Modern technology in medicine and healthcare

GEK 1540
Frank Watt Dept of Physics

1. Fibre optics and endoscopy: Reaching the parts not easily reached.

2. Healing with light: Lasers in medicine and surgery

3. Seeing with sound: Imaging using ultrasound.

4. X-ray vision: 2D and 3D imaging using X-Rays.

5. Radioactive imaging: 2D and 3D imaging using nuclear radiation.

6. Radiation therapy: Cancer therapy using radiation.

7. Magnetic imaging: Magnetic Resonance Imaging (MRI).

8. The very small heals the very large: Nanomedicine.

Extracts from the NIH (National Institute of Health USA) overview
on Nanomedicine:
What if doctors could search out and destroy the very first cancer cells that
would otherwise have caused a tumor to develop in the body?
What if a broken part of a cell could be removed and replaced with a miniature
biological machine?
What if pumps the size of molecules could be implanted to deliver life-saving
medicines precisely when and where they are needed?
These scenarios may sound unbelievable, but they are the long-term goals of the
NIH Roadmap's Nanomedicine initiative that we anticipate will yield medical
benefits as early as 10 years from its launching in 2005.

Nanomedicine, an offshoot of nanotechnology, refers to highly specific medical

intervention at the molecular scale for curing disease or repairing damaged
tissues, such as bone, muscle, or nerve.
A nanometer is one-billionth of a meter, too small to be seen with a conventional
lab microscope. It is at this size scale about 100 nanometers or less that
biological molecules and structures inside living cells operate.
 The very small heals the very large:
Nanomedicine

Contents:
Nanotechnology and Nanomedicine: What is it?
Nanomedicine and drug delivery.
Nanomedicine using magnetic nanoparticles
Nanotechnology and nano-robots.
Nanoparticle toxicology?

Note: The contents of this chapter describe a possible future for nano-
technology in medicine. Most of this work is at the research stage or
futuristic and should not be taken as definitive knowledge!
 Nanotechnology and Nanomedicine: What is it?

Nanotechnology, involves the control of matter on an atomic and

molecular scale. Generally nanotechnology deals with structures of the
size 100 nanometers or smaller in at least one dimension, and involves
developing materials or devices within that size.
Nanotechnology is very diverse, ranging from extensions of conventional
device physics where devices are made smaller (top-down) to completely
new approaches based upon molecular self-assembly (bottom-up
approach or the control and assembly of matter on the atomic scale).

Video: How nanotechnology works.

Nanomedicine: The use of nanotechnology in medicine:

There is a wide variety of research into nanotechnology and nanomedicine:
We will concentrate on the design and manipulation of nanoparticles and
nanostructures applied to the medical diagnosis and treatment of disease.
 Types of nanoparticles used:

Fullerenes: Buckyballs and Carbon tubes: Carbon based, lattice-like, potentially porous
molecules. Buckyballs are spherical in shape while carbon tubes are cylindrical.

Liposomes: Lipid-based nanoparticles used in the pharmaceutical and cosmetic industries

because they break down inside cells, once their delivery function has been met.
[Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins]

Nanoshells: Spherical cores of a particular compound surrounded by a shell or outer coating

of another, which is a few nanometers thick.

Dendrimers: Dendrimers are highly branched structures gaining wide use in nanomedicine
because of the multiple molecular "hooks" on their surfaces that can be used to attach
cell-identification tags, fluorescent dyes, enzymes and other molecules.

Quantum dots: Nano-sized semiconductors that, depending on their size, can emit light in all
colours of the rainbow. They act like giant atoms (with electron transitions emitting
visible photons) quantum confinement.

Superparamagnetic nanoparticles: Attracted to a magnetic field but do not retain residual

magnetism after the field is removed. Example: Nanoparticles of iron oxide with
diameters in the 5-100 nm range.

Nanorods: Typically 1-100 nm in length, nanorods are most often made from semiconducting
materials and used in nanomedicine as imaging and contrast agents.
http://biotech.about.com/od/nanotechnology/a/typesnanopart.htm
 Examples of nanoparticles.

