Christopher S. Brazel, Ph.D., P.E.

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Christopher S. Brazel, Ph.D., P.E.

• Associate Professor
• University of Alabama Department of Chemical and
  Biological Engineering

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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
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U.S. Mortality Statistics, 2004
No. of deaths
of all 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
Rate Per 100,000
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
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.
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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
• Was the treatment effective?

http//nano.cancer.gov
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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 ? -Fe2O3 Nickel
Palladium NixPdy
10 nm
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Magnetic Induction Heating
Magnetic Induction Hyperthermia Chamber 0-5 kW
50-485 kHz
Heating Curves for Cobalt-Ferrite Nanoparticles
80
70
60
Temperature (oC)
50
40
30
20
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In Vivo Testing of Magnetic Hyperthermia
Images of tumor regression
(a)
(b)
Tumor CoFe2O4 Field (Exp 3)
Tumor (Exp 1)
D.-H Kim et al., Key Engineering Materials,
284-286 (2005)
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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 Materials,
284-286 (2005)
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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
Healthy Tissue Region
Heated Tumor Region
Radius
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Numerical Solution to Heating Profile
t 0 sec
t 150 sec
Model is used to guide experimental conditions -
nanoparticle concentration - optimal
particle size - exposure time - frequency of
magnetic field
Temperature (oC)
Temperature (oC)
Radius
Radius
Height
Height
t 500 sec
t 300 sec
Temperature (oC)
Temperature (oC)
Radius
Radius
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/loca
lization 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
7. Activation Off, Pores Close
4. Heat Dissipation
5. Grafts Collapse, Pores Open
6. Drug Delivery
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Magnetothermal Drug Delivery
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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
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Self-Assembled Nanostructures as Drug Carriers
Meltable Poly(ethylene glycol-b-e-caprolactone)
Micelles
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
tumor
MRS enables REPORTING for treatment efficacy
since a decrease in ATP levels signals cell
death
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Collaborative Team
Magnetic Nanoparticle Chemistry
Characterization David Nikles Jeremy
Pritchett Dong-Hyun Kim Lauren Blue Kyle Fugit
Cancer Cell Targeting Adenoviruses and
Antibodies Maaike Everts David Curiel Joel
Glasgow Vaibhav Saini Jacqueline Nikles
Magnetically-Triggered Chemotherapeutics Christo
pher Brazel Indu Ankareddi John Melnyczuk Mary
Kathryn Sewell Andrei Ponta
Hyperthermia Experiments and Modeling Christopher
Brazel Chuanqian Zhang Johnathan Harris
MRI for Cancers Thian Ng Huadong Zeng
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The Brazel Research Group
Collaborators
Thian Ng
David Curiel
Maaike Everts
Joel Glasgow
Jacqueline Nikles
David Nikles
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Questions?
Thank You