Christopher S. Brazel, Ph.D., P.E.
Associate Professor:
University of Alabama Department of Chemical and
Biological Engineering
Nanomedicine for Diagnosis
and Treatment of Cancer:
Development of a Nanoplatform to Target Cancer
Cells and Provide Magnetically-Triggered
Combination Chemotherapy and Hyperthemia
Christopher S. Brazel
he University of Alabama College of Engineerin
Department of Chemical and Biological Engineering
U.S. Mortality Statistics, 2004
No. of % of all
deaths deaths
1. Heart Diseases 652,486 27.2
2. Cancer 553,888 23.1
3. Cerebrovascular diseases 150,074 6.3
4. Chronic lower respiratory diseases 121,987 5.1
5. Accidents (Unintentional injuries) 112,012 4.7
6. Diabetes mellitus 73,138 3.1
7. Alzheimer disease 65,965 2.8
8. Influenza & pneumonia 59,664 2.5
9. Nephritis 42,480 1.8
10. Septicemia 33,373 1.4
Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease
Control and Prevention, 2006.
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U.S. Change in Death Rates, by
Cause, 1950-2004
600 586.8
500
Rate Per 100,000
400
300
217.0
193.9 185.8
200 180.7
100
50.0 48.1
19.8
0
Heart Cerebrovascular Pneumonia/ Cancer
Diseases Diseases Influenza
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease
Control and Prevention, 2006
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Cancer Treatment Options
• Surgery
• Chemotherapy
• Radiation Therapy
• Hyperthermia
In most cases, COMBINATION therapy is more effective.
The University of Alabama Chemical and Biological Engineering
Goals
Create a versatile nanoplatform with
multiple functionalities to target,
image and treat cancerous cells
Maximize effectiveness of treatment
to include metastatic cancers while
minimizing side effects
Nausea & vomiting ● Hair loss ● Fatigue ● Digestive Problems
● Cataracts ● Reduced Resistance to Infection
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Multifunctional Targeting, Imaging
and Treatment of Cancer
• Novel approaches are needed for
treatment of cancer
• Approaches need to include:
– Targeting
• Accumulate sufficient dose at tumor
site
• Avoid side-effects in healthy tissue
– Imaging
• Early detection improves survival
– Treatment
• Stop further tumor growth
• Kill tumor cells
• Multiple mechanisms of action
– Reporting
http://nano.cancer.gov
• Was the treatment effective?
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Outline
• TARGETING: use vectors that can reach specific cancer cells
ability to engineer adenovirus to express cysteine, histidine
or lysine loops to attach magnetic nanoparticles
• NANOPARTICLE DESIGN: to achieve self-
limiting hyperthermia or thermal ablation
(Curie temperatures of 50 - 60 oC)
• IMAGING technique to identify metastasized cancers and report
efficacy of treatment
• HYPERTHERMIA THERAPY using AC magnetic fields
• HEATING-ACTIVATED DRUG DELIVERY using phase-
separating polymers
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Targeting Cancer Cells
LOCALIZE
Target with antibodies,
folic acid, adenovirus
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Nanodevice for Targeting
& Treating Cancer
Adenovirus Platform:
Hexon Region of
Capsid
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Magnetic Nanoparticles
TEM Image of
Fe.33Pt.67 Nanospheres
Magnetic Materials
Magnetite Fe3O4
Cobalt Ferrite CoFe2O4
Manganese Ferrite CoFe2O4
Iron Platinum FexPty
Maghemite γ -Fe2O3 10 nm
Nickel Palladium NixPdy
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Magnetic Induction Heating
Magnetic Induction Heating Curves for
Hyperthermia Chamber Cobalt-Ferrite Nanoparticles
0-5 kW; 50-485 kHz 80
80 634 G
316 G
70
70
Temperature (oC)
254 G
158 G
60
60
Temperature ( C)
o
50
50
40
40
30
30
20
20
-100 0 100 200 300 400 500 600 700
Time (Sec)
Start 10 min
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In Vivo Testing of
Magnetic Hyperthermia
Images of tumor regression
(a) Tumor (Exp 1) (b) Tumor + CoFe2O4 + Field (Exp 3)
D.-H Kim et al., Key Engineering Materials, 284-286 (2005)
The University of Alabama Chemical and Biological Engineering
In Vivo Testing of
Magnetic Hyperthermia
Exp 1: CONTROL
(no magnetic nanoparticles)
Exp 2: Magnetic Nanoparticles but
no AC Field
Exp 3: Magnetic Nanoparticles with
AC Field to Heat
Tumors went into regression
with magnetic hyperthermia
D.-H Kim et al, Key Engineering M aterials, 284-286 (2005)
The University of Alabama Chemical and Biological Engineering
Modeling Magnetic Heating
Pennes’ Bio-Heat Equation
By tuning Curie Temperature
of nanoparticles, magnetic heating
can be done effectively without
risk of overheating.
