Physical Perspective on Radiation Acknowledgment Response Modulation of Tumors … · 2011. 8. 18. · 1 Physical Perspective on Radiation Response Modulation of Tumors with Gold

1

Physical Perspective on Radiation

Response Modulation of Tumors

with Gold Nanoparticles

Sang Hyun Cho, Ph.D.

Medical Physics Program

Woodruff School of Mechanical Engineering

Georgia Institute of Technology

Atlanta, Georgia

Acknowledgment

• Georgia Tech:

S.-K. Cheong, B. Jones, A. Siddiqi, F. Liu,

N. Manohar, K. Dextraze

• M. D. Anderson Cancer Center:

S. Krishnan, P. Diagaradjane

• Georgia Research Alliance

Prologue

Perfecting Radiation therapy …

Radiation

Response

Modulation of

Tumor

Image guidance / tumor trackingControl of organ motion

Variation of

radiation qualityh, e-, n, p, …

Manipulation of

radiation intensity / fluence

2

● Almost universally achievable in theory

with enough accumulation (< ~ 10 wt. %)

● Efficacy varying dependent on the ability

to control the two following parameters:

- Amount of physical dose enhancement

- Location of high Z materials: sites of

interactions with radiation

Radiation Response Modulation of

Tumors using high Z media

Rationale for Use of GNPs

• Mediators for increased secondary electron

production in tissue irradiated with h, e-, p, etc.

- Example: Interaction probability for

photoelectric absorption ~ Z4 to Z4.8

- iodine (Z=53)

- gadolinium (Z=64)

- platinum (Z=78)

- gold (Z=79)

Why GNPs ?

water

• Possibility of uniform delivery of gold to tumor

site due to particle size in nm range: enhanced

permeability and retention (EPR) due to passive

extravasation of nanoparticles through leaky

tumor vasculature “Passive Targeting”

Why GNPs ?

Adapted from Brigger et al, Adv. Drug Deliv. Rev. 54, 2002

3

• Possibility of achieving high tumor specificity of

gold by conjugating GNPs with antibodies for

tumor markers (e.g., EGFR) or angiogenesis

markers (e.g., VEGFR) “Active Targeting”

Why GNPs ?

Adapted from Katz et al, Nanoparticles, Ed. G. Schmid 2004

• Possibility of achieving significant cellular

uptake of GNPs via active targeting

“Internalization”: high Z gold in close proximity

to the cell nucleus and DNA, the main target for

radiation damage

Why GNPs ?

• Possibility to generate therapeutic dose of heat

through photothermal effect / plasmon resonance

Why GNPs ?

Source: Nanospectra Bioscience, Inc.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

400 500 600 700 800 900

Wavelength (nm)

No

rma

lize

d O

D

Abs max

• acceptable toxicity for high concentration (up to

3% of body weight) of gold in the body

- potential toxicity of GNPs: inconclusive at this

time and needs to be investigated further

• possibility to perform in-vivo molecular imaging

before/during/after the treatment through x-ray

fluorescence imaging (e.g., XFCT)

Why GNPs ?

4

GNP-mediated Physical

Dose Enhancement

Physical Dose Enhancement around GNPs

Physical Dose Enhancement around GNPsMacroscopic Estimation of

Dose Enhancement

• Average dose enhancement across tumor

• Applicable to passive targeting scenario or

so-called contrast-enhanced radiation therapy

• Dose enhancement as a function of GNP

concentration and photon beam quality

- Uniform distribution of GNPs within the tumor

- Uniform mixture of gold and tissue

- MC calculations or Analysis of energy absorption

coefficients

5

tumor + GNPs

photon/x-ray beam

tissue phantom

(30 x 30 x 30 cm3)

SSD

MC Simulation Geometry:

External beam casesMacroscopic Dose Enhancement Factor (MDEF)

External beam cases

MDEF = average tumor dose with Au / average tumor dose without Au

FF: flattening filter, NFF: no flattening filter

Concentration

( per gram of tumor ) 140 kVp 6 MV FF 6 MV NFF 4 MV FF 4 MV NFF

7 mg Au 2.114 1.007 1.014 1.009 1.019

18 mg Au 3.811 1.015 1.032 1.019 1.044

30 mg Au 5.601 1.025 1.053 1.032 1.074

Macroscopic Dose Enhancement Factor (MDEF)

250 kVp in-vivo experiment

250 kVp MDEF(50 cm SSD, 1.5x1.5 FS, 1 cm^3 tumor)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Depth (cm)

MD

EF

no gold

0.07% gold

0.2% gold

0.7% gold

1.8% gold

MC Simulation Geometry:

Brachytherapy cases

brachytherapy source

at the center30 cm radius tissue phantom

tumor + GNPs

6

MDEF: Ir-192 & Yb-169

0.5

1.0

1.5

2.0

2.5

3.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Radial Distance (cm)

