kyung a. kang department of chemical engineering university of louisville britton chance symposium...
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Kyung A. Kang
Department of Chemical Engineering
University of Louisville
Britton Chance SymposiumJune 3-4, 2011
Growing-Up under Dr. Chance as Mentor and Thereafter:
Near Infrared and Nanometal Particles for
Molecular Imaging/Cancer Treatment
Growing-Up under Dr. Chance as Mentor and Thereafter:
Near Infrared and Nanometal Particles for
Molecular Imaging/Cancer Treatment
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Working for Dr. ChanceWorking for Dr. Chance Working for Dr. ChanceWorking for Dr. Chance
• Time: August 1991-January 1994Time: August 1991-January 1994 (Between Drs. E. Sevick and H. Liu)(Between Drs. E. Sevick and H. Liu)
• Near Infrared Spectroscopy:Near Infrared Spectroscopy: - Oxygen Saturation- Oxygen Saturation
- Detection & Characterization of- Detection & Characterization of Bio-heterogeneity (e.g., Tumor) Bio-heterogeneity (e.g., Tumor)
• Time: August 1991-January 1994Time: August 1991-January 1994 (Between Drs. E. Sevick and H. Liu)(Between Drs. E. Sevick and H. Liu)
• Near Infrared Spectroscopy:Near Infrared Spectroscopy: - Oxygen Saturation- Oxygen Saturation
- Detection & Characterization of- Detection & Characterization of Bio-heterogeneity (e.g., Tumor) Bio-heterogeneity (e.g., Tumor)
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My Studies on NIR at PENNMy Studies on NIR at PENN•The Same Concept as Mass (or heat) Transfer in the System with The Same Concept as Mass (or heat) Transfer in the System with Diffusion and Consumption (e.g., Oxygen Transport to Tissue). But it Diffusion and Consumption (e.g., Oxygen Transport to Tissue). But it happens at a rate of 6 order of magnitude faster.happens at a rate of 6 order of magnitude faster.
My Studies on NIR at PENNMy Studies on NIR at PENN•The Same Concept as Mass (or heat) Transfer in the System with The Same Concept as Mass (or heat) Transfer in the System with Diffusion and Consumption (e.g., Oxygen Transport to Tissue). But it Diffusion and Consumption (e.g., Oxygen Transport to Tissue). But it happens at a rate of 6 order of magnitude faster.happens at a rate of 6 order of magnitude faster.
• Breast Cancer Detection/CharacterizationBreast Cancer Detection/Characterization (With Radiology Department)(With Radiology Department)
• New Analysis Approach for TRS dataNew Analysis Approach for TRS data
• New Bio-Heterogeneity Detection MethodNew Bio-Heterogeneity Detection Method - - Phased ArrayPhased Array
• Breast Cancer Detection/CharacterizationBreast Cancer Detection/Characterization (With Radiology Department)(With Radiology Department)
• New Analysis Approach for TRS dataNew Analysis Approach for TRS data
• New Bio-Heterogeneity Detection MethodNew Bio-Heterogeneity Detection Method - - Phased ArrayPhased Array
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Systems Systems IdentificationIdentificationusing Transfer Function, G(s)=Y(s)/X(s)using Transfer Function, G(s)=Y(s)/X(s)
Systems Systems IdentificationIdentificationusing Transfer Function, G(s)=Y(s)/X(s)using Transfer Function, G(s)=Y(s)/X(s)
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Frequency Response Analysis of TRS data (time domain->frequency domain)
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Concept of NIR Phased ArrayConcept of NIR Phased ArrayConcept of NIR Phased ArrayConcept of NIR Phased Array
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Personal Memories of Dr. ChancePersonal Memories of Dr. ChancePersonal Memories of Dr. ChancePersonal Memories of Dr. Chance
•Dr. Chance’s 80Dr. Chance’s 80thth Birthday Birthday
•His Visit to University of Maryland for LectureHis Visit to University of Maryland for Lecture
•Dr. Chance’s 90Dr. Chance’s 90thth Birthday Birthday
