Module 1
Imaging and Therapy Basics
BioE 498/598DP
Dipanjan Pan, PhD, FRSC
Department of Bioengineering
Beckman Institute of Advanced Imaging and Science
Department of Materials Science and Engineering
dipanjan@illinois.edu
Why Imaging?
Images Speak for Themselves
First Flight (Wright Brothers, 1903)
Triassic period, 231.4 million years Tyrannosaurus
rex (1902 and 1908, Montana, U.S.)
First landing on Moon
Neil Armstrong July 20, 1969
"First" clear image ever transmitted from the surface of Mars shows rocks near the Viking 1 Lander (July 20, 1976)
3500 BCE
Image Provides Us Information to Use
What is our goal: Use it for human health
Find abnormalities non invasively
The First Image Ever Taken
circa 1826
View from the Window at Le Gras,
Joseph Nicéphore Niépce
http://www.hrc.utexas.edu/exhibitions/permanent/firstphotograph/
1838
Taken by Louis Daguerre, in Paris
http://www.burnstudio.co.za/blog/first-photo-of-a-human-being/
How It All Started?
U.S. President James Garfield was shot in 1881
Physicians were unable to determine if the bullet had
entered a vital organ. This knowledge was needed
quickly to decide the medical treatment required to
save Garfield’s life.
For the next 80 days, 16 doctors were consulted. The
first doctor, stuck a non-sterile finger into the wound
followed this by inserting a non sterile probing
instrument to find the bullet. He never found the
bullet.
Followed by the navy surgeon general who searched
with his finger so deeply that he really did puncture
the liver.
President James Garfield
20th President of the US
Mar 4, 1881-Sept 19, 1881
Alexander Graham Bell
Inventor of phone
Mar 3, 1847 – Aug 2, 1922
Alexander Graham Bell had just invented
telephone and an induction coil (metal
detector)
Alexander Graham Bell rigged up a crude
metal detector to help find the bullet. Bell
had located the bullet and it was much
deeper than was originally thought.
With Garfield's condition growing steadily
worse, doctors decided to cut him open to
remove the bullet. It was not found.
What Bell had actually located so deep in
the body was the metal spring under the
mattress!!
Failed but “first” attempt to locate something inside human body
Noninvasively
Why We Need Imaging for Human Health?
Because it is dark inside!
Various imaging methods
cut through darkness
noninvasively
Fluorescence, ultrasound,
computed tomography
(CT), positron emission
tomography, Magnetic
resonance imaging
Bioluminescent Jellyfish
First Medical Image Ever Taken
Image of Röntgen’s wife's hand
The first X-ray image ever recorded
Sharper X-ray image
116 yrs
1895
The first x-ray of the human body, taken by Conrad Röntgen on
November 8, 1895. He called the new form of radiation he had
discovered x-rays, with the X standing for unknown.
An x-ray revealed that an 18-month-old boy had swallowed two disc batteries.
(Source: Cedars-Sinai)
Probing the Past
This CAT scan shows calcification in the
bilateral carotid, bilateral subclavian,
and brachiocephalic veins of Hatiay, a
male Egyptian scribe aged 40–50 yrs,
(1570–1293 Before Common Era),
A recent CT scan of a 2,400-year-old Egyptian mummy held in the Archaeological
Museum of Zagreb, Croatia, revealed a rare example of an ancient tool used by
embalmers for the removal of the brain during the mummification procedure
CT image of a broken arm with pins
CT image of a hip replacement
Aortic aneurysm
A volume rendering (VR) of a three-dimensional set of computed
tomography (CT) images shown as a two-dimensional projection.
http://www.cedars-sinai.edu/Patients/Programs-and-Services/Imaging-Center/Image-Gallery-images/CapAngio01-Color-Pirouette.gif
Heart valve, left, and heart valve in a heart, right.
left: Normal subclavians; right: abnormal subclavians with positive occlusion (arrow).
A specialized MRI of the Brain with Diffusion Tensor Imaging (DTI) Analysis showing
the neural pathways, which displays how different parts of the brain are connected.
When the pathways are tangled it can be an indication of shaken-baby syndrome.
“A man’s brain being removed and cut into
hundreds of pieces to be handed out all around
the world—without his family’s knowledge……..”
