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Gold Nanorods as Absorption Contrast Agents for Noninvasive Detection of Cancer and Arterial Vascular Disorders . Dr. Rinat Ankri and Dr . Dror Fixler Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar- Ilan University, Israe l. Specular. Diffuse. - PowerPoint PPT Presentation
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Gold Nanorods as Absorption Contrast Agents for Noninvasive Detection of Cancer and Arterial Vascular Disorders
Dr. Rinat Ankri and Dr. Dror Fixler
Faculty of Engineering and the Institute of Nanotechnology and
Advanced Materials, Bar-Ilan University, Israel
Input DiffuseReflection
Absorption
Diffuse Transmission
Scattering
SpecularReflection
Direct Transmission
Light Interaction with a Turbid Medium
Light Path in Irradiated Tissues- The Diffusion Theory
13( ')a s
D
2a
J D J Jt
Where: ρ= light source-detector distance
Thus, the diffusion reflection (DR) intensity depends on µa and µs’:
12( ) exp( )m
c c
Where:
2 3 's ac
Schmitt et al., 1990m = 1 or 2
m= ?
250 µm per step650 nm PD Output
Digital ScopePD InputOptical fiber
PD
The experimental set-up
Sample
Fiber Optic
Detector1mm
250 µm per step
1 2 2 4 5 6-2.5
-2
-1.5
-1
-0.5
0
(mm)
ln(
((
))
0.0137 mm-1
0.0182 mm-1
0.0227 mm-1
The Diffusion Theory; m=1
0.01 0.012 0.014 0.016 0.018 0.02 0.022 0.0240
0.05
0.1
0.15
0.2
0.25
f(x) = 8.61054770891312 x − 0.0143171977361507
f(x) = 8.22666502644852 x + 0.0205806933202116
m=1SimulatedLinear (Simulated)Exprimental
Absorption coefficient (mm-1)
slope
2
Expected µs’=1.6 mm-1*
* Cubeddu et.al., 1993
Experimental µs’~2.8 mm-1
Simulation
Experiments
1 2ln( ( ))m c c
2 3 's ac
1 2 3 4 5 6-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
(mm)
ln(
2 ((
))
0.0182 mm-1
0.0137 mm-1
0.0227 mm-1
0.01 0.012 0.014 0.016 0.018 0.02 0.022 0.0240
0.05
0.1
f(x) = 4.44673158121791 x − 0.0393530535243912
f(x) = 4.75326397465863 x − 0.0268147770882027
m=2SimulatedLinear (Simulated)Exprimen-tal
absorption coefficient (mm-1)Sl
ope2
The Diffusion Theory; m=2
Expected µs’=1.6 mm-1*
Experimental µs’~1.5 mm-1
* Cubeddu et.al., 1993
Simulation
Experiments
Ankri et.al, The Open Optics Journal, 2011
m= 2 !
Diffusion Reflection and Gold Nano Particles
Structural Imaging Molecular Imaging
The Vision“Fantastic Voyage” Isaac Asimov (1966)
Why Gold?
Subcellular Cellular Whole
body
TEM FAAS CT
The Concept
Hand with Ring (Wilhelm Röntgen,1895)
Surface plasmon resonance
Figure: Schematic of plasmon oscillation for a sphere, showing
the displacement of the conduction electron charge cloud
relative to the nuclei.
When a nanoparticle is much smaller than the wave length of light, coherent oscillation of the conduction
band electrons induced by interaction with an electromagnetic field. This resonance is called Surface
Plasmon Resonance (SPR).
Optical Properties of Gold Nanorods
15
Gold nanorods have shape and size-dependent optical properties originating from anisotropic shape and tunable aspect ratio.
Aspect Ratio (AR) = L/W
L
W
Nikoobakht et al. Chem Mater. 2003, 15, 1957-1962.
Gold Nanorods
16
Under electromagnetic field of light, the conduction band electrons undergo a collective coherent oscillation in resonance with
the frequency of the incident light. This is known as the localized surface plasmon resonance (LSPR) .
Due to their anisotropic shape, 2 extinction peaks can be observed from gold
nanorods.Huang et al. Adv Mater. 2009, 21, 4880-4910.
A new method for cancer detection based on diffusion reflection measurements of targeted
gold nanorods
400 450 500 550 600 650 700 750 800 850 9000
20
40
60
80
100
Wavelength [nm]
Nor
mal
ized
Inte
nsity
(A.U
)
GNR (25 x 65 nm) UV-Vis absorption spectra (normalized) and TEM image
Au Au
Head & Neck Cancer Cell
Tumor detection based on DR measurements of targeted gold nanorods (GNR)
Enhancing the tumor absorption
coefficient by EFGR labeled GNR
injection.
650 nm
400 450 500 550 600 650 700 750 8000.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
Bare GNR
PEG coated GNR
Anti-EGFR coated GNR
Wavelength (nm)
Nor
mal
ized
abs
orpti
on (a
.u.)
Tumor µa 650 nm
Diffusion Reflection measurements
Before t =10 h0.5
1Cancerous
Normal
Time [hours]Sl
ope
of ln
(Г(ρ
))
Diffusion reflection decreases faster due to GNRs accumulation
6
6
-6 6
6
-6
GNRs injection
Before t=0 t >10 h0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1CancerousNormal
Time [hours]
Slop
e of
ln(Γ
(ρ))
1 2 3 4 5 6-3.5
-2.5
-1.5
-0.5
0
(mm)
ln(
())
Normal before injection
Tumor before injectionNormal, t=10 h
Tumor, t=10 h
Tumor detection based on DR of targeted gold nanorods (GNR)
The tumor presents a slope different from the normal
tissue’s slope even more than 20 hours post injection.
Ankri et.al; A new method for cancer detection based on diffusion reflection measurements of targeted gold nanorods, International journal of Nanomedicine, 2012
2
( )
ln( ( )) 3 '' 0
a s
s GNR
Expected µa (mm-1) Slope2 Experimental µa (mm-1)
0.0123 0.011±0.006 0.012±0.0007
0.0132 0.0143±0.003 0.0131±0.0031
0.0152 0.0256±0.003 0.0146±0.0007
0.0216 0.0625±0.004 0.0229±0.001
0.0312 0.137±0.0016 0.0397±0.0004
0.0986 0.42±0.001 0.104±0.0002
0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.090
0.2
0.4
0.6
0.8
1
GNR concentration (mg/ml)
Abso
rptio
n (O
.D)
GNR exntinction coefficient
1 ml/mg*mm
2 3 's ac Different absorption coefficients
Ankri et.al; In-vivo tumor detection using diffusion reflection measurements of targeted gold nanorods- a quantitative study, Journal of Biophotonics, 2012
GNR conc. in tumor FAA spectroscopy
=
Calculating tumor GNR concentration from the DR profile in-vivo
EGFR- targeted
Time (∆Slope)2 GNR concentration (mg/ml)
Before GNR injection 0 0
t=15 min post GNR injection ------------------ ------------------
t= 5 h post GNR injection 0.0036 0.0096
t= 10 h post GNR injection 0.0275 0.015
1 2 3 4 5 60
0.2
0.4
0.6
0.8
1
1.2
1.41.4
(mm)
ln(
2 ((
))
Tumor beforet = 15 mint=5 ht=10 h
slopes= GNR concentration
DR measurements of high concentrations of GNR-
a Red shift is observed
Dark field Microscopy:
GNR with different densities
450 500 550 600 650 700 750 800 850 9000
0.2
0.4
0.6
0.8
1
1.2
Wavelength (nm)
Nor
mal
ized
abs
orpt
ion
(a.u
)
0.01 0.02 0.05 0.1 0.15 0.20
0.2
0.4
0.6
0.8
1
1.2
1.4650 nm780 nm
Concentration (mg/ml)
∆Slo
pe
450 500 550 600 650 700 750 800 850 9000
0.2
0.4
0.6
0.8
1
1.2
Wavelength (nm)
Abs
orpt
ion
(a.u
)
λ0 ∆λ
DR measurements of tumor bearing mice with different
concentrations of targeted GNR-
a spectral broadening is observed
1 2 3 4 5 6
-3
-2.5
-2
-1.5
-1
-0.5
0
(mm)
ln(
())
Before, 650 nmBefore,780 nmt>10,650 nmt>10, 780 nm
1 2 3 4 5 6
-6
-5
-4
-3
-2
-1
0
(mm)
ln(
())
Before, 650 nmBefore, 780 nmt>10 h, 650 nmt>10 h, 780 nm
Ankri et.al; Intercoupling surface plasmon resonance and diffusion reflection measurements for real-time cancer detection, Journal of Biophotonics, 2012
NEJM Dec 2013
The Aim: To develop a new, easy to use, and non-invasive method at low cost, to locate atherosclerotic vascular disease at its early
stages, particularly unstable plaques with ongoing inflammation prone to rupture
Stable vs. Unstable (vulnerable) Plaques
Rich in extracellular matrixsmooth muscle cells, thick cap
Rich in macrophages, foam cells,inflammatory cells, thin fibrous cap
Macrophages before incubation with GNRs
Macrophages+ GNRs 0.02 mg/ml Macrophages+ GNRs 0.2 mg/ml
450 470 490 510 530 550 570 590 610 630 65010
12
14
16
18
20
Wavelength (nm)
Refle
ction
(a.u
)
Phantom+GNRs Phantom no GNRs Phantom+ macrophages+GNRs
Phantom+ macrophages
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Slop
e of
DR
profi
le
1 1.5 2 2.5 3 3.5 4 4.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
Source-detector seperation (mm)
Nor
mal
ized
refle
ctan
ce in
tens
ity (a
.u)
Macrophages +/-GNRs
Homogenous and GNRs
A cross-section of a rat balloon-injured carotid artery 2 weeks post-injury stained withhematoxylin and eosin (H&E) clearly depicts cellular-rich neointima development.Magnification is 100x for the large photomicrograph. A right carotid artery B left injured carotid artery
IN VIVO ; RAT INJURY MODEL
First in vivo DR measurements of atherosclerosis with GNR
Before GNR injection
24h post GNR injection
Control0
2
4
6
8
10
12
3D CT ARTERY IMAGING