Magnetically-Guided Nanoparticles for
Targeted Drug Delivery
Final 2011 RET Report
Prepared by
Seth Baker
Percy Julian Middle School
Laboratory for Product and Process Design
Director: Andreas A. Linninger
____________________
Seth Baker
RET Fellow
____________________
Prof. Andreas Linninger
RET Mentor
University of Illinois at Chicago, Chicago, IL.
Date: 8/4/2011
1.0 Abstract
Because of the complexity in the vasculature, the natural endothelial barriers and
the delicate nature of brain tissue, targeted drug delivery to the brain has remained a
challenge for scientists. Magnetically-guided nanoparticles offer a possible therapeutic
method for effective targeted drug delivery into brain tissue. Experiments are conducted
using 35 and 173 pound pull force magnets to guide magnetite (Fe3O4) nanoparticles
toward specific areas in brain phantom agarose gels using magnetic fields. Preliminary
testing on the delivery of magnetic nanoparticles in rat brain tissue and a brief overview
of the brain vasculature, nanoparticles and magnetism is also given.
2.0 Table of Contents
1.0 Abstract ………………………………………………………………………… 2
2.0 Table of Content ……………………………………………………………….. 3
3.0
Introduction …………………………………………………………………......4
4.0 Background …………………………………………………………………….. 5
4.1 Nanoparticles ………………………………………………………………..6
4.2 Functionalizing………………………..………………………………….…...7
4.3 Magnetism …………………………………………………………………8
5.0 Motivations ………………………………………………………………..........10
6.0 Current Study …………………………………………………………………...11
7.0 Methods and Materials …………….……………………………………………12
7.1
Preparing Nanoparticles……..…………………………………………..12
7.2
Magnetite Guidance during Convection-Enhanced Delivery of
magnetite…………..…………………………………………………..………....13
7.3 Capillary Experiments in Agarose Gel………………………………...…15
7.4 Delivery of Magnetite in Rat Brain Tissue …………………………………...17
8.0 Results ………………………………………………………………………..… 18
9.0 Conclusion ……………………………………………………………..……......21
9.1 Future Studies……………………………………………………………...22
10.0
Acknowledgements ………………………………………….…………….......23
11.0
References …………………………………………………………………..…25
3.0 Introduction
Treatment options for many neurological conditions are often inadequate due to
the limited approaches to accurately deliver therapeutic drugs to the brain. A major
factor in this limitation is the inability to target therapeutics to a specific area of the brain.
Therapeutics that penetrate or by-pass the brain's blood brain barrier, a natural protective
mechanism located in the brain microvasculature, can lead to systemic toxicity and affect
unintended areas of the brain. A novel approach to target the delivery of therapeutics is
the use of magnetically-guided nanoparticles infused through convection-enhanced
delivery (Perlstein 2008). This approach involves using magnets to guide functionalized
nanoparticles to site specific areas and by pass the blood brain barrier. Convection
enhanced delivery infuses fluids while maintaining a constant pressure gradient.
In order to establish a standard protocol for magnetically-guided nanoparticle
delivery into brain tissue, a series of surrogate brain gels and magnets can be used to
determine the variables that affect the movement of nanoparticles. Once variables have
been tested, a standardized protocol for targeting nanoparticles into brain tissue can be
designed.
Protocols must also be determined to allow for accurate measurement of
nanoparticle delivery into brain tissue. These protocols include preparing brain tissue,
delivering magnetic nanoparticles to brain tissue, and staining the samples for accurate
visualization of nanoparticle movement. Rat brain samples can also be used to measure
the accuracy of the brain gel phantoms, as well as to study the unique properties of brain
tissue.
Once effective methods in delivery and guidance of magnetic nanoparticles are
established, medical applications can be developed. However before studying the future
of brain therapeutics, a general understanding of brain vasculature, nanoparticles and
magnetism is necessary.