The Story
• Year 1955: Autopsy on Albert Einstein
was performed by pathologist Thomas S.
Harvey
• Photographed the scientist’s brain
• Shared slices of it with fellow
pathologists!
• Harvey kept pictures of the dissected
brain and pieces (170) of it for himself!
• No permission for the removal and
preservation had been given by Einstein or
his family
• Year 2007: Harvey died
• Items eventually unearthed and given to
the National Museum of Health &
Medicine, in Silver Spring, Md.
Harvey with Einstein’s ‘pickled’ brain
MRI Distribution Maps of Corpus Callosum
Thickness Between Einstein and the Old Age
Control Group
Brain2013, DOI: 10.1093/brain/awt252).
MRI Distribution Maps of Corpus Callosum
Thickness Between Einstein and the Young Age
Control Group
Measurements of corpus callosum (CC)
morphology and brain between Einstein and the
two different age control groups
Close to Our Heart
Paul C Lauterbur
(May 6, 1929 -Mar 27, 2007)
Sir Peter Mansfield
Raymond Damadian, First MRI Patent, 1974
When Lauterbur’s paper was rejected by Nature, however, after
his persistance, it was published and is now acknowledged as a
classic Nature paper.
The Nature editors pointed out that the pictures accompanying
the paper were too fuzzy
They were the first images to show the difference between heavy
water and ordinary water!
Nobel Prize for MRI, 2003
Nature 242, 190-191 (1973)
Why Contrast Agents?
Types of Contrast Agents-1
Radio Contrast Agent
Optical Contrast Agent
A mouse’s brain
cerebellum tumor
in optical imaging
Cerebral angiogram
MRI Contrast Agent
Stroke
Modality Specific
Improve the visibility of
internal structures in
X-ray based imaging
Sonographic Contrast Agent
altering the magnetic
properties of nearby
hydrogen nuclei
Nuclear Contrast Agent
Hepatocellular carcinoma
Sound waves are reflected from interfaces
between substances (backscattering)
Whole body PET
scans showing the
distribution of
radio-labeled
monamine oxidase
Types of Contrast Agents-2
Biological Targeting
Orange areas of a PET/CT image indicate the uptake
of 18F-fluoro-2-deoxy-D-glucose in a primary cancer
lesion and a lymph node (Sam Gambhir, Stanford)
Colon cancer scan captured by GE's PET/CT
and the imaging agent FDG. The fused
volume rendering of a PET/CT angiography
provides both vascular and metabolic
information.
Bone (gray), vessels
(red), and skin (brown)
SEEING BLOOD A normal mouse reveals
its vasculature with Fenestra.
BioE 498/598DP
Trends in Imaging
En route to ‘Molecular’ Imaging
Anatomical
Imaging
Physiological
Imaging
Molecular
Imaging
Structure
Mechanism
Target
Morphology
Morphometry
Hemodynamics
Vascular Permeability
Tissue oxygenation/hypoxia
CNS activity
Metabolites
pH
Receptor mediated imaging
Targeted contrast agents
In vivo distributive properties
So Many Modalities
Things to consider
Resolution
“Speckle
artifacts”
Fast
Slow; Strong
influence from
motion
Depth penetration
Speed of acquisition
Ca interference
Quantification
Sensitivity
Ca interference
No single modality
is ideal for every
application
Quantitative
Quantitative
Comparison of resolution and imaging depths of the modalities; the "pendulum" length represents
imaging depth, and the "sphere" size represents resolution.
BioE 498/598DP
Modified from http://obel.ee.uwa.edu.au/research/oct/intro/
Resolution and Contrast Material Concentration
What Structure You Would Like to Resolve?
