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 Diagnosisand Treatment of Cancer:

Development of a Nanoplatform to Target Cancer Cells and Provide Magnetically-Triggered

Combination Chemotherapy and Hyperthemia

The University of Alabama College of Engineering Department of Chemical and Biological Engineering

Christopher S. Brazel

U.S. Mortality Statistics, 2004

The University of Alabama Chemical and Biological Engineering

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

No. of deaths

% of all deaths

Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

U.S. Change in Death Rates, by Cause, 1950-

2004

19.8

180.7

48.1

586.8

193.9

50.0

185.8217.0

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

Rate

Per

100,0

00

* 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


Cancer Treatment Options

• Surgery

• Chemotherapy

• Radiation Therapy

• Hyperthermia

In most cases, COMBINATION therapy is more effective.


GoalsCreate a versatile nanoplatform withmultiple 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

Multifunctional Targeting, Imaging and 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


• Novel approaches are needed for treatment of cancer

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


Targeting Cancer CellsLOCALIZE Target with antibodies, folic acid, adenovirus


Nanodevice for Targeting & Treating Cancer


Adenovirus Platform:Hexon Region of Capsid

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

Nickel Palladium NixPdy

10 nm10 nm


Magnetic Induction HeatingMagnetic Induction

Hyperthermia Chamber0-5 kW; 50-485 kHz

Heating Curves for Cobalt-Ferrite Nanoparticles

-100 0 100 200 300 400 500 600 700

20

30

40

50

60

70

80

Temperature (

oC)

Time (Sec)

634 G 316 G 254 G 158 G

Start 10 min

Tem

per

atu

re (

oC

)

60

70

80

50

40

30

20


In Vivo Testing of Magnetic Hyperthermia

(a) (b)Tumor (Exp 1) Tumor + CoFe2O4 + Field (Exp 3)

D.-H Kim et al., Key Engineering Materials, 284-286 (2005)

Images of tumor regression


In Vivo Testing of Magnetic Hyperthermia

D.-H Kim et al, Key Engineering Materials, 284-286 (2005)

Tumors went into regressionwith 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


Modeling Magnetic Heating

By tuning Curie Temperatureof nanoparticles, magnetic heating can be done effectively without risk of overheating.

Pennes’ Bio-Heat Equation


Modeling Magnetic Heating

1≈ΔTcw

P

bb

Pennes’ Bio-Heat Equation

HeatedTumorRegion

HealthyTissueRegion

Radius


Numerical Solution toHeating Profile


00.5

10

0.51

40

45

50

55

r/radiusz/height

t=500sec

Temperature(

°C)

00.5

10

0.51

40

45

50

55

r/radiusz/height

t=300sec

Temperature(

°C)

00.510

0.51

40

45

50

55

r/radiusz/height

t=150sec

Temperature(

°C)

00.5

1

00.5

1

40

45

50

55

Temperature(

°C)

z/height r/radius

t=0sect = 0 sect = 150 sec

t = 500 sec

t = 300 sec

Tem

per

atu

re (

oC

)

Tem

per

atu

re (

oC

)

Tem

per

atu

re (

oC

)

Tem

per

atu

re (

oC

)

Height Height

Height Height

RadiusRadius

Radius

Radius

Model is used toguide experimentalconditions:

- nanoparticle concentration- optimal particle size- exposure time- frequency of magnetic

field

Fluorescent Tagging of Magnetic Nanoparticles

GOAL: Observe how nanoparticles interact with cells and cell surfaces


Triggering Drug ReleaseTriggering 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/tissueor photoinitiated reactions during angioplasty {West and Hubbell, 1990s}

Magnetic Fieldplacement/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


Magnetothermal Delivery

1. Injection

2. Localization to Tumor

3. External Activation with Magnetic Field

5. Grafts Collapse,Pores Open

7. Activation Off, Pores Close

6. Drug Delivery

Magnetic Nanorods

4. Heat Dissipation


Drug Diffusion Coefficients as f(T)

0.00E+00

2.00E-09

4.00E-09

6.00E-09

8.00E-09

1.00E-08

1.20E-08

PHEMA -Theophylline

PNIPAAm-Theophylline

P(HEMA-g-NIPAAm)-

Theophylline

Diffusion coefficient, D (cm

2/s) 12 C

25 C

37 C

Model Drug: Theophylline

MW 180

BASE HYDROGEL

THERMO-SENSITIVE

GEL

GRAFTEDGELD

iffu

sio

n C

oeffi

cie

nt,

D (

cm

2/s

)

D

Grafted Gel Releases Drug When Heated

Magnetothermal Drug Delivery


Developing a Perfusion System

to Study Magnetic Triggering

- mimic blood flow effect on heat transfer

- study drug release activiated by magnetic field

UV/VIS

37oCSpectrophotome

ter

Hot water bath

Hyperthermia coils

Sample


Self-Assembled Nanostructures as Drug CarriersMeltable Poly(ethylene glycol-b-ε-caprolactone) Micelles

m

m

m

m

m

m

m

mm

m m

m

m

m

m

mm

mTemp

m = magnet = drug


ImagingMRI

Potential to detect individualcells (METASTATIC CANCERS)


Can our magneticnanoparticles bothHEAT and IMAGE?

Comparison to Gadolinium as phasecontrast agent

Imaging to Report Cell Death


31P MRS (Magnetic Resonance Spectroscopy) of a mouse s.c. tumor at 9.4T

-NTP

-NTP-NTP

PCr

Pi

PMEDPDE

T. Ng et al., UAB, unpublished data

tumor

MRS enables REPORTING for treatment efficacy since a decrease in ATP levels signals cell death

Collaborative TeamMagnetic Nanoparticle

Chemistry & Characterization

David NiklesJeremy PritchettDong-Hyun Kim

Lauren BlueKyle Fugit

Cancer Cell TargetingAdenoviruses and Antibodies

Maaike EvertsDavid Curiel

Joel GlasgowVaibhav Saini

Jacqueline Nikles

Hyperthermia Experiments andModeling

Christopher BrazelChuanqian ZhangJohnathan Harris

Magnetically-Triggered Chemotherapeutics

Christopher BrazelIndu AnkareddiJohn Melnyczuk

Mary Kathryn SewellAndrei Ponta

MRI forCancers

Thian NgHuadong Zeng


The Brazel Research Group

Collaborators

David Nikles

Maaike Everts

Joel Glasgow

David Curiel

Jacqueline Nikles

Thian Ng


Questions?

Thank You


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

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