4.0 Background
Vasculature is the arrangement of blood vessels in a body or organ. There are
five general types of vessels found in the human body, arteries and arterioles, vessels that
send blood away from the heart, veins and venules, vessels that send blood back to the
heart, and capillaries, which form a mesh that connects arterioles to venules. Both
arteries and veins form an intricate branched system throughout the body with vessels
ranging in size from the 2-3 cm diameter of the aorta and vena cava, to the 5 μm diameter
of capillaries. Nowhere in the human body is the vasculature more intricate than in the
brain. Although the brain is only 2% of your total body mass, it receives up to 20% of the
blood flow from your heart (Chudler 2007). The neuron cells in the brain must receive a
constant supply of oxygen, and capillaries are arranged to allow this to occur in a nonpulsating steady flow (Mchedlishvili 1986).
An important mechanism in the brain vasculature is the blood brain barrier. This
selectively permeable barrier creates an interface between the brain’s vascular blood flow
and peripheral brain tissue. Substances that can successfully cross the blood brain barrier
are lipid soluble compounds and small micromolecules, generally less than 500 Da
molecular weight (Pardridge 1998). Nanoparticles with diameters less than10 nm are
able to penetrate the tight junctions of the blood-brain barrier as well (Anderson 2001).
What allow nanoparticles access to brain tissue are the unique cellular structures of the
blood brain barrier and their miniscule size.
4.1 Nanoparticles
Nanoparticles are generally defined as particles with a diameter of less than 100 nm.
One nanometer is 10 -9 m, with the average somatic cell size ranging from 10-100 μm. (1
μm = 10 -6 m). Nanoparticles administered intravenously can range from 5.5 nm to 200
nm in diameter depending on the clinical use (Pankhurst 2003). Nanoparticles that have
a diameter greater than 200 nm cannot be effectively used in biomedicine unless targeted
for the spleen. This is due to the spleen’s natural filtration of particles greater than 200
nm in size. Similarly, nanoparticles with a diameter of less than 5.5 nm are filtered by
the kidneys, and therefore most effective for delivery of therapeutics only to the kidneys
(Sun 2008). Within the range of 5.5-200 nm however, nanoparticles are sufficiently
small enough to have direct interaction with cellular structures (Arruebo 2007). Cell
membranes are generally permeable to nanoparticles with the smallest particles able to
cross both the cellular and nuclear membranes. These nanoparticles can be “loaded” into
macrophages or coated for receptor-mediated transport across the blood brain barrier.
Nanoparticles can be synthesized from many compounds including liposomes,
dendrimers, and biodegradable polymers. Nanoparticles delivered directly to the brain
are functionalized with coatings made of polymers and surfactants that allow the
nanoparticles improved permeability across the blood brain barrier. (Chakraborty 2009).
Nanoparticles infused into the brain via convection-enhanced delivery often utilize
coatings of polyethylene glycol (PEG) or dextran, a glucose polymer to increases the
infusion efficacy (Perlstein 2008). Many nanoparticles are also small enough to penetrate
tumor tissue due to the enhanced permeability and retention (EPR) quality of tumors (Jin
2007). This hyperpermeability allows nanoparticles to enter tumors through the
increased blood flow that develops as tumors grow. This passive targeting can be
enhanced through magnetic guiding as well (Arruebo 2007).
Nanoparticles used in biomedicine must have a prolonged circulation time in the
bloodstream to be able to deliver therapeutics to targeted sites (Arruebo 2007). Therefore
knowledge of the immune and lymphatic systems is necessary to understand how
nanoparticles are metabolized in the body. Nanoparticles such as magnetite (Fe3O4) are
biocompatible and biodegradable. The iron ions are absorbed into the body’s iron stores
during metabolism and eventually used in the synthesis of hemoglobin (Sun 2008).
4.2 Functionalizing
A major benefit of using nanoparticles for biomedicine is the ability to
functionalize nanoparticles with various agents. These agents can include surface
receptors for binding targeted cells, florescence markers for visualizing the movement of
nanoparticles, chemicals to monitored drug release, and attaching a wide range of
therapeutics. [Figure 1] The nanoparticle coating can provide various functions for
clinical purposes and also help the nanoparticles “hide” from the body’s immune and
filtration systems (Sun 2008). Nanoparticles also need surface protection to reduce
degeneration. Over a period of time, “naked” magnetic nanoparticles will oxidize,
resulting in lower magnetism and dispersion. The smaller the nanoparticle, the more
susceptible they are to oxidation. There are generally two types of coatings used to
functionalize nanoparticles, organic shells made of polymers or liposomes, or inorganic
shells made of metals such as gold and silver. (Lu 2007). Nanoparticle coatings often
regulate the solubility, hydrophilic or hydrophobic properties, stability, and the targeting
ability of the particles.
