10
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List of abbreviations
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Chapter 01
Introduction
Any nano material including iron oxide nano particles are developed in a sequential
manner starting from tiny pure metal, metal oxide, organic polymer particles up to
functionalized advanced generation particles. Though few protocols show slight
exceptions a generalized scheme can be illustrated.
Though advanced generation particles may further be self assembled to yield a complex
tow dimensional and three dimensional structures, In general biomedical function of
MIONPS deals with advanced generation particles-functionalized with bio-active
components. In few cases it is second generation particles.
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Chapter 02
Synthesis of MIONPs
2.1 Challenges
There are two main challenges to make all biomedical applications of MIONPs come true:
1) a good synthesis route for manufacturing first generation monodisperse MNPs with
diameters <20nm; and 2) a good method to functionalize the surface of this nanoparticles.
The latter determines the ability of the MNPs to interact in a well-defined and controllable
manner with living cells. Such an interaction is mainly achieved by coating the
nanoparticles with biological ligands specific for certain receptors on the cell surface (i.e.,
receptor-mediated interaction). However, in some cases, a chemical functionality can also
be "attractive" for a cell surface (i.e., nonspecific interaction). Once bound to the cell
surface, the nanoparticle can stay there or a mechanism of cellular uptake can be triggered
by which the nanoparticle is engulfed through the cellular membrane and brought into the
cell body ( figure 2.5).
Fig 2.5
Possible
interactions
between (bio-
active)
magnetic
nanoparticles
and living
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stable in solution without showing any sign of nanoparticle aggregation. As for all
nanoparticles, aggregation is also commonly observed for MNPs due to their extremely
large surface-to-volume ratio and the large surface energy they express. Furthermore, they
could magnetically interact with each other when not properly stabilized.
Theory behind producing first generation nano particles is simply a nucleation process as
occur in chemical precipitations there the reaction yields iron oxides and it forms tiny
nuclei suspension initially, followed by aggregating further produced iron oxides on these
nuclei to yield particles that form the precipitation. In nano technology particle diameter
and dispersed nature of the particle is controlled by using different matrix and conditions.
Thus giving rise to deferent techniques in nanoparticle synthesis such as micro-emulsion,
co-precipitation and Thermal decomposition.
2.3 Protocols
Many protocols available today for the synthesis of MIONPs based on micro-emulsion,
co-precipitation, and other water-based methods.
Micro emulsion
Controlling the very low interfacial tension in precipitation matrix (~10-3 mN/m) through
the addition of a co surfactant (e.g., an alcohol of intermediate chain length), these micro
emulsions are produced spontaneously without the need for significant mechanical
agitation. The technique is useful for large-scale production of nanoparticles using
relatively simple and inexpensive hardware (Higgins 1997).
Co precipitation
Metal oxide precipitation and a polymerization reaction is carried out at the same time so
that the developing particles are trapped inside the tiny polymer beads.
The disadvantages of these water-based methods are that the size uniformity and
crystallinity of the MNPs are rather poor, and nanoparticle aggregation is commonly
observed. A Recently developed protocol (Sun et al)utilize thermal decomposition giving
us a simple synthetic procedure that enables the synthesis of very monodisperse and
highly crystalline MNPs with sizes between 3nm and 20nm without showing any sign of
nanoparticle aggregation. Further this method is very useful in producing diverse range of
MNPs allowing a fine surface tuning in further steps (chapter 2.4) to construct MNPs with
diverse functions.
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Furthermore, it was shown that the presence of these end groups strongly determines the
water dispersibility of the nanoparticles. Out of these nine different silanes, only the
amino, carboxylic acid, and poly(ethylene glycol) end functions were found to render the
nanoparticles perfectly soluble in aqueous solutions over a wide pH range. Enhanced
long-term stability and increased resistance against mild acid and alkaline environments
were observed compared to those of other ligands commonly used to stabilize MNPs.
These characteristics are due to the strong covalent linkage of the silane layers onto the
nanoparticles' surface. Combined with Sun's method for synthesizing MNPs, the
functionalization procedure described above results in monodisperse, water-soluble
(thus biocompatible) MNPs with properties that can easily be tuned to the requirements of
the specific application.