Gold nanorods and gold nanoparticles

(SEM images) Crystal structure of C60
(Buckminister Fullerene

Transmission electron
microscope images
(TEM) of 15nm Fe3O4
magnetic nano-
particles
Bottles of liquid containing different
sized CdSe quantum dots (1 5nm).
The dots fluoresce with a colour Examples of carbon nanotubes
depending on their size.

http://en.wikipedia.org/wiki/
 Nanomedicine and drug delivery

Most human diseases involve a

molecular malfunction at the cellular
level, and cell function is largely
controlled by gene expression and its
resulting protein synthesis.

Nanoparticle Drug Delivery

Systems (DDS).
Nanoparticles exhibit characteristics
that have high potential for successful
DDS.

Penetration into the cell

Targeting and delivering the drug.
 Nanomedicine and drug delivery

(a) NPshavereduceddimensionsandthe
abilitytopenetratecellmembranes
withoutmodifyingtheirintegrity.
(b) Thepossibilitytoundergosurface
functionalization (chemicalmodification)
soastomakethenanoparticles soluble
inwater(ie toavoidaggregation)eg
usingPEG(PolyethyleneGlycol).
(c) Thepossibilitytoundergosurface
functionalization soastotargetthe
nanoparticles andthereforedrugs,to
specificcellsandcellorganelles.Eg folic
acidforcancercells.
(d) Thepossibilitytoundergosurface
functionalization soastodeliverdrugsto
thetarget(eg theanticancerdrug
Paclitaxel).
 Nanoparticle targeting and drug delivery

Chemical functionalization of Au NPs, QDs and CNTs with drug molecules and targeting agents.
Example:Cancertreatment:

Thecellsurfacereceptorforfolicacid(folate receptor)doesnotfunctionin
healthycellsbutisexpressedonthesurfaceofcancercells.

Functionalised theNPswithPEGsurfacemodification(inordertomakethem
solubleinwater,andnotaggregate).

Functionalise theNPswithfolicacid(soastoonlytargetcancercells)

Functionalise theNPswithananticancerdrug(eg Paclitaxel:Achemical

whichpromotespolymerizationoftubulin aprimecomponentofstructural
microtubules causingcelldeathbydisruptingthedynamicsnecessaryforcell
division).

Inthiswaythecancerdrugistargetedonlytocancercells.TheNPspenetrate
thecancercellwall,andthePaclitaxel killsthecell.Inprinciplethisspecific
targetingwillreducesideeffectsofthedrug..

Video: nanotechnology animation

 Nanomedicine using magnetic nanoparticles
a) Removal of cancer cells using
magnetic nanoparticles

Tagging magnetic nanoparticles on to

cancer cells and moving them out of
the body using a magnet..

Nanoparticles, in brown, attach themselves to Video: Magnetic Nanoparticles Migrate

cancer cells, in violet, from the human abdominal through a Fluid.
cavity. Credit: Ken Scarberry/Georgia Tech.
Selective removal of ovarian cancer cells from human ascites fluid using magnetic nanoparticles: Kenneth
E. Scarberry, Erin B. Dickerson, Z. John Zhang, Benedict B. Benigno, John F. McDonald - Nanomedicine 2009
A majority of ovarian cancer metastases result from the shedding of malignant cells from the
primary tumor into the abdominal cavity. Free-floating cancer cells in serous effusions of late-stage
ovarian cancer patients may spread to internal organs making effective treatment extremely difficult.
Selective removal of ovarian cancer cells from serous fluids may abate metastasis and
improve long-term prognoses. We have previously shown that superparamagnetic nanoparticles
conjugated to an ephrin-A1 mimetic peptide with a high affinity for the EphA2 receptor can be used
to capture and remove cultured human ovarian cancer cells from the peritonea of experimental mice.
Here we demonstrate the potential clinical utility of the methodology by in vitro capture and isolation
of cancer cells from the ascites fluid of ovarian cancer patients
 Nanomedicine using magnetic nanoparticles
b) Image enhancement using magnetic nanoparticles

Early events in atherosclerosis: Low density lipoprotein

(LDL the bad cholesterol) penetrates the artery wall and
starts a chain of events leading to inflammation, cell death
and plaque build up.