Figure 1 – Functionalizing nanoparticles
4.3 Magnetism
According to Faraday's law of magnetic induction, when a material is placed in the
presence of a magnetic field, the material's electrons will be affected. How they are
affected depends on the atomic structure of the material, whether the electrons are paired
and balanced. The more balance among the electrons, the lower magnetic response.
There are three basic classifications of magnetism with respect to a material's electron
configuration, diamagnetic, paramagnetic, and ferromagnetic. Materials with all
electrons in pairs are called diamagnetic and have a weaker response to a magnetic field.
Diamagnets are slightly repelled by a magnetic filed, and lose any magnetic properties
when a magnetic field is not present. Diamagnetic elements include copper, gold, and
silver.
Materials with some unpaired electrons are called paramagnetic and possess
slightly greater susceptibility to magnetic fields. These elements have a weak attraction
to a magnetic field and like diamagnets, lose magnetic properties when a magnetic field
is removed. Paramagnetic elements include magnesium, molybdenum, lithium, and
tantalum.
Ferromagnets are materials that have a high susceptibility to a magnetic field.
These materials (iron, cobalt, nickel) have unpaired electrons and have a strong attraction
to a magnetic field.
Ferromagnets are composed of magnetic domains, areas that
develop as the material naturally forms. These domains contain atoms with electrons that
are aligned in a uniform direction. In the presence of a magnetic field, multiple magnetic
domains become aligned until the material is magnetically saturated. Unlike diamagnets
and paramagnets, ferromagnets will retain magnetic properties in the absence of a
magnetic field.
Another classification of magnetism is called superparamagnetism and occurs
only at the nanoscale. Ferromagnetic particles with diameters less than 14 nm, lose their
ferromagnetic properties and behave as a paramagnet. The magnetic domains remain
isolated and the material is classified as superparamagnetic. Superparamagnetism has
higher magnetic susceptibility than paramagnetism, nearly the level of magnetically
saturated ferromagnets (Neuberger 2005) but in the absence of an external magnetic field,
superparamagnetic particles lose magnetic properties. These are ferromagnetic materials
acting as a paramagnet, but with much higher susceptibility. This allows scientists to
“flip” these seemingly paramagnetic materials into near ferromagnetic susceptibility in
the presence of a magnet (Thorek 2005).
5.0 Motivations
According to recent reports from the World Health Organization, nearly 1 billion
people suffer from neurological disorders such as Alzheimer’s, Parkinson’s, depression,
stroke, and epilepsy (World Health Organization 2009). Many of the individuals who are
afflicted with these disorders remain untreated due to limited options for therapeutic drug
delivery (Pardridge 1997). The World Health Organization also projects that 25% of the
world’s current population will develop one or more neurological disorders (World
Health Organization 2001). With the prevalence rising for neurological disorders,
research is necessary to develop new treatments. Delivering therapeutics to the brain
creates unique challenges because of the complexity of the brain’s vasculature, and
natural endothelial barriers such as the blood brain barrier. According to William
Pardridge from the University of California, Los Angeles, School of Medicine, “The
blood-brain barrier is the bottleneck in brain drug development and is the single most
important factor limiting the future growth of neurotherapeutics” (Pardridge 2005).
There are also problems when medicinal chemistry creates drugs with increased lipid
solubility. While it increases the permeability across the blood brain barrier, it also
increases permeability across all other body membranes which minimizes the uptake in
the brain, and can lead to toxicity in the body. Nanoparticles loaded with therapeutics
can move across the blood brain barrier by passive diffusion, however without guidance
therapeutics entering the brain will disperse systemically. Controlling the distribution and
targeting specific sites in the brain therefore becomes critical as cytotoxic drugs need to
be limited in their delivery with systemic toxicity greatly reducing the effectiveness of
therapeutics (Dobson 2006). A possible strategy for delivering medication to targeted
areas of the brain is the use magnetically guided nanoparticles. This method has greater
control over fluid distribution than diffusion and reduces systemic toxicity that blood
brain barrier disruption and implantations can create. Use of magnetically guided
nanoparticle delivery can also allow for lower therapeutic dosage, which in turn also
reduces systemic toxicity.