MD

EF

Yb-169 & 7 mg Au

Yb-169 & 18 mg Au

Yb-169 & 7 mg Au + 2 mg Au

Ir-192 & 7 mg Au

Ir-192 & 18 mg Au

Ir-192 & 30 mg Au

tumor tissue

MDEF: 50 kVp & I-125

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Radial Distance (cm)

MD

EF

50 kVp & 7 mg Au

50 kVp & 18 mg Au

50 kVp & 7 mg Au + 2 mg Au

I-125 & 7 mg Au

I-125 & 18 mg

I-125 & 7 mg + 2 mg Au

tumor tissue

Secondary Electron Spectra for 125-I

1.E-07

1.E-06

1.E-05

1.E-04

1.E-03

1.E-02

1.E-01

1.E+00

0.00 0.01 0.02 0.03 0.04

Energy (MeV)

Ele

ctr

on

s p

er

So

urc

e P

ho

ton Water and 0.7 wt% Au

Water

Secondary electron spectra

I-125 gamma ray irradiation Secondary Electron Spectra for 6 MV X-rays

1.E-08

1.E-07

1.E-06

1.E-05

1.E-04

1.E-03

0.01 0.10 1.00 10.00

Energy (MeV)

Ele

ctr

on

s p

er

So

urc

e P

ho

ton Water and 0.7 wt% Au

Water

Secondary electron spectra

6 MV photon irradiation

7

Experimental Verification of Dose Enhancement

GNP-loaded Radio-sensitive Gels irradiated by 110 kVp

MAGIC+Formaldehyde Gel Calibration Curve

1% Au + No

radiation

1% Au+12 Gy

y = 0.0242x + 4.6565

R2 = 0.9037

4.50

4.60

4.70

4.80

4.90

5.00

5.10

5.20

5.30

5.40

5.50

0 5 10 15 20 25 30

Dose (Gy)

R2 (

1/s

)

Microscopic Estimation of Dose Enhancement

• Dose enhancement around GNP on nanoscale

• Applicable to active/passive targeting scenarios

with heterogeneous distribution of GNPs

• Basis for GNP-mediated DNA damage calculations

• Computational Approaches

- Detailed history MC calc with hypothetical

dimensionless GNPs

- Mixed history MC calc with various sizes of GNPs

- Semi-analytic calc using microscopic e- energy

deposition kernel/pattern


Dose point kernels

GNP Hypothetical Water NP


microscopic dose enhancement factor (mDEF)

8







250 kVp


alternative approach using mixed history MC simulations

21 MeV e-

250 MeV p

GNP d=20 nm H2O d=20 nm

GNP d=20 nm H2O d=20 nm

9

Correlation between physical

model and biological outcome ● Quantification of physical dose

enhancement on micro-/nano-scale

(cellular & DNA level estimation)

● Identification of GNP locations within

tumor (cell)

● Identification of proper biological

pathways (known & unknown)

Modeling of GNP-mediated

Radiation Response Modulation

Left image re-created from Herold et al, Int. J. Radiat. Biol. Vol. 76, 2000

micro-/cellular-dosimetry regime nanodosimetry regime

on the order of 10 m

e-e-

e-

Cellular & DNA level quantification of

microscopic dose enhancement

2 nm

e-

e-

e-

e-

6 MV

Microscopic dose enhancement in tissue

10

Microscopic dose enhancement in tissue Microscopic dose enhancement in tissue

Microscopic dose enhancement in tissue GNP-mediated radiosensitization with 6 MV?

• In-vitro setting: ~ 20% per cell survival assays

10s of m

Predictable using calculated mDEF for 6 MV !

h

11

GNP-mediated radiosensitization with 6 MV?

• In-vivo setting: Inconclusive

Physically, no significant dose enhancement again,

but the location of GNP is probably the key ….

Gold Nanoparticle-aided

Radiation Therapy (GNRT)

● Dual action

- tumor blood vessel disruption

- enhanced cell-killing: increase in

relative biological effectiveness (RBE)

for radiation

● Further improvement of therapeutic

ratio for radiotherapy

Biological Consequences of GNRT

Passive targeting

Or

GNP contrast agent

Active targeting

Various GNRT scenarios

h h h

Active targetingInternalized GNPs

t

12

● Brachytherapy sources

- Yb-169

- 50 kVp miniature x-ray source

● External beam sources

- low-energy enhanced MV beam

- synchrotron/monochromatic or

orthovoltage x-ray beams:

tomotherapy/rotational delivery

- electron and proton

Radiation sources for GNRT

Epilogue

● The concept appears to be applicable to

human cancer treatment

● Physical model alone may not be

adequate to explain all biological

outcomes

● Even so, physical model based on

realistic outlook may still play an

important role for clinical translation

Radiation Response Modulation of

Tumors using GNPs

Thank you for your attention !

Documents

Physical Perspective on Radiation Acknowledgment Response Modulation of Tumors … · 2011. 8. 18. · 1 Physical Perspective on Radiation Response Modulation of Tumors with Gold