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Chemically active nano particle can then be coated with bio-active components such as
ligands, antibodies using the knowledge of surface chemistry of the particle(Fig 2.4), or
these particles can be trapped (by co precipitation) in a nano beads like liposomes, bio
degradable polymers which already have active components such as Drugs. Therapeutic
gene, RNA.
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Chapter 03
Magnetic nanoparticles (MNPs) have variety of Biological and Medical uses. Ranging
from contrast agents for magnetic resonance imaging to bio-separation, hyperthermia
treatment for cancer. ( figure 3.1).
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Another application is the selective magnetic labeling all kinds of biological entities,
such as cells, DNA, and proteins biological entities, via surface coated antibodies.
Advantages compared to conventional labels such as enzymes, fluorescent dyes,
chemiluminescent molecules, and radioisotopes are that MNP labeling enables us to
detect (using MRI), transport and purify biological components at the same time. Further
multi functional MNPs may have many different functions on particular entity,
Labeling with these MNPs detects a particular therapeutic process. Main applications
using monoclonal antibody mediated MNP (biologically activated using Mabs) labels
include.
1.) Selective bio-separation and cell isolation using an external magnetic filed (in vitro
and in vivo) the attraction between an external magnet and the MNPs enables separation
of a wide variety of biological entities. Examples are the isolation of cancer cells in blood
samples or stem cells in bone marrow to allow for improved diagnosis and the removal of
toxins from the human body or blood (Hemoperfusion). Furthermore, MNPs can be
biologically activated to allow the uptake of cells via endocytotic pathways, thereby
allowing certain cellular compartments to be specifically addressed. Once taken up, the
desired cellular compartments can be magnetically isolated and accurately studied using
proteomic analysis.
2.) Labeling of stem cells to noninvasive monitor the distribution and fate of
transplanted stem cells in the human body.
3.) Magnetic labels in biosensing is used in magnetic micro arrays and magnetic
immunoassays. For example, magnetically labeled cancer cells can be purified,
transported, and detected on a single chip surface, enabling simple and cost-effective
cancer screening in a lab-on-a-chip approach.
As thy are small and low toxic to humans, MNPs can be transported in blood stream
through an external magnetic field gradient, to the targeted site in the body and
penetrating deep into the human tissue. In this way, controlled transport of drugs to target
sites can be achieved. The latter usage is realized by attaching a drug to a biocompatible
MNP carrier, injecting the ferro fluid into the bloodstream, and applying an external
magnetic field to concentrate the drug/carrier complexes at the target site. As one
example, this principle is used with cytotoxic drugs in cancer treatments. Tissue targeted
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delivery can be further improved by fabricating the particle surface with tissue specific
antibody or ligands and using bio degradable polymers.
Drug
particles
Magnetite
particles
. Another interesting therapy is based on the ability of MNPs to be heated when a time-
varying magnetic field is applied. This characteristic is used to burn away cancer cells
(hyperthermia), often in combination with chemotherapy. MIONPs are biologically
functionalized to target the tumor. It is in fact known that cancer cells are more sensitive
to temperatures in excess of 41°C than their normal counterparts. This confirms that the
surrounding normal cells are well safeguarded during the process.
Investigators use folic acid to target magnetic nanoparticles to tumor cells. As tumor cells
express folic acid receptors in higher levels, MIONPs functionalizes to have folic
acids(ligand) on the surface. This MIONPs binds to folic acid receptors facilitating the
receptor mediated uptake in to malignant cells. Once the tumor cells engulfed the
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nanoparticles, the researchers then heated the nanoparticles with a rapidly oscillating
magnetic field. Preliminary data from these experiments suggest that the nanoparticles
should be able to heat up cells beyond 43 °C – a known lethal temperature – after being in
the oscillating magnetic field for 20 minutes. Using electron microscopy and cells
growing in culture, the researchers were able to document that only cancer cells bearing
folic acid receptors on their surfaces were able to take up the magnetic nanoparticles.
Chapter 4
Conclusion
Magnetic iron oxide nanoparticles are bio compatible, less toxic and can be manipulated
very effectively in vivo and ex vivo to get many tasks done, including processors which
cannot be achieved or difficult to achieve using older and conventional methods. Much
research focus has to be on MIONPs biomedical uses and It seeks further developments.
References
5. S. Sun at el -Nanoparticles," Journal of the American Chemical Society, 126, pp. 273–
279, 2004.
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