•His Visit to University of Louisville for LectureHis Visit to University of Louisville for Lecture•His Visit to Brown Cancer Center for Lecture (Two His Visit to Brown Cancer Center for Lecture (Two Times)Times)
•His Visit to Louisville for the 36His Visit to Louisville for the 36 thth ISOTT ISOTT
•Visiting Dr. Chance Lecture Series in 2009Visiting Dr. Chance Lecture Series in 2009
•Dr. Chance’s 80Dr. Chance’s 80thth Birthday Birthday
•His Visit to University of Maryland for LectureHis Visit to University of Maryland for Lecture
•Dr. Chance’s 90Dr. Chance’s 90thth Birthday Birthday
•His Visit to University of Louisville for LectureHis Visit to University of Louisville for Lecture•His Visit to Brown Cancer Center for Lecture (Two His Visit to Brown Cancer Center for Lecture (Two Times)Times)
•His Visit to Louisville for the 36His Visit to Louisville for the 36 thth ISOTT ISOTT
•Visiting Dr. Chance Lecture Series in 2009Visiting Dr. Chance Lecture Series in 2009
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Dr. Chance at the 36Dr. Chance at the 36thth ISOTT ISOTT Conference in LouisvilleConference in Louisville
Dr. Chance at the 36Dr. Chance at the 36thth ISOTT ISOTT Conference in LouisvilleConference in Louisville
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Specific and Senstive Optical Contrast Agent using Gold
Nanoparticles
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ICG, FDA approved Fluorophore: Ex/Em, 780/830 nm; 2 cm S-D separation, Modulation frequency of 0.1 GHz. Heterogeneity - vitamin E capsule
Absorber 1.0 cm 1.5 cm 2.0 cm 2.5 cmDepth
Fluorescence ContrastBy an ICG containing Absorber
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Fluorescence Fluorescence and Gold Nanoparticleand Gold NanoparticleFluorescence Fluorescence and Gold Nanoparticleand Gold Nanoparticle
Distance
Fluorescence
When a fluorophore is placed near a particle, fluorescence can be altered depending upon the field strength (i.e., the distance from the particle).
Quenching Enhancement
negative sensing/ molecular beacon
negative sensing/ molecular beacon
Improve sensitivity
Improve sensitivity
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Distance control by polymer layer Distance control by polymer layer with known thicknesswith known thickness
Distance control by polymer layer Distance control by polymer layer with known thicknesswith known thickness
Layer-by-layer polymer coating on GNP for distance control
Polymer: PAH (+), PSS (-)
Cypate conjugated polymer: PAHCy
GNP: 10 nm
PAH PSS PAHCy
GNP GNP-(PAH/PSS)-
PAHCy
GNP-(PAH/PSS)
GNP-PAH
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Fluorophore of our choice, CypateFluorophore of our choice, CypateFluorophore of our choice, CypateFluorophore of our choice, Cypate
FDA approved, Indocyanine Green (ICG) based, NIR fluorophore. Ex/Em, 780/830 nm (developed by Dr. Achileful at the Washington University)
Near infrared (NIR): Deep penetration in tissue Better differentiated from autofluorescence
FDA approved, Indocyanine Green (ICG) based, NIR fluorophore. Ex/Em, 780/830 nm (developed by Dr. Achileful at the Washington University)
Near infrared (NIR): Deep penetration in tissue Better differentiated from autofluorescence
ICG Cypate
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Cypate fluorescence at various Cypate fluorescence at various distance from GNP surfacedistance from GNP surface
Cypate fluorescence at various Cypate fluorescence at various distance from GNP surfacedistance from GNP surface
Control (Without GNP)
0
5
10
15
20
0 1 2 3 4 5 6 7 8 9 10
Distance between from GNP surface (nm)
Rel
ativ
e F
luor
esce
nce
(Fol
d)
Distance from GNP surface (nm)
**
****
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Utilizing Both Utilizing Both Quenching and Enhancement Quenching and Enhancement
in One Entity?in One Entity?
Utilizing Both Utilizing Both Quenching and Enhancement Quenching and Enhancement
in One Entity?in One Entity?