6.0 Current Study
There are two related topics in the current study. First, convection – enhanced
delivery and capillary infusion is used to investigate magnetically guided nanoparticles in
agarose gel brain phantoms. For this study, a standard protocol to inject nanoparticles is
investigated by varying the nanoparticle diameter, catheter design, and magnetic field. A
second study is conducted to investigate magnetic nanoparticle delivery into brain tissue,
along with staining techniques for visualizing nanoparticles and brain slicing techniques.
In the first section, the methods and materials for both infusion methods in
agarose gel and magnetic nanoparticle delivery into brain tissue are discussed. Next, the
results of the infusions are presented followed by a conclusion section. In this section,
the results are analyzed and future studies including infusion into cerebral spinal fluid
and the use of spinal phantoms as well as future techniques in reducing agglomeration of
nanoparticles are discussed.
7.0 Methods and Materials
Convection – enhanced delivery and capillary infusion were both conducted in
agarose gel brain phantoms. The experimental design distribution profiles are observed
to investigate a standard protocol for infusion and guiding magnetic nanoparticles into
porous material. Nanoparticles used in the experiments were obtained from
Northwestern University and ranged in size from 8-30 nm. The particles contained a
magnetite core and were coated with sucrose, or ficoll.
7.1 Preparing the Nanoparticles
Nanoparticles solutions were prepared by taking 0.5 ml of an acidic solution of
suspended magnetite particles and adding 0.5 ml of 2M sodium hydroxide to neutralize
the solution. This solution was then vortex to mix the solution and centrifuged to remove
the supernatant from the nanoparticles. The nanoparticles were then washed with1 ml of
distilled water and sonicated until the nanoparticles were evenly dispersed. The pH was
tested and the solution was centrifuged again; removing the supernatant and the washing
of nanoparticles was repeated until a neutral pH was obtained. The nanoparticles were
then tested for magnetic susceptibility. This was done by placing the neutral
nanoparticles near a magnet to observe magnetic attraction. [Fig 2] Once magnetic
susceptibility was determined, the nanoparticles could be used in the agarose gel
experiments.
Figure 2 – 30 nm magnetite at a) 0 minutes b) 4 minutes c) 8 minutes above a 173 lb pull force magnet
7.2 Magnetic guidance during convection–enhanced delivery of magnetite
0.6% agarose gel was chosen as a brain phantom as it has similar porosity and
tortuosity of gray brain matter (Chen 1999). To prepare the gel, 0.6 g of dry agarose type
1 (Sigma) and 0.9 g of sodium chloride (Sigma) was added to 100 ml of distilled water.
Next, the mass of the mixture was measured, then heated to a low boil and stirred
continuously with a magnetic stirrer. The gel was allowed to cool and additional distilled
water was added to adjust for evaporation. The gel was then maintained at 50 oC in an
Isotemp water bath.
Next, 10 ml B-D plastic syringes were filled with 8 ml of olive oil using an 18
gauge needle, connected to 18 gauge polyethylene tubing. Olive oil was used to fill the
syringes, therefore limiting the amount of nanoparticles necessary for the infusion. The
nanoparticles were inserted only into the polyethylene tubing. This tubing was then
connected to 1 mm diameter tubing using threaded joint fittings. From this a step
catheter was attached. Step design catheters for this experiment used polyethylene,
PEEK, and fuzed silicia tubing with internal diameters of 1 mm, 0.3 mm, and 0.16 mm.
[Fig 3].
Figure 3 – 0.16 mm step catheter tip inserted into 0.3 mm tubing
Each smaller diameter tube was inserted into the end of a larger diameter and
super glue was applied to seal the connection. This design reduces reflux of
nanoparticles along the catheter (Krauze 2005). The step catheters were then filled with
nanoparticle solution. Syringes were placed in a New Era syringe pump to ensure precise
infusion rates. Each catheter was positioned in a plastic cell (3.8cm x 6.7cm x 2.2cm)
and surrounded by liquid agarose gel. The catheter tips were positioned ¼ inch above the
bottom of the cell to insure that the magnets were placed ¼ inch from the infused
particles. Two cells were placed directly above 173 pound pull force magnets and two
cells were use as controls. [Fig 4]. The gel was given an hour to solidify before the
infusion. Once infusion began, digital photos were taken after nanoparticles were
infused. Infusion rates were set at 0.5 μl/min. Once the infusion was completed, the
agarose was removed from the plastic cells, and placed in petri dishes filled with Prussian
blue stain to visualize the magnetite. [Fig 5] The gel was stained for four hours, washed
quickly three times with distilled water and then washed overnight in distilled water for
12 hours before visualization of nanoparticle distribution.
