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

1. Christopher S. Brazel, Ph.D., P.E. Associate Professor: University of Alabama Department of Chemical and Biological Engineering

2. The University of Alabama College of Engineering 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

3. The University of Alabama Chemical and Biological Engineering U.S. Mortality Statistics, 2004 No. of deaths % of all deaths 1. Heart Diseases 652,486 27.2 2. Cancer553,888 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.

4. U.S. Change in Death Rates, by Cause, 1950-2004 The University of Alabama Chemical and Biological Engineering 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

5. Cancer Treatment Options The University of Alabama Chemical and Biological Engineering • Surgery • Chemotherapy • Radiation Therapy • Hyperthermia In most cases, COMBINATION therapy is more effective.

6. Goals The University of Alabama Chemical and Biological Engineering 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

7. 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 • Reporting • Was the treatment effective? http://nano.cancer.gov

8. Outline The University of Alabama Chemical and Biological Engineering • • 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

9. Targeting Cancer Cells The University of Alabama Chemical and Biological Engineering LOCALIZE Target with antibodies, folic acid, adenovirus

10. Nanodevice for Targeting & Treating Cancer The University of Alabama Chemical and Biological Engineering Adenovirus Platform: Hexon Region of Capsid

11. Magnetic Nanoparticles The University of Alabama Chemical and Biological Engineering 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 nm

12. Magnetic Induction Heating The University of Alabama Chemical and Biological Engineering 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 Start 10 min

13. The University of Alabama Chemical and Biological Engineering 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)

14. 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)

15. Modeling Magnetic Heating The University of Alabama Chemical and Biological Engineering Pennes’ Bio-Heat Equation By tuning Curie Temperature of nanoparticles, magnetic heating can be done effectively without risk of overheating.

16. Modeling Magnetic Heating The University of Alabama Chemical and Biological Engineering Pennes’ Bio-Heat Equation Healthy Tissue Region Heated Tumor Region Radius

17. Numerical Solution to Heating Profile The University of Alabama Chemical and Biological Engineering 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

18. Fluorescent Tagging of Magnetic Nanoparticles The University of Alabama Chemical and Biological Engineering GOAL: Observe how nanoparticles interact with cells and cell surfaces

19. Triggering Drug Release The University of Alabama Chemical and Biological Engineering 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

20. Magnetothermal Delivery The University of Alabama Chemical and Biological Engineering 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

21. Magnetothermal Drug Delivery D The University of Alabama Chemical and Biological Engineering Grafted Gel Releases Drug When Heated Drug Diffusion Coefficients as f(T) Model Drug: Theophylline MW 180 Diffusion Coefficient, D (cm2/s) BASE HYDROGEL THERMO- SENSITIVE GEL GRAFTED GEL

22. Developing a Perfusion System to Study Magnetic Triggering The University of Alabama Chemical and Biological Engineering - mimic blood flow effect on heat transfer - study drug release activiated by magnetic field Hot water bath 37oC Hyperthermia coils UV/VIS Spectrophotometer Sample

23. m m m m m Temp m m m m m m m m m m m m m The University of Alabama Chemical and Biological Engineering Self-Assembled Nanostructures as Drug Carriers Meltable Poly(ethyleneglycol-b-ε-caprolactone) Micelles m = magnet = drug

24. Imaging The University of Alabama Chemical and Biological Engineering MRI Can our magnetic nanoparticles both HEAT and IMAGE? Comparison to Gadolinium as phase contrast agent Potential to detect individual cells (METASTATIC CANCERS)

25. Imaging to Report Cell Death a-NTP g-NTP PCr PME DPDE -NTPb Pi T. Ng et al., UAB, unpublished data The University of Alabama Chemical and Biological Engineering 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

26. Collaborative Team The University of Alabama Chemical and Biological Engineering 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 Christopher 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

27. The Brazel Research Group The University of Alabama Chemical and Biological Engineering Collaborators Thian Ng David Curiel Maaike Everts Joel Glasgow Jacqueline Nikles David Nikles

28. Questions? Thank You The University of Alabama Chemical and Biological Engineering