Distance from NGP surface
Fluorescence
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Optical Contrast Agent, NanoPPET (Nanometal Particle Plasmon Energy Transfer)
(with Drs. Nantz and Achilefu)
Optical Contrast Agent, NanoPPET (Nanometal Particle Plasmon Energy Transfer)
(with Drs. Nantz and Achilefu)
Molecule for cancer target
NGP
Fluorophore
Structure to be cleaved by Cancer secreting enzyme
Excitation Light Fluorescence
Short Linker for fluorescence quenching
Long Linker for fluorescence enhancement
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Cancer cell
Fluorescence quenchedThe complex being delivered to the cancer
ExEm
Em
Ex
Ex
Em
Ex
Em
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Cancer cell
Some complexes targeting cancer cell
Some are washed out by blood stream
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Cancer cell
Enzyme from cancer cell cleave short spacer
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Cancer cell
Short spacer is cut off -> long spacer determines the distance -> Fluorescence enhanced
Em
Ex
Em
Ex
Ex
Em
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NGPNGP
Cypate
Plasmon field
PEG
PEG with G-G-R peptide sequence
4-Hydroxytamoxifen
Molecular Beacon like Molecular Beacon like NanoparticleNanoparticle SystemSystem(Our Model System)(Our Model System)
Cancer cell Urokinase type
Plaminogen Activator
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Urokinase Sensitive Short Spacer: Quenching and Restoring
Samples in 0.01M PBS buffer; Cypate Conc., 12.8 µM; GNP size, 10 nm; GNP concentration, 3.0 nM
Fluorescence Quenching by GNP
Restoration of Fluorescence by Cleaving Spacer by Urokinase (UPA)
Our Short Spacer is GGGRGG, 2.5 nm (theoretical estimation)
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Fluorescence with Long Spacers
Long spacers and their estimated
lengths by molecular simulation
Linkers Length (nm)
HS-(CH2)12-PEG4-ONH2 3.1
HS-(CH2)12-PEG6-ONH2 3.9
HS-(CH2)12-PEG8-ONH2 4.6
Cypate at 3.8 µM in water; GNP size, 10 nm
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Nano-entity as Target Specific
Thermal Guide
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AEM field for Hyperthermia - Magnetic Nanoparticle as Thermal Guide
Minimal normal tissue heating Non-invasive heating Relatively Low cost Magnetic nanoparticles can be heated by
AEM field -> Cancer specific heating
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AEM Field Generator & Probe
(Dimension, 51x92x38 cmPower, 12.5 kW, Wt: 80 kgFrequency, 35-100, 135-400 kHz)
Generator
Probe of Common Configuration
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Effect of Particle Size and Concentration on Heating
Experimental Conditions: 1 ml sample; 300 KHz; ~3 KW; 5 minutes; solenoid coil.
Size of the nanoparticles, nm
0 10 20 30 40 50 60
C
-2
0
2
4
6
8
10
12
14
16
0.01 wt%0.03 wt%0.05 wt%0.08 wt%0.1 wt%
Concentration, wt.%
0.00 0.02 0.04 0.06 0.08 0.10 0.12
C
-2
0
2
4
6
8
10
12
14
16
10 nm20 nm30 nm50 nm
Size Concentration
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Probe Configurations vs. Field Distributions
Solenoid (most commonly used)
Pancake
Sandwich
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Tumor Specific Dual-functional Nano-entity
Gold coated magnetic nanoparticle for both optical detection and hyperthermia (and for x-ray& MRI contrast)
Biocompatible polymer layer
Tumor specific biomolecules -> for tumor target
Spacer
Fluorophore -> for cancer detection
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Injection of PF127/MNP/anticancer drug mixture into tumor
Instant gel formation at body temperature
Sustained drug release
Hyperthermia and sustained drug release
heat
Nanoparticle/Temperature Sensitive Polymer for Hyperthermia and sustained drug release
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To me, Dr. Chance was:To me, Dr. Chance was:
• Curious• Positive• Research/Work• Communicate with Anyone• Minimally Materialistic• Help Others behind the Scene
• Curious• Positive• Research/Work• Communicate with Anyone• Minimally Materialistic• Help Others behind the Scene
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Primo Vascular SystemPrimo Vascular System
-32-
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