The disease usually remains undetectable until a heart attack or stroke happens.
It would be good to have some means of identifying any disease progression.can
we identify increased inflammation or macrophage activity?
 Nanomedicine using magnetic nanoparticles
b) Image enhancement using magnetic nanoparticles

Brief description:

The injection of magnetic nanoparticles into the blood stream are

taken up by scavenger cells (macrophages).

The macrophages concentrate around areas of inflammation ie in

atherosclerotic lesions.

The increase in iron nanoparticles in the lesions give an increased

MRI signal and can be observed using (T2) images, thus giving an
indication of whether or not atherosclerosis is present or not.
 Nanomedicine using magnetic nanoparticles
b) Image enhancement using using magnetic nanoparticles
(Circulation. 2006;114:II-337.): 2006 American Heart Association, Inc.
ABSTRACT 1724: Inflammation and Adhesion Molecules: Imaging in Mice and Man
MRI Enhanced with Magnetic Nanoparticles Measures Inflammatory Burden in Atherosclerosis In Vivo:
Kunio Morishige; Daniel Kacher; Peter Libby; Lee Josephson; Ralph Weissleder; Masanori Aikawa,

Background: Inflammation contributes to the progression and acute complications of atherosclerosis.

Imaging of macrophages in vivo may predict risk of subclinical lesions and identify individualized
therapeutic targets.

Methods and Results: To test the hypothesis that nanoparticle-enhanced, high-resolution MRI can
measure plaque macrophage accumulation in vivo, we employed a 3.0 Tesla magnet with clinically-
approved, phagocyte-targeted super-paramagnetic iron oxide (MION47, 10 mgFe/kg, iv) in 6 cholesterol-fed
New Zealand White rabbits 6 months after balloon injury.
MRI visualized in vivo thickened abdominal aortas on T1 and T2-weighted spin echo (T1SE, 20 axial
slices/animal; T2SE, 28 slices). Images 72 hours after MION47 injection exhibited signal reduction
(darkening) in aortas on T2SE (signal intensity ratio: aortic wall/muscle; pre 1.44 0.26 vs. post 0.950.22,
165 slices, p<0.01) while T1SE showed no significant effect. MRI also demonstrated ex vivo darkening of
aortas on T2 weighted images in MION47-injected rabbits unlike control aortas (no injection).
Histological assays further colocalized iron accumulation (Prussian blue staining) with immunoreactive
macrophages in the intima, and correlated the magnitudes of T2 darkening in vivo with macrophage areas in
situ (155 slices, r =0.77, P<0.01). Moreover, in vitro validation studies revealed a concentration-dependent
MION47 uptake and shortened T2 relaxation time during differentiation of human primary macrophages.

Conclusion: MION47-enhanced MRI can detect plaque macrophages in vivo, offering the important
information on inflammatory burden in atherosclerosis
 Nanomedicine using magnetic nanoparticles
c) Destruction of cancer cells using magnetic nanoparticles

Therapeutic strategy using magnetic

nanoparticles.
Functionalise magnetic nanoparticles so
that they accumulate in cancer cells in
tumours.
The magnetic nanoparticles, if they
accumulate in the tumour, can then can be
imaged using MRI.
If the accumulated nanoparticles are then
subjected to an alternating magnetic field,
the nanoparticles heat up (hyperthermia)
thereby killing the cancer cells.

Magnetic nanoparticles can be used

for cancer diagnosis at the same
Video: Fighting Cancer with Magnetic time as therapy.
Nanoparticles brain tumour - hyperthermia
 Nanotechnology and nano-robots.
The idea is that nano-robots, constructed using molecular self assembly,
can flow through the bloodstream, and perform nanorobotic therapeutic
procedures on specified individual cells within the human body.
Very futuristic..!

Chemically self-assembled complex

platinum nanostructure

Examples of current structures produced using molecular self assembly.

 Nanotechnology and nano-robots.

This image, originally titled

"Nanotechnology" as the winner of the
2002 Visions of Science Award by The
Daily Telegraph of London and
Novartis, was created to show one of
the possible applications of
nanotechnology in medicine in the
future - microscopic machines roaming
through the bloodstream, injecting or
taking samples for tests.