Figure 4 – Experimental set up for agarose gel infusion
Figure 5 – Staining and washing of agarose gel infused with nanoparticles
7.3 Capillary Experiments in Agarose Gel Brain Phantoms
Agarose gel was prepared with the same methods as discussed for convectionenhanced delivery. Next, five 16 gauge needles were attached to 1 ml BD syringes
primed with distilled water and inserted into a hole drilled in the side of a 2 ¼ inch
diameter petri dish. The hole was located ¼ inch above the base of the petri dish. Once
the syringe needles were inserted, they were surrounded by liquid agarose gel. [Fig 6]
Figure 6 – Capillary experiment set up
Once the gel was allowed to set for an hour, the needle was removed, leaving a 16
gauge lumen in the agarose. Next, a 27 gauge needle attached to a 1 ml BD syringe
primed with water was used to remove the remaining water housed inside the 16 gauge
lumen embedded in the gel. Then a 1 ml BD syringe primed with nanoparticle solution
and attached to a different 27 gauge needle was used to fill the 16 gauge needle lumen
with nanoparticle solution. Next, the 16 gauge needle was very carefully removed from
the gel while the nanoparticle solution was injected into the lumen and filled the void
space created by the embedded 16 gauge needle. Adhesive putty was used to seal the
hole in the petri dish. Finally two petri dishes were placed directly above 173 pound pull
force magnets and two were used as controls. The gels were then allowed to set for 24
hours, after which they were stained with Prussian blue and washed in distilled water to
visualize any distribution of magnetite nanoparticles throughout the gel.
7.4 Delivery of Magnetite in Rat Brain Tissue
Before investigating the movement of magnetic nanoparticles in brain tissue, the
sensitivity of Prussian blue stain on brain tissue was first determined. Unfixed or fresh
rat brain samples were first sliced into ¼ inch coronal slices using a glass microscope
cover slip. [Fig 7] These samples were then place in a solution of Prussian blue stain for
24 hours. [Fig 8] All tools used for brain preparation were non-metallic to limit rat brain
tissue exposure to metal. This exposure could affect the results when Prussian blue stain
was used to visualize the nanoparticles
Figure 8 – Unfixed brain tissue in Prussian blue stain
Figure 7 – Unfixed brain slicing with glass slide
Next, to determine the susceptibility of brain tissue to magnetite nanoparticles, 10
μl of 30 nm magnetite nanoparticle solution was delivered to the surface of ¼ inch
coronal slices of unfixed rat brain tissue. [Fig 9] The nanoparticle solution was prepared
the same way as discussed earlier. The brain tissue was then placed in a plastic petri dish
and covered with Prussian blue stain for 24 hours. The tissues were washed in distilled
water and digital photos were taken.
Figure 9 – Delivery of nanoparticles to unfixed brain tissue
8.0 Results
A consistent result of many convection enhanced infusions was agglomeration of
nanoparticles. As the nanoparticles were placed in the tubing and the agarose gel
solidified, the particles began to become attracted to each other and cluster. As the
infusion began and pressure increased in the tubing, the agglomerated particles blocked
the nanoparticle solution from infusing into the gel. If the fluid could overcome the
initial pressure from the blockage, the agarose gel would sheer from the sudden force of
the nanoparticle solution or the solution would reflux up the catheter. Step catheters
connected to larger gauge tubing resulted in fewer occurrences of reflux, however
inconclusive results of magnetic attraction of nanoparticles were produced [Fig 10-11]
with no noticeable difference in nanoparticle movement between the 35 and 173 pound
pull force magnets.
