Targeted Hyperthermia

Treatment in Glioblastoma

Winship Cancer Institute Summer Scholars ProgramSydney WadeAlexandros Bouras MD, Milota Kaluzova PhD, Jing Su PhD, Costas Hadjipanayis MD PhDJuly 11, 2014

Glioblastoma (GBM)

• Most common malignant brain tumor in adults

• Around 10,000-15,000 cases of GBM per year in the US

• With traditional therapies, less than 5% of patients with GBM survive 5 years past diagnosis; median survival rate is less than 15 months

• Difficulties in treating GBM include the blood-brain barrier (BBB) and glioblastoma stem cells (GSCs)

Human GBM MRI

Magnetic Nanoparticles (MNPs) in Thermotherapy

• The MNPs typically consist of an iron oxide core and have a low toxicity

• MNPs can be detected via magnetic resonance imaging (MRI) and can also provide therapy (via conjugation to therapeutic agents or thermotherapy)

• In thermotherapy, an alternating magnetic field (AMF) induces a high frequency current around injected MNPs in the brain, causing a temperature increase of the MNPs surrounding the GBM cells and initiating protein denaturation and apoptosis in the GBM and GSC cells

New Treatment Methods with MNPs

• In human patients with recurrent GBM, thermotherapy with MNPs has shown to be beneficial as a concomitant therapy to radiation

• We focused on treating new cases of GBM with MNP thermotherapy alone

• Method of delivery: Convection-Enhanced Delivery (CED) which directly infuses to MNPs to the tumor site (overcomes BBB)

Objectives

• To determine the frequency, current, and location within an induction heating coil which will induce an homogenous alternating magnetic field (AMF) in vitro

• To measure the temperature increase of different concentrations of MNPs

• To use the homogenous AMF to heat the appropriate concentration of MNPs in intracranial GBM tumors in mice for the treatment of GBM

Fig. 1: Schematic illustration of iron oxide nanoparticle with amphiphilic blocked polymer coating Hadjipanayis, Machaidze, Mao. Cancer Res. Aug 1, 2010. 70(15): 6303-6312

Fig. 2: Image of U87MGwtEGFR cells grown in DMEM media

Fig. 3: Schematic illustration of Convection-Enhanced Delivery in mouse brainE. Allard et al., “Convection-enhanced delivery of nanocarries for the treatment of brain tumors”, Biomaterials 30 (2009), 2302-2318

Materials and Procedures

The Induction Heating System

Oscilloscope (top) with the Induction Heating System (bottom)

Flowmax Heat Exchanger System (for cooling)

Induction Heating System (left) with the cylinder and oscilloscope probe

1

2

4

5 3

Schematic illustration of the five-hole cylinder used for

coil characterization/calibration

Experiment Results

• The area within the coil with the homogenous magnetic field is located 1 cm above and below the center of the coil

• There is a linear relationship between the amplitude of the magnetic field and the induced current

• There is a concentration-dependent temperature increase of the MNPs when placed at the center of the coil

Characterization and Calibration Graphs for Central Hole

-2 -1 0 1 2202224262830323436

Central Hole

Distance from Hole Center (cm)

Ampl

itude

(kA/

m)

Characterizati

on

Fig. 4: Magnetic flux density vs. the vertical probe distance from the center of the coil

0 100 200 300 400 500 6000

100

200

300

400

Coil Center

Current (Amps)

Ampl

itude

(Gau

ss)

Calibratio

n

Fig. 6: Magnetic flux density magnitude at the center of the coil at different currents

Fig. 5: Voltage readings at the center of the coil with a current of 400A showing an AMF in both radial (CH1) and axial (CH2) directions

(image taken by TDS 1001C-EDU oscilloscope).

Fig. 3: Average voltage readings at the center of the coil with a current of 400A showing an AMF in both radial (CH1) and axial (CH2)

directions

MNPs Temperature Measurements

Fig. 7: Change in temperature of the MNPs at different concentrations vs. time

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 130022.0

24.0

26.0

28.0

30.0

32.0

34.0

36.0

38.0

40.0

42.0

44.0

46.0

MNPs Temperature Measurements

Water (Control)

0.5 mg/mL

1.0 mg/mL

2.0 mg/mL

5.0 mg/mL

10.0 mg/mL

Time (s)

Tem

pera

ture

(°C)

Induction Heating System: Mouse Setting

Conclusion & Further Studies

• The mouse head should be positioned in the center of the induction heating coil with a current of 400A, a frequency of 356 kHz, and power of 1100 W which will induce a magnetic field with an amplitude of 24.8 kA/m

• Research will continue to see how effectively hyperthermia with MNPs conjugated to therapeutic agents kills GBM cells and GSCs in mice with intracranial human GBM tumors

References

1. Wankhede, M., Bouras, A., Kaluzova, M., Hadjipanayis, C.G. (2012). Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy. Expert Review of Clinical Pharmacology, 5(2), 173-186.

2. Hadjipanayis, C.G., Van Meir, E.G. (2009). Brain cancer propagating cells: biology, genetics and targeted therapies. Trends in Molecular Medicine, 15(11), 519-530.

3. Hadjipanayis, C.G., Machiadze, R., Kaluzova, M. (2010). EGFRvIII antibody—conjugated iron oxide nanoparticles for magnetic resonance imaging—guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res, 70, 6303-6312.

4. Attaluri, A., Ma, R., Qiu, Y., Li, W., Zhu, L. (2011). Nanoparticle distribution and temperature elevations in prostatic tumours in mice during magnetic nanoparticle hyperthermia. International Journal of Hyperthermia, 27(5), 491-502.

5. Bordelon, D., Goldstein, R.C., Nemkov, V.S., et al. (2012). Modified solenoid coil that efficiently produces high amplitude AC magnetic fields with enhanced uniformity for biomedical applications. IEEE Transactions on Magnetics, 48(1), 47-52.