Kyung A. Kang Department of Chemical Engineering University of Louisville

1. Growing-Up under Dr. Chance as Mentor and Thereafter: Near Infrared and Nanometal Particles for Molecular Imaging/Cancer Treatment Kyung A. Kang Department of Chemical Engineering University of Louisville Britton Chance Symposium June 3-4, 2011

2. Working for Dr. Chance • Time: August 1991-January 1994 • (Between Drs. E. Sevick and H. Liu) • Near Infrared Spectroscopy: • - Oxygen Saturation • - Detection & Characterization of • Bio-heterogeneity (e.g., Tumor)

3. My Studies on NIR at PENN • The Same Concept as Mass (or heat) Transfer in the System with Diffusion and Consumption (e.g., Oxygen Transport to Tissue). But it happens at a rate of 6 order of magnitude faster. • Breast Cancer Detection/Characterization • (With Radiology Department) • New Analysis Approach for TRS data • New Bio-Heterogeneity Detection Method - Phased Array

4. Systems Identification using Transfer Function, G(s)=Y(s)/X(s)

5. Frequency Response Analysis of TRS data (time domain->frequency domain)

6. Concept of NIR Phased Array

7. Personal Memories of Dr. Chance • Dr. Chance’s 80th Birthday • His Visit to University of Maryland for Lecture • Dr. Chance’s 90th Birthday • His Visit to University of Louisville for Lecture • His Visit to Brown Cancer Center for Lecture (Two Times) • His Visit to Louisville for the 36th ISOTT • Visiting Dr. Chance Lecture Series in 2009

8. Dr. Chance at the 36th ISOTT Conference in Louisville

9. Specific and Senstive Optical Contrast Agent using Gold Nanoparticles

10. Fluorescence Contrast By an ICG containing Absorber Absorber1.0 cm 1.5 cm 2.0 cm 2.5 cm Depth ICG, FDA approved Fluorophore: Ex/Em, 780/830 nm; 2 cm S-D separation, Modulation frequency of 0.1 GHz. Heterogeneity - vitamin E capsule

11. Quenching Enhancement Fluorescence Distance