Figure10 – Polymer step catheter
Figure 11 – non-step catheter with reflux
Capillary experiments with nanoparticles did indicated some attraction of
nanoparticles toward a magnetic force. [Figs 12-14] Both 35 and 173 pound full force
magnets were positioned directly below each petri dish for 24 hours. Compared to the
control, magnetite nanoparticles above the 35 pound pull force magnet were attracted
1/16th inch toward the magnet and nanoparticles above the 173 pound pull force moved
1/8th inch toward the magnet.
Figure 12 – Control for 0.6% agarose gel capillary experiment. Red line indicates syringe line
Figure 13 – 35 pound pull force magnet trials. Magnetic force from below.
Figure 14 – 173 pound pull force magnet trials. Magnetic force from below.
One of the most consistent results of the convection enhanced delivery
experiments was the agglomeration of nanoparticles in the infusion tubes [Fig 15].
Agglomerated particles resulted in clogging the infusion lines and prevented infusion into
the gels. The larger the nanoparticle diameter, the more frequently agglomeration
occurred.
Figure 15 – Magnetite nanoparticles agglomerated in 18 gauge polyethylene tubing
Results for experimentation on rat brain tissue indicate that unfixed brain tissue
does not naturally contain properties that would result in staining from Prussian blue. [Fig
16] and 30 nm magnetite nanoparticles were able to penetrate unfixed rat brain tissue.
The location of the particles was able to be visualized using Prussian blue stain. [Fig 17]
Figure 16 – Coronal slices of rat brain tissue after 24 hours of Prussian blue staining
Figure 17 – Coronal slice of rat brain tissue with 30 nm magnetite particles delivered and stained with
Prussian blue on surface.
9.0 Conclusion
The infusion of nanoparticles into agarose gel presents many challenges.
Although a standard protocol has been determined to achieve reflux free convection
enhanced delivery using metal catheters, and the step design construction of polymer
catheters allows for reflux free infusions, the unique properties of the nanoparticles
prevent consistent infusion to occur. While preparing and setting up the agarose gel
infusion experiments, the nanoparticles in the tubing would begin to agglomerate. This
agglomeration lead to blockage of the tubing prior to the start of infusion. Using
different surfactants including sodium dodecyl sulfate and polysorbate 20 as a method to
reduce surface tension and disperse the nanoparticles also had limited success. The
surfactants would cause the nanoparticle solution to gel and clog the infusion lines, or the
surfactant would be infused, leaving the nanoparticles in the tubing. With limited success
infusing nanoparticles into the gel, studying the influence a magnetic force has on
magnetic nanoparticles in the brain phantoms was restricted.
Based on the results from the capillary experiments, when nanoparticles were able
to be injected into the agarose directly after being prepared, they were more likely to have
limited agglomeration. This allowed the magnetic field to influence the movement of the
nanoparticles and the particles were guided toward both the 35 and 173 pound pull force
magnets. There was greater movement toward the stronger magnetic field.
According to the results of the staining and delivery of magnetite nanoparticles on
rat brain tissue, there are no natural artifacts in unfixed brain tissue that would limit the
use of Prussian blue as a visualizing stain. Magnetite nanoparticles also penetrated into
the brain tissue and stain remained in the brain tissue after washing with distilled water.
The nanoparticles and staining technique described could be used as part of future
research on nanoparticle delivery to brain tissue.
9.1 Future Research
Future research is needed to determine an effective method for infusing magnetic
nanoparticles. The challenge of infusing involves preventing the agglomeration of
nanoparticles. This could be approached in a variety of ways. One method includes
setting up the experiment in separate stages. Letting the agarose gel set before inserting
the catheter would allow for the nanoparticles to be infused directly after preparation.
Minimal agglomeration was observed in the capillary experiments during which
nanoparticles could be prepared directly before injecting into the agarose gel. Similarly,
allowing the infusion to occur prior to placing the magnets could allow the nanoparticles
to infuse without the potential of agglomeration due to the magnetic field. Once infusion
was completed, the magnets could be placed according to protocol, allowing the
nanoparticles to then move toward the magnetic field. Without the magnet placement
during infusion, metal catheter could be used, also reducing the possibility of reflux.
Synthesizing nanoparticles with a surfactant coating may also reduce agglomeration.
