1. PET-detectable bimetallic (Zn@Au) nanoparticles for radiotherapy and molecular imaging applications
AAPM Annual Meeting, Anaheim, California
July 13, 2015
J Cho1, M Wang2, C Gonzalez-Lepera1, E Zubarev2, and S H Cho1.
1 University of Texas MD Anderson Cancer Center, Houston, TX
2 Department of Chemistry, Rice University, Houston, TX
PET imaging for proton therapy verification.
Please interrupt me anytime for questions.
(MO-FG-303-8 (Monday) 4:30 PM - 6:00 PM Room: 303)

2. Motivation Gold nanoparticles (GNP) Sufficient GNP in-tumor uptake
→ great radiosensitizers
Sufficient GNP in-tumor uptake
→ essential for radiosensitization
Pre-treatment in-vivo imaging of GNP in-tumor uptake is ideal
→ motivated to develop dual-function GNPs – imaging & therapy
The first motivation of my research is improving the current way of dose and range calculation as well as verification by providing tissue elemental composition.
The second motivation is on verifying the proton range with implantable dosimeters.
I was looking for some elements that are proton activated very strongly at very low proton energy and decay slowly so that we can observe the activation of these dosimeters as the sign of the proton distal end. By using these implantable dosimeters for proton range verification, we do not have to worry about first, biological diffusion, not activating at the very end of the proton range, also spending big bucks for in-room PET scanner.

3. GNP mediated radiotherapy
Injection of GNPs.
Targeting of tumors with GNPs.
Passive: leaky vessel.
Active: targeting moiety.
~ 24 hours for maximum in- tumor uptake.
Radiation bombards GNPs.
→ Create electrons.
→ Kill tumors.
Radiation

4. Perez’s work that motivated our study
Perez-Campana et. al.
Protons
O18
F18
Ti18O2-NPs
18F (T½=110 min)
→ 18O + e+
Challenges:
Difficult to make.
Low Z NPs → inferior radiosensitizer.
Imaged only for hours not for days.
Significant patient dose.

5. To overcome: Bi-metallic Zn@Au nanoparticle
1) Synthesis
21 nm
2) Irradiation using
medical cyclotron
3) PET imaging

6. Synthesis of Zn@Au nanoparticle
ZnCl2 + PVP
Zn NPs
HAuCl4
LiBH4 N2
Mesitylene (solvent) N2
Sodium citrate / NaBH4
Reflux, 24 h
H2O (solvent)
NPs
(water dispersable)
Zn NPs
NPs
Capping agent exchange
Work up
20 nm
20 nm
Au coating
Zn NPs
NPs
TEM image
TEM image

7. Proton activation of Zn@Au NP
5 µA, 5 min activation
4.5 hr post-irradiation delay/1.5 hr gamma counting
Advantages
Externally GNPs.
Stable compared with attached radionuclides.
Imaged for hours - days.
Minimal patient dose (inject after ~ 6 hrs of decay).

8. 1) Zn@Au NPs – enough activity for PET imaging?3)
270 mg of NPs activated per cyclotron target setting
23 mg of NP
5 µA proton beam,
5 min irradiation 4)
Specific activity
Ga66 – 0.82 mCi/g
Ga68 – mCi/g
Total – 11 mCi/g 5)
Patient GNP injection 70 kg patient: ~ 1 g of GNP 2)
12 hr post-irradiation
delay, 5 min PET scan 6)
1 g of GNP provides
10 mCi of activity
which is sufficient for PET scan

9. 2) Compromise in radiosensitization? Zn@Au NP vs GNP
21 nm
21 nm
Zn occupies only 4%
volume of entire NP.
96% is Au.
< 4 % different
< 4 % different

10. Future of hybrid NP mediated radiotherapy
2) PET/CT
scan
1) Injection
3) Mapping
Nanoparticle
4) Radiation
therapy

11. Thank you.
Acknowledgement: Dr. Mawlawi Funding: NIH/NCI grant R01CA AAPM seed research grant Hiring students: Author contact:

12. Current approaches for in-vivo GNP imaging
Photo-acoustic imaging
X-ray fluorescence
imaging
Jones et. al. Phys. Med. Biol. 2012
Quantification is difficult.
Low spatial resolution.
Compton scatters require high dose.
Superficial cancer only.
(Source: bench-top polychromatic x-ray)

13. Current approaches for in-vivo GNP imaging
Radiolabeling GNP
Perez-Campana et. Al.
Protons
18O
18F
Ti18O2-NPs
18F (T½=110 min)
→ 18O + e+
Disadvantages:
Stability of radiolabeling & GNP mobility.
Difficult to make.
Non-gold NPs → inferior radiosensitizer.
Imaged only for hours, significant patient dose.

14. 2) Radiosensitization in 250 kVp Orthovoltage
21 nm
21 nm
 Monte Carlo (TOPAS) simulation
GNP NP
Volume
 100.00
Mass
 97.67
Number of 2ndary particles created
 96.09
Total energy released to medium
 96.82

15. Synthesis of bi-metallic Zn@Au nanoparticle
Zncl2 + Mesitylene + PVP
N2 + LiBH4
Reflux & cool
centrifuge
& wash
Zn NPs
N2 + citrate Na + NaBH4
NPs
TEM image of
NPs
TEM image
of Zn NPs
20 nm
20 nm

16. Biosensors and Bioelectronics, 2009, 24, 2155-2159 My results
NaBH4
H2O, vigorous stirring
Ice-bath
SDS
Sodium citrate
HAuCl4, NaBH4
Ice-bath
SDS
CuSO4/KI
Cu NPs Au
(SDS: sodium dodecyl sulfate)
Biosensors and Bioelectronics, 2009, 24,
My results
10 nm
Cu core: ~5 nm
Au layer: 7~12 nm
20 nm

18. Zn@Au nanoparticle Advantages Disadvantages Structurally stable.
2 hr post-irradiation
12 hr gamma counting
~ 1 mg of NP
Advantages
Structurally stable.
Imaged for hours to days.
Less patient dose (inject after ~ 6 hrs of delay).
Disadvantages
Some non-511 keV gamma.
70 hr post-irradiation
12 hr gamma counting
~ 10 mg of NP

19. Radio-sensitization comparison: GNP vs. Zn@Au NP
21 nm
21 nm

20. Radio-sensitization comparison: GNP vs. Zn@Au NP
21 nm
21 nm

21. Zn@Au NP proton activation
5 µA, 5 min activation
4.5 hr post-irradiation delay/1.5 hr gamma counting
Advantages
Externally GNPs.
Stable compared with attached radionuclides.
Imaged for hours - days.
Minimal patient dose (inject after ~ 6 hrs of decay).

22. 2) Zn@Au NP – compromise in radiosensitization ?
21 nm
21 nm
 Monte Carlo (TOPAS) simulation
GNP NP
Volume
 100.00
Mass
 97.67
Number of 2ndary particles created
 97.08
Total energy released to medium
 95.86
Zn occupies
only 3.7%
volume of
entire NP.
96.3% is Au.

23. Motivation GNP Gold nanoparticles Sufficient GNP in-tumor uptake
Photo/Auger
electrons
Proton or
X-ray
GNP
Direct
DSB
Free radical
creation
Gold nanoparticles
→ great radiosensitizers
Sufficient GNP in-tumor uptake
→ essential for radiosensitization
In-vivo imaging of GNP uptake
→ motivated to develop dual-function GNPs – imaging & therapy
Cell kill
The first motivation of my research is improving the current way of dose and range calculation as well as verification by providing tissue elemental composition.
The second motivation is on verifying the proton range with implantable dosimeters.
I was looking for some elements that are proton activated very strongly at very low proton energy and decay slowly so that we can observe the activation of these dosimeters as the sign of the proton distal end. By using these implantable dosimeters for proton range verification, we do not have to worry about first, biological diffusion, not activating at the very end of the proton range, also spending big bucks for in-room PET scanner.