What is Therapy
Next Generation
A Whole Spectrum of Modern Therapies
• Personalized
Vitruvian Man: a male figure in two superimposed positions•with
his arms and legs
Molecularly-directed
apart and simultaneously inscribed in a circle and square
• Preemptive
Conventional
• Surgery
• Chemotherapy
• Radiation
• Immunotherapy
• Stem cell transplant
• Hormone therapy
Complementary
• Nutrition
• Pain management
• Exercise
• Spiritual support
• Neutraceuticals
• Physical therapy
Leonardo da Vinci circa 1490 (correlations of ideal human proportions with geometry
described by Roman architect Vitruvius -Book III of De Architectura)
Symmetry of the human body
Cancer Therapy
Adjuvant and Neoadjuvant Therapy
Angiogenesis Inhibitors
Biological Therapies for Cancer
Bone Marrow and Peripheral Blood
Stem Cell Transplantation
Breast Reconstruction After
Mastectomy
Cancer Therapy
Cancer Vaccines
Cryosurgery in Cancer Treatment
Hormone Therapy
Hyperthermia in Cancer Treatment
Lasers in Cancer Treatment
Photodynamic Therapy for Cancer
Cancer Therapy
Sentinel Lymph Node Biopsy
Surgery to Reduce the Risk of Cancer
Personalized therapy
Radiation Therapy for Cancer
Targeted Cancer Therapies
Drugs that block the growth and spread of cancer by interfering with specific
molecules involved in carcinogenesis (the process by which normal cells are
transformed into cancer cells) and tumor growth.
Modalities of treatment:
• 1-local therapy:
– -surgery.
– -radiation therapy.
• 2-systemic treatment:
– chemotherapy.
– Hormonal therapy.
– Monoclonal antibodies.
– Radioactive material.
• 3-supportive care.
• 4-non-conventional therapy.
Classification of cytotoxic drug
• Cytotoxic agent can be roughly categorized
based on their activity in relation to the cell
cycle.
cytotoxicdrug
phasenonspecific.
phasespecific
Cont :
• What is the difference between phase specific &
phase non specific?…..
• Phase non-specific:
– The drugs generally have a linear dose-response
curve( the drug administration ,the  the
fraction of cell killed).
• Phase specific:
– Above a certain dosage level, further increase in
drug doesn’t result in more cell killing
– Can be adjusted with the duration of infusion.
Chemotherapeutic agents
•
•
•
•
•
•
•
Alkylating agents
Antimetabolites
Antitumor antibiotic
Plant alkaloids
Other agents
Hormonal agent
Immunotherapy
Criteria used to describe response
• Complete response (complete remission)is the
disappearance of all detectable malignant disease.
• Partial response: is decrease by more than 50% in
the sum of the products of the perpendicular
diameters of all measurable lesions.
• Stable disease: no increase in size of any lesion nor
the appearance of any new lesions.
• Progressive disease: means an increase by at least
25% in the sum of the products of the perpendicular
diameters of measurable lesion or the appearance of
new lesions.
Endocrine therapy
• Many hormonal antitumor agents are functional
agonist or antagonist of the steroid hormone family.
• Adrenocorticoids
• Antiandrogen
• Estrogen
• Antiestrogen
• Progestins
• Aromatase inhibitor
• Gonadotropin-releasing hormone agonists
• Somatostatin analogues
Biologic therapy:
• Immunotherapy:
– Cytokines
– Cellular therapy.
– Tumor vaccine:
• Hematopoietic growth factors.
• Gene Therapy
Drug Delivery and Mass Balance
• The concentration of the drug at the site of action,
over time.
• Drug delivery is about the complex mechanisms to
getting that concentration profile to happen.
Intravenous
Injection
Gastrointestinal
Tract
Circulatory
System
Intramuscular
Injection
Tissues
Subcutaneous
Injection
Metabolic
Sites
Excretion
Oral
Administration
Site Specific Delivery
RES
1. Controlling release rate
2. Site-specific delivery
Small molecule (conventional drug)
Macromolecules (polymers,…)
Particulates (10-200 nm)
Passive targeting
Active targeting
Lungs
Liver
Spleen
Site specific
delivery- active or
passive targeting
Reticuloendothelial System (RES)
Reticuloendothelial system (RES) (Mononuclear
phagocyte system)
• Reticuloendothelial system is an older term for the
mononuclear phagocyte system.
• Most endothelial cells are not macrophages.