Magnetic targeting of nanoparticles can also be applied to research in drug delivery
to the central nervous system through infusion into the cerebral spinal fluid. The use of
spinal phantoms could allow researchers the chance to model the movement of
nanoparticles along the spinal cord with possible delivery into brain tissue. The potential
for therapeutic application of magnetically-guided nanoparticles is considerable.
Nanotechnology can play a critical role in the development of “smart” drugs, with further
research needed to determine the protocol for proper infusion of and reduction in the
agglomeration of magnetic nanoparticles.
10.0 Acknowledgements
I would like to thank the National Science Foundation CBET EEC-0743068 grant
for providing funding for the Research Experience for Teachers (RET) and Research
Experience for Undergraduates (REU) summer 2011 projects at The University of Illinois
Chicago.
In addition I would like to thank the many individuals who assisted me during my
RET experience. Dr. Andreas Linninger for sponsoring the RET/REU site at UIC and
creating a meaningful way for teachers to continue to develop their craft. The members
of the Laboratory for Product and Process Design at UIC including Dr. Linninger, Eric
Lueshen and Sukhi Basati for their constant guidance and support, Joe Kanikunnel, Indu
Venugopal and Bhargav Desai for their generosity in providing their expertise. Finally,
thanks to Dr. Victoria Sharts, and Timothy Walsh for their encouragement to become
involved and pursuit to always improve science instruction and Caroline for her
continued support.
11.0 References
Anderson, James. Molecular structure of tight junctions and their role in epithelial
transport. News in Physiological Sciences. 2001, 16:126-130.
Arruebo, Manuel et al. Magnetic nanoparticles for drug delivery. Nanotoday. 2007,
2:22-32.
Chakraborty, C. et al. Future prospects of nanoparticles on brain targeted drug delivery.
Journal of Neuro-Oncology. 2009, 93:285-286.
Chen, Michael Y. et al. Variable affecting convection-enhanced delivery to the striatum:
a systematic examination of rate of infusion, cannula size, infusate concentration,
and tissue-cannula sealing time. Journal of Neuosurgery. 1999, 90:315-320.
Chudler, E. “The blood supply of the brain.” 1 Aug 2006. <http://faculty.washington.edu
Chudler/vessel.html> 2 Aug 2006.
Cornford, E.M. New systems for delivery of drugs to the brain in neurological diseases.
Lancet Neurology. 2002,5 :306-315.
Dobson, Jon. Magnetic nanoparticles for drug delivery. Drug Development Research.
2006, 67:55-60.
Jin, S and Ye, K. Nanoparticle-mediated drug delivery and gene therapy. Biotechnology
Progress. 2007,23:32-41.
Krauze, MT et al. Reflux-free cannula for convection-enhanced high-speed delivery of
therapeutics agents. Journal of Neurosurgery. 2005,103:923-929.
Lu, An et al. Magnetic nanoparticles: Synthesis, protection, functionalization and
application. Angewandte Chemie International Edition. 2007,46:1222-1244.
Mchedlishvili, G. Arterial Behavior and Blood Circulation in the Brain. New York:
Pleum Press, 1986.
Neuberger, T. et al. Superparamagnetic nanoparticles for biomedical applications.
Journal of Magnetism and Magnetic Materials. 2005,293:483-496.
Pankhurst, Q.A. et al. Applications of magnetic nanoparticles in biomedicine. Journal of
Physics D: Applied Physics. 2003,36:167-181.
Pardridge, William. The blood-brain barrier: bottleneck in brain drug development. The
Journal of the American Society for Experimental NeuroTherapeutics. 2005, 2:
3-14.
Pardridge, William. CNS drug design based on principles of blood-brain barrier
transport. Journal of Neurochemistry. 1998, 70: 1781-1793.
Perlstein, B. et al. Convection-enhanced delivery of maghemite nanoparticles: increased
efficacy and MRI monitoring. Journal of Neuro-Oncology. 2008,10:153-161.
Sun, C. et al. Magnetic nanoparticles in MR imaging and drug delivery. Advanced Drug
Delivery Reviews. 2008,60:1252-1265.
Thorek, D. et al. Superparamagnetic iron oxide nanoparticle probes for molecular
imaging. Annals of Biomedical Engineering. 2006,34:23-38.