In Vivo Applications of Near-Infrared Quantum Dots
John V. Frangioni, M.D., Ph.D.Assistant Professor of MedicineAssistant Professor of Radiology
Harvard Medical School
Moungi G. Bawendi, Ph.D.Professor of Chemistry
Massachusetts Institute of Technology
The Cancer Detection Problem
Time
CellNumber
1012
109 Threshold forDetection
Death of Patient1 kg
1 g
2X = 1000X = 10
Cell Divisions“Remission”
Cancer Fates in the United States
CuredBy
Surgery
NotCured
Cured by Chemotherapy and/orRadiotherapy
Approximately 1.3 x 106 Non-Skin Cancers DiagnosedEach Year in the U.S.
Cancer Fates in the United States
CuredBy
Surgery
NotCured
Cured by Chemotherapy and/orRadiotherapy
Chemistry (Molecular Targeting)Engineering (Instrumentation)
The Nanotechnology SolutionRequires 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
† Nakayama et al., Mol. Imaging, 2002; 1(4): 365-377
SurgicalField
785 nmDichroicMirror
NIRCamera
VideoCamera
810 ± 20 nm NIR Emission Filter
400 nm - 700 nm Bandpass Filter
ZoomLens
771 nm, 250 mWLaser Diode System
NIR-Depleted150 W Halogen
White Light Source
= Visible Light Path
= NIR Fluorescence Light Path
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Computer &Electronics
Cart
Excitation/EmissionModule
ArticulatedArm
Mobile Large Animal Intraoperative Imaging System
† DeGrand & Frangioni, Submitted
Fluorescent Semiconductor Nanocrystals (Quantum Dots)M.G. Bawendi and S.J. Kim (MIT)
Potential Advantages Potential DisadvantagesPeak emission tunable anywhere from UV to IR Potential toxicity of materialsHigh non-aqueous QYs Difficult to synthesizeBroadband absorption increasing to the blue Size/material limitations (?solved)High photostabilityConjugatable to tumor targeting ligands
Organic CoatingShell
Core
3 - 20 nm (Determines BioD)
Modeling of Near-Infrared and Infrared Photon Transmission
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Wavelength-Dependent Scatter
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High H2O to Hb Ratio High Hb to H2O Ratio
High H2O to Hb Ratio High Hb to H2O Ratio
Wavelength-Independent Scatter
† Lim et al., Mol. Imaging, 2003; 2(1): 50-64
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Wavelength-Independent Scatter
High Hb to H2O Ratio
Infrared (1320 nm) QDs vs. NIR (840 nm) QDs
† Lim et al., Mol. Imaging, 2003; 2(1): 50-64
Near-Infrared Fluorescent (Quantum Dots)
IRDye78-CA NIR QDs
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Tme (Minutes)
CdTeCoreCdSe Shell
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† Kim et al., Manuscript Submitted
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 lymphnode 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
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?
Summary of Quantum Dots for In Vivo Applications
Emission HydrodynamicType Material Molar Ratio Range(nm) Diameter (nm)I CdSe Cd:Se=1:1 480-650 2.6-9.8I CdTe Cd:Te=1:1 580-740 4-12II CdTe(CdSe) Cd:Te:Se=1:x:(1-x) 700-1100 4-16I InAs In:As=1:1 800-1300 2-7I PbSe Pb:Se=1:1 1100-2200 2.5-10I InP In:P=1:1 600-730 2-5I HgS Hg:S=1:1 500-800 1-5I CdHgTe Cd:Hg:Se=x:(1-x):1 750-1100 6-12
Emission HydrodynamicType Material Molar Ratio Range(nm) Diameter (nm)I HgSe Hg:Se=1:1 660-1600 4-6I HgTe Hg:Te=1:1 660-1960 5-8I PbS Pb:S=1:1 950-2060 4-8I PbTe Pb:Te=1:1 780-2100 4-8I InSb In:Sb=1:1 650-1330 8-12I GaAs Ga:As=1:1 640-830 6-14I GaSb Ga:Sb=1:1 800-1390 6-12II ZnTe(CdS) Zn:Cd:Te:S=x:y:x:y 630-940 4-16II ZnTe(InAs) Zn:In:Te:As=x:y:x:y 660-1000 4-16
Rep
orte
d D
ata
The
oret
ical
Dat
a
Summary of QD PossibleSemiconductor Routes of
Materials AdministrationAntimonide Intravenous
Arsenide IntraperitonealCadmium SubcutaneousGallium SubdermalIndium IntravaginalLead PO
Mercury Per-rectumPhosphide IntravesicalSelenide AerosolSulfide
TellurideZinc
Unresolved Regulatory/Toxicity Issues
Will QDs be regulated as devices or drugs?
Will QDs be regulated based on theirchemical form (i.e., salts), or as individual metals?
Does route of administration matter or doindividual materials prevail?
Special design of toxicity studies?
Disposal of medical waste containing QDs
What We Need as Investigators
Guidance regarding “acceptable” materials orearly indication that translation to the clinic
is not possible
Assistance with the design and implementationof toxicity studies
Interagency cooperation regarding issues ofdrug delivery and disposal of QD-
containing biological material
Acknowledgements (Presented Data)
Frangioni Laboratory: Yong Taik LimJaihyoung LeeAlec M. DeGrand
Bawendi Laboratory: Sungjee KimNathan E. StottJonathan Steckel
Mihaljevic Laboratory: Edward G. SolteszRita LaurenceDelphine DorLawrence Cohn