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

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
The University of Alabama
College of Engineering
Department of Chemical and Biological Engineering
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.
The University of Alabama
Chemical and Biological Engineering
U.S. Change in Death Rates, by
Cause, 1950-2004
600
586.8
Rate Per 100,000
500
400
300
217.0
100
0
193.9 185.8
180.7
200
50.0
Heart
Diseases
Cerebrovascular
Diseases
48.1
19.8
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
The University of Alabama
Chemical and Biological Engineering
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
The University of Alabama
Chemical and Biological Engineering
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
http://nano.cancer.gov
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– Reporting
• Was the treatment effective?
Chemical and Biological Engineering
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 selflimiting 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 phaseseparating polymers
The University of Alabama
Chemical and Biological Engineering
Targeting Cancer Cells
LOCALIZE
Target with antibodies,
folic acid, adenovirus
The University of Alabama
Chemical and Biological Engineering
Nanodevice for Targeting
& Treating Cancer
Adenovirus Platform:
Hexon Region of
Capsid
The University of Alabama
Chemical and Biological Engineering
Magnetic Nanoparticles
Magnetic Materials
TEM Image of
Fe.33Pt.67 Nanospheres
Magnetite Fe3O4
Cobalt Ferrite CoFe2O4
Manganese Ferrite CoFe2O4
Iron Platinum FexPty
Maghemite γ -Fe2O3
Nickel Palladium NixPdy
The University of Alabama
10 nm
Chemical and Biological Engineering
Magnetic Induction Heating
Magnetic Induction
Hyperthermia Chamber
0-5 kW; 50-485 kHz
Heating Curves for
Cobalt-Ferrite Nanoparticles
634 G
316 G
254 G
158 G
7070
6060
Temperature ( C)
(oC)
Temperature
o
80
80
5050
4040
30
30
20
20
-100
0
100
200
300
400
500
600
700
Time (Sec)
Start
10 min
The University of Alabama
Chemical and Biological Engineering
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 Materials, 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.
The University of Alabama
Chemical and Biological Engineering
Modeling Magnetic Heating
Pennes’ Bio-Heat Equation
P
wb cb T
1
Healthy
Tissue
Region
Heated
Tumor
Region
Radius
The University of Alabama
Chemical and Biological Engineering
50
t = 0 sec
t=0sec
45
40
1
1
0.5
z/height
oC)
Temperature
Temperature( ( C)
Height
0 0
0.5
r/radius
t=300sec
45
40
0
1
0.5
z/height
Height
55
50
t=150sec
45
40
1
0
0.5
z/height
Height
55
50
o
Temperature
Temperature( (C)C)
55
0 1
0.5
r/radius
o
Temperature
Temperature( (C)C)
(oC)
Temperature
Temperature(  C)
Numerical Solution to
Heating Profile
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0.5
r/radius
0 1
- nanoparticle
concentration
- optimal particle size
- exposure time
- frequency of magnetic
field
55
50
t=500sec
45
40
1
Model is used to
guide experimental
conditions:
0
0.5
z/height
Height
0 1
0.5
r/radius
Chemical and Biological Engineering
Fluorescent Tagging of
Magnetic Nanoparticles
GOAL: Observe how nanoparticles interact with cells and cell surfaces
The University of Alabama
Chemical and Biological Engineering
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
The University of Alabama
Chemical and Biological Engineering
Magnetothermal Delivery
1. Injection
2. Localization
to Tumor
5. Grafts Collapse,
Pores Open
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3. External Activation with
Magnetic Field
Magnetic
Nanorods
4. Heat Dissipation
7. Activation Off,
Pores Close
6. Drug Delivery
Chemical and Biological Engineering
2
Diffusion
coefficient, D (cm
D/s)(cm2/s)
Coefficient,
Diffusion
Magnetothermal Drug Delivery
Grafted Gel Releases
Drug When Heated
Drug Diffusion Coefficients as f(T)
1.20E-08
1.00E-08
Model Drug:
Theophylline
8.00E-09
MW 180
12 C
25 C
37 C
6.00E-09
4.00E-09
2.00E-09
0.00E+00
PHEMA Theophylline
BASE
PNIPAAmTheophylline
THERMO-
HYDROGEL
SENSITIVE
GEL
P(HEMA-gNIPAAm)Theophylline
GRAFTED
GEL
D
The University of Alabama
Chemical and Biological Engineering
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
37oC
UV/VIS
The University of Alabama
Spectrophotometer
Sample
Chemical and Biological Engineering
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
The University of Alabama
Chemical and Biological Engineering
Imaging
MRI
Can our magnetic
nanoparticles both
HEAT and IMAGE?
Comparison to
Gadolinium as phase
contrast agent
Potential to detect individual
cells (METASTATIC CANCERS)
The University of Alabama
Chemical and Biological Engineering
Imaging to Report Cell Death
31P
MRS (Magnetic Resonance Spectroscopy)
of a mouse s.c. tumor at 9.4T
g-NTP
a-NTP
PCr
PME
DPDE
-NTPb
tumor
Pi
T. Ng et al., UAB, unpublished data
The University of Alabama
MRS enables REPORTING
for treatment efficacy since
a decrease in ATP
levels signals cell death
Chemical and Biological Engineering
Collaborative Team
Magnetic Nanoparticle
Chemistry & Characterization
Cancer Cell Targeting
Adenoviruses and Antibodies
David Nikles
Jeremy Pritchett
Dong-Hyun Kim
Lauren Blue
Kyle Fugit
Maaike Everts
David Curiel
Joel Glasgow
Vaibhav Saini
Jacqueline Nikles
Magnetically-Triggered
Chemotherapeutics
Christopher Brazel
Indu Ankareddi
John Melnyczuk
Mary Kathryn Sewell
Andrei Ponta
The University of Alabama
Hyperthermia Experiments and
Modeling
MRI for
Christopher Brazel
Cancers
Chuanqian Zhang
Thian Ng
Huadong Zeng
Johnathan Harris
Chemical and Biological Engineering
The Brazel Research Group
Collaborators
Thian Ng
David Curiel
Maaike Everts
Joel Glasgow
David Nikles
The University of Alabama
Jacqueline
Nikles
Chemical and Biological Engineering
Thank You
Questions?
The University of Alabama
Chemical and Biological Engineering