Any bloodstream nanobot would need to

have a structure size of less than 4 microns
to avoid being trapped in the smallest-
diameter human capillary vessels.
coneyl@coneyljay.com

http://www.foresight.org/Nanomedicine/Gallery/Captions/
 Nanotechnology and nano-robots.

In an artist's conception, a
microscopic robot cleans
deposits from a blood
vessel in order to prevent
atherosclerosis.
Researchers predict the
creation of microscopic
robotic devices that will
patrol the human body and
fight disease.

Tom Herzberg
Video: Nanobots
cleaning an artery wall.
http://www.foresight.org/Nanomedicine/Gallery/Captions/
 Nanoparticle toxicology

The use of nanoparticles in medicine may also represent a health

threat:
Substances that are normally innocuous at macro (larger)
dimensions can trigger intense chemical reactions and cause
biological anomalies when used at nano dimensions.
Although little work has been carried out on such effects,
nanoparticles can exhibit physicochemical properties which are
dependent on size, chemical composition, surface structure,
solubility, shape, and aggregation.
 Nanoparticle toxicology

The dangers of asbestos fibres

Asbestos is the name given to a group of minerals

that occur naturally in the environment as bundles
of fibers that can be separated into thin, durable
threads. These fibers are resistant to heat, fire, and
chemicals and do not conduct electricity. For these
reasons, asbestos has been used widely in many
industries in the early 1900s.
People may be exposed to asbestos in their In the late 1970s, the U.S.
workplace, their communities, or their homes. If Consumer Product Safety
products containing asbestos are disturbed, tiny Commission (CPSC) banned the
asbestos fibers are released into the air. When use of asbestos in wallboard
asbestos fibers are breathed in, they may get patching compounds and gas
trapped in the lungs and remain there for a long fireplaces because the asbestos
time. Over time, these fibers can accumulate and fibers in these products could be
cause scarring and inflammation, which can affect released into the environment
breathing and lead to serious health problems. during use.
 Nanoparticle toxicology
The dangers of diesel fumes

Diesel particulate matter (DPM), sometimes also called

diesel exhaust particles (DEP), is the particulate
component of diesel exhaust, which includes diesel soot
and aerosols such as ash particulates, metallic abrasion
particles, sulfates, and silicates. When released into the
atmosphere, DPM can take the form of individual
particles or chain aggregates, with most in the invisible
sub-micrometre range of 100 nanometers, also known as
ultrafine particles (UFP) or PM0.1.
Exposures have been linked with acute short-term
symptoms such as headache, dizziness, light- Typical soot emissions from a
headedness, nausea, coughing, difficult or labored diesel exhaust
breathing, tightness of chest, and irritation of the eyes
and nose and throat.
Long-term exposures can lead to chronic, more
serious health problems such as cardiovascular
disease, cardiopulmonary disease, and lung cancer.
Nanoparticle toxicology Oxidative stress hypothesis

Excessive Generation of Oxidative

transition Free radicals Damage
metals eg Fe, Cu Fenton chemistry Cell death

H2O2 + Fe2+ OH + OH + Fe3+ Fenton reaction

O2 + H2O2 2+ OH + OH + O2 Harbor-Weiss reaction
Fe

Free radical damage: Iron nanoparticles range in size from a diameter of ~20
nanometers to superparamagnetic particles of iron oxide (SPIO) with a diameter
of ~100 nanometers. These iron particles can catalyse free radicals (eg OH-)
which can cause DNA damage and cell death.
To counteract this toxic effect, the iron nanoparticle can be coated in
dextran (a polysaccharide made of many glucose molecules), which
protects the cell against free radical damage..
 Conclusions:
The use of nanoparticles and nanotechnology in
biomedicine shows great potential, but much more
work (research and development) needs to be carried
out on the applications (to see if NPs offer
advantages over existing techniques), and on any
potential toxicology.

It may be that even if nanoparticles (in doses needed

for diagnosis and therapy) are toxic, then we may have
to balance the therapeutical effect with any potential
toxicity.
The end