• It is a network of connective tissue fibers inhabited by
phagocytic cells such as macrophages ready to attack
and ingest microbes
• RES is an essential component of the immune system
• Cellular components of RES: Monocytes; Macrophage
[Located in all tissues such as skin (histiocytes), liver
(kupffer), spleen, bone marrow, lymph nodes, lung]
Endothelial cells: bone marrow, spleen, lymph node
BioE 498/598DP
General Function of RES
1. Phagocytosis: Bacterial, dead cells, foreign particles
(direct)-Part of the natural, or innate, immune
process,
Macrophages are a powerful phagocytic cells:

Ingest up to 100 bacteria,

Ingest larger particles such as old RBC
Get rid of waste products
2. Immune function: processing antigen and antibodies
production (indirect)
3. Breakdown of aging RBC
4. Storage and circulation of iron
BioE 498/598DP
• Even with controlled delivery side effects cannot
be avoided
Might cause severe
side effects- spread
over body
Site specific
delivery- active or
passive targeting
Passive Targeting of Particulate by EPR
Mechanism
Enhanced permeability and retention (EPR) effect
• Disorganization of tumor vasculature
• Poor lymphatic drainage
Active Targeting
Ringsdorf’s Model
Various Drug Delivery System
Chemically-Controlled DDS
Major Classes of Matrix in DDS
Environmentally Responsive System
pH Responsive System
Absorption of drugs could vary within the same
administration route
Drug Delivery System (DDS)
Toxicity
Therapeutic Window
No Therapeutic Effect
• Controlled delivery system
• Site specific delivery of drugs
Plasma concentration
(mg/mL)
Unsuccessful
therapy
Successful
therapy
Time (min)
Conventional Anti-Cancer Therapy
• Chemotherapy: Imperfect
– Systematic nature of cytoxicity
– Agents lack intrinsic anti-tumor selectivity
– Anti-proliferative mechanism on cells in cycle,
rather than specific toxicity directed towards
particular cancer cell
– Host toxicity: treatment discontinued at dose
levels well below dose required to kill all viable
tumor cells
Antibody-based Therapy
• Emil von Behring in 1890
– Discovered antibodies
• Paul Ehrlich (16 years later)
– Coined phrase, “magic bullets and poisoned arrows”: use
of antibodies to specifically target toxic substances in
pathogenic substances
• Kohler and Milstein in 1975
– Discovery of monoclonal antibodies (mAb) directed against
well-characterized antigens
– Use of DNA bio-engineered technologies within last 25
years
Rationale
• mAb as efficient carriers for delivery of anti-tumor
agents
– Enhanced vascular permeability of circulating
macromolecules for tumor tissue and subsequent
accumulation in solid tumors
– Normal tissue: blood vessels have intact endothelial layer that
permits passage of small molecules but not entry of macromolecules
(like mAb)
– Tumor tissue: blood vessels leaky, so small and large molecules have
access to malignant tissue
-tumor tissue generally do not have a lymphatic drainage system;
therefore, macromolecules are retained and can accumulate in
solid tumors
Patho-physiology of Tumor Tissue
• Angiogenesis
• Hypervasculature
• Impaired lymphatic drainage
***Due to these characteristics, tumors can be
exploited for tumor-selective drug
delivery****
Angiogenesis
Biological process of forming new blood vessels
65
Passive Targeting of Particulate by EPR
Mechanism
Enhanced permeability and retention (EPR) effect
• Disorganization of tumor vasculature
• Poor lymphatic drainage
3. Delivery of Cytotoxic Agents
• Physically link antibodies to toxic substances
for delivery
– Radio-immunoconjugates (aim of delivering
radiation directly to the tumor)
– Toxin-immunoconjugates (deliver toxins
intracellularly)
– Antibody-directed enzyme pro-drug therapy
(ADEPT): localize enzymes to tumor cell surfaces
General Drug Delivery System
• Drug molecules bound
to macromolecule
through spacer
molecule
– Drug released from
macromolecule after
cellular uptake of the
conjugate
– Targeting moiety =
monoclonal antibody
Immunoconjugate
• BR96-doxorubicin conjugate
(BR96-DOX)
– Promising toxinimmunoconjugate
– mouse/human chimeric mAb
– Targets antigen over-expressed
on surface of human carcinoma
cells of breast, colon, lung, and
ovary
– Disulfide reduction attaches mAb
to drug, BR96
– Dose that can be safely
administered every 3 weeks is
insufficient
Next Lecture:
Biological Barriers
Targeting
Nanomedicine