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Modeling Magnetic Heating
Pennes’ Bio-Heat Equation
P
1
wb cb T
Healthy
Tissue
Region
Heated
Tumor
Region
Radius
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Numerical Solution to
Heating Profile
Temperature (C)C)
C)
55
Temperature (oC)
55
o
50
t = 0 sec
t=0sec t=150sec
50
Temperature(
Temperature(
45
Model is used to
45
guide experimental
40 40
1 0 conditions:
1 0.5 1 0.5
0.5 0.5 r/radius
z/height 0 0 r/radius z/height 0 1
Height Height - nanoparticle
concentration
- optimal particle size
Temperature (oC)
Temperature( ( C)
- exposure time
C)
55
Temperature C)
55
o
t=300sec t=500sec
50 50 - frequency of magnetic
Temperature(
45 45 field
40 40
0 0
1 1 0.5
0.5 0.5
r/radius 0.5 r/radius
z/height 0 1 z/height 0 1
Height Height
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Fluorescent Tagging of
Magnetic Nanoparticles
GOAL: Observe how nanoparticles interact with cells and cell surfaces
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Triggering Drug Release
Triggering Events:
Change in Environmental Conditions:
Temperature, pH, Ionic Strength, Chemical Concentration,
Pressure, Magnetic Field, Radiation/Light
Infrared or Light Energy
limited by light penetration through dermis/tissue
or photoinitiated reactions during angioplasty {West and Hubbell, 1990s}
Magnetic Field
placement/localization of particles (e.g., blood brain barrier)
pulsatile delivery by forcing/squeezing drug from gel {Edelman & Langer, ‘80s}
Electronic
devices with external (user/monitor) triggering
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Magnetothermal Delivery
3. External Activation with
Magnetic Field
1. Injection
Magnetic
Nanorods
2. Localization
to Tumor 4. Heat Dissipation 7. Activation Off,
Pores Close
5. Grafts Collapse, 6. Drug Delivery
Pores Open
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Magnetothermal Drug Delivery
Grafted Gel Releases
Drug When Heated
Diffusion Coefficient,(cm /s) 2/s)
Drug Diffusion Coefficients as f(T)
Diffusion coefficient, D D (cm
1.20E-08
Model Drug: 12 C
2
1.00E-08
Theophylline 25 C
8.00E-09 MW 180
37 C
6.00E-09
4.00E-09
2.00E-09
0.00E+00
PHEMA - PNIPAAm- P(HEMA-g-
Theophylline
BASE Theophylline
THERMO- NIPAAm)-
Theophylline
HYDROGEL SENSITIVE GRAFTED
GEL GEL
D
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Developing a Perfusion System
to Study Magnetic Triggering
- mimic blood flow effect on heat transfer
- study drug release activiated by magnetic field
Hot water
bath
Hyperthermia
coils
37 oC
Spectrophotometer
UV/VIS
Sample
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Self-Assembled Nanostructures
as Drug Carriers
Meltable Poly(ethylene glycol-b-ε-caprolactone) Micelles
m
m
m
m
m
m
m Temp m
m m
m
m
m m
m m
m m
m = magnet
= drug
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Imaging
MRI Can our magnetic
nanoparticles both
HEAT and IMAGE?
Comparison to
Gadolinium as phase
contrast agent
Potential to detect individual
cells (METASTATIC CANCERS)
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Imaging to Report Cell Death
31P MRS (Magnetic Resonance Spectroscopy)
of a mouse s.c. tumor at 9.4T
a-NTP
g-NTP
PCr
PME tumor
DPDE -NTPb
Pi
MRS enables REPORTING
for treatment efficacy since
a decrease in ATP
T. Ng et al., UAB, unpublished data levels signals cell death
The University of Alabama Chemical and Biological Engineering
Collaborative Team
Magnetic Nanoparticle Cancer Cell Targeting
Chemistry & Characterization Adenoviruses and Antibodies
David Nikles Maaike Everts
Jeremy Pritchett David Curiel
Dong-Hyun Kim Joel Glasgow
Lauren Blue Vaibhav Saini
Kyle Fugit Jacqueline Nikles
Magnetically-Triggered
Chemotherapeutics Hyperthermia Experiments and
Christopher Brazel Modeling
Indu Ankareddi MRI for Christopher Brazel
John Melnyczuk Cancers Chuanqian Zhang
Mary Kathryn Sewell Johnathan Harris
Andrei Ponta Thian Ng
Huadong Zeng
The University of Alabama Chemical and Biological Engineering
The Brazel Research Group
Collaborators
David Curiel Thian Ng
Maaike Everts
Joel Glasgow
David Nikles Jacqueline
Nikles
The University of Alabama Chemical and Biological Engineering
Thank You
Questions?
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