In Vivo Applications of Near-Infrared
Quantum Dots
John V. Frangioni, M.D., Ph.D.
Assistant Professor of Medicine
Assistant Professor of Radiology
Harvard Medical School
Moungi G. Bawendi, Ph.D.
Professor of Chemistry
Massachusetts Institute of Technology
Outline
I.
The Clinical Problem
II. The Nanotechnology Solution
III. The Regulatory Conundrum
Outline
I.
The Clinical Problem
II. The Nanotechnology Solution
III. The Regulatory Conundrum
The Cancer Detection Problem
1012
109
1 kg
Death of Patient
1g
Threshold for
Detection
Cell
Number
“Remission”
Time
2X = 1000
X = 10
Cell Divisions
Cancer Fates in the United States
Cured by Chemotherapy and/or
Radiotherapy
Not
Cured
Cured
By
Surgery
Approximately 1.3 x 106 Non-Skin Cancers Diagnosed
Each Year in the U.S.
Cancer Fates in the United States
Cured by Chemotherapy and/or
Radiotherapy
Not
Cured
Cured
By
Surgery
Chemistry (Molecular Targeting)
Engineering (Instrumentation)
Outline
I.
The Clinical Problem
II. The Nanotechnology Solution
III. The Regulatory Conundrum
The Nanotechnology Solution
Requires the Synergy of:
Engineering: Intraoperative Near-Infrared
Fluorescence Imaging System
Chemistry: Highly Sensitive, Properly-Sized,
and Stable Near-Infrared Fluorescent Contrast
Agents (Quantum Dots)
Near-Infrared Fluorescent Surgical Imaging System
NIR
Camera
810 ± 20 nm NIR Emission Filter
785 nm
Dichroic
Mirror
771 nm, 250 mW
Laser Diode System
Video
Camera
NIR-Depleted
150 W Halogen
White Light Source
400 nm - 700 nm Bandpass Filter
Zoom
Lens
= Visible Light Path
100
= NIR Fluorescence Light Path
75
Normal Light
Near Darkness
50
25
0
350 400 450 500 550 600 650 700
Wavelength (nm)
†
Surgical
Field
Nakayama et al., Mol. Imaging, 2002; 1(4): 365-377
Mobile Large Animal Intraoperative Imaging System
Articulated
Arm
Excitation/
Emission
Module
Computer &
Electronics
Cart
†
DeGrand & Frangioni, Submitted
Deployment in the Surgical Suite
A.
B.
†
DeGrand & Frangioni, Submitted
The Surgeon’s View
†
DeGrand & Frangioni, Submitted
Fluorescent Semiconductor Nanocrystals (Quantum Dots)
M.G. Bawendi and S.J. Kim (MIT)
Organic Coating
Shell
Core
3 - 20 nm (Determines BioD)
Potential Advantages
Peak emission tunable anywhere from UV to IR
High non-aqueous QYs
Broadband absorption increasing to the blue
High photostability
Conjugatable to tumor targeting ligands
Potential Disadvantages
Potential toxicity of materials
Difficult to synthesize
Size/material limitations (?solved)
Modeling of Near-Infrared and Infrared Photon Transmission
Wavelength-Independent Scatter
1.00
High H2O to Hb Ratio
1.00
0.75
0.75
0.25 cm
1 cm
0.50
0.25 cm
1 cm
0.50
0.25
0.25
0.00
400
High Hb to H2O Ratio
800 1200 1600
Wavelength (nm)
Band Band Band
1
2
3
0.00
400
2000
Band
4
800 1200 1600
Wavelength (nm)
Band Band Band
1
2
3
2000
Band
4
Wavelength-Dependent Scatter
1.00
High H2O to Hb Ratio
1.00
0.75
0.75
0.25 cm
1 cm
0.50
0.25
0.00
400
High Hb to H2O Ratio
0.25 cm
1 cm
0.50
0.25
800 1200 1600
Wavelength (nm)
Band Band Band
1
2
3
†
Band
4
2000
0.00
400
800 1200 1600
Wavelength (nm)
Band Band Band
1
2
3
Lim et al., Mol. Imaging, 2003; 2(1): 50-64
Band
4
2000
Infrared (1320 nm) QDs vs. NIR (840 nm) QDs
High Hb to H2O Ratio
Wavelength-Independent Scatter
Scatter
15
10
5
0
0
10 20 30 40 50
Absolute Scatter at 630 nm
Thickness
10 4
20
10 3
15
10 3
10 2
10
10 2
10 1
5
10 1
10 0
60
0
0.2
0.4 0.6 0.8 1.0
Tissue Thickness (cm)
10 4
10 0
1.2
Wavelength-Dependent Scatter
7
6
5
4
3
2
1
0
Scatter
10 4
20
10 3
15
Thickness
10
10 2
0
10 20 30 40 50
Absolute Scatter at 630 nm
†
10 1
60
5
0
0.2
0.4 0.6 0.8 1.0
Tissue Thickness (cm)
Lim et al., Mol. Imaging, 2003; 2(1): 50-64
10 6
10 5
10 4
10 3
10 2
10 1
10 0
1.2
Near-Infrared Fluorescent (Quantum Dots)
1.2x10 07
1.0x10 07
0.75
8.0x10 06
6.0x10 06
1.0
0.50
0.5
4.0x10 06
0.25
2.0x10 06
450
CdTe CdSe Shell
Core Thickness
1.00
550 650 750 850
Wavelength (nm)
0.00
0.0
600
IRDye78-CA
1000
NIR QDs
1000
1250
600 mW/cm2
400 mW/cm2
200 mW/cm2
100 mW/cm2
50 mW/cm 2
30 mW/cm 2
1000
750
500
250
0
700
800
900
Wavelength (nm)
750
500
250
0
10
20 30 40 50
Time (Seconds)
60
†
600 mW/cm 2
400 mW/cm 2
200 mW/cm 2
100 mW/cm 2
50 mW/cm 2
30 mW/cm 2
5
10
15
Tme (Minutes)
Kim et al., Manuscript Submitted
20
Sentinel Lymph Node Mapping with 860 nm Quantum Dots
(15-20 nm hydrodynamic diameter)
Pig Femoral Lymph Node Model
200 µL of 2 µM Solution (400 pmol) of CdTe(CdSe)
QDs in PBS Injected Intradermally
Movie
Immediate Clinical Applications of NIR QDs
• Image guidance during sentinel lymph
node mapping
• Image guidance during cancer resection
• Image guidance for avoidance of critical
structures (e.g., nerves and blood vessels)
during general surgery
• High sensitivity tool for surgical pathologists
Outline
I.
The Clinical Problem
II. The Nanotechnology Solution
III. The Regulatory Conundrum
We have the clinical need.
NIBIB has funded the science.
We now have the
nanotechnology solution.
But, can NIR and IR Fluorescent
Quantum Dots ever be Translated
to the Clinic?
Theoretical Data
Reported Data
Summary of Quantum Dots for In Vivo Applications
Type
I
I
II
I
I
I
I
I
Type
I
I
I
I
I
I
I
II
II
Material
CdSe
CdTe
CdTe(CdSe)
InAs
PbSe
InP
HgS
CdHgTe
Material
HgSe
HgTe
PbS
PbTe
InSb
GaAs
GaSb
ZnTe(CdS)
ZnTe(InAs)
Molar Ratio
Cd:Se=1:1
Cd:Te=1:1
Cd:Te:Se=1:x:(1-x)
In:As=1:1
Pb:Se=1:1
In:P=1:1
Hg:S=1:1
Cd:Hg:Se=x:(1-x):1
Emission
Range(nm)
480-650
580-740
700-1100
800-1300
1100-2200
600-730
500-800
750-1100
Hydrodynamic
Diameter (nm)
2.6-9.8
4-12
4-16
2-7
2.5-10
2-5
1-5
6-12
Molar Ratio
Hg:Se=1:1
Hg:Te=1:1
Pb:S=1:1
Pb:Te=1:1
In:Sb=1:1
Ga:As=1:1
Ga:Sb=1:1
Zn:Cd:Te:S=x:y:x:y
Zn:In:Te:As=x:y:x:y
Emission
Range(nm)
660-1600
660-1960
950-2060
780-2100
650-1330
640-830
800-1390
630-940
660-1000
Hydrodynamic
Diameter (nm)
4-6
5-8
4-8
4-8
8-12
6-14
6-12
4-16
4-16
Summary of QD
Semiconductor
Materials
Antimonide
Arsenide
Cadmium
Gallium
Indium
Lead
Mercury
Phosphide
Selenide
Sulfide
Telluride
Zinc
Possible
Routes of
Administration
Intravenous
Intraperitoneal
Subcutaneous
Subdermal
Intravaginal
PO
Per-rectum
Intravesical
Aerosol
Unresolved Regulatory/Toxicity Issues
Will QDs be regulated as devices or drugs?
Will QDs be regulated based on their
chemical form (i.e., salts), or as individual metals?
Does route of administration matter or do
individual materials prevail?
Special design of toxicity studies?
Disposal of medical waste containing QDs
What We Need as Investigators
Guidance regarding “acceptable” materials or
early indication that translation to the clinic
is not possible
Assistance with the design and implementation
of toxicity studies
Interagency cooperation regarding issues of
drug delivery and disposal of QDcontaining biological material
Acknowledgements (Presented Data)
Frangioni Laboratory:
Yong Taik Lim
Jaihyoung Lee
Alec M. DeGrand
Bawendi Laboratory:
Sungjee Kim
Nathan E. Stott
Jonathan Steckel
Mihaljevic Laboratory:
Edward G. Soltesz
Rita Laurence
Delphine Dor
Lawrence Cohn
Acknowledgements (Cont.)
Funding
NIBIB EB-00673
NIH R21/R33 CA88245
NIH R21 CA88870
DOE DE-FG02-01ER63188
Doris Duke Charitable Foundation
CaPCURE
Stewart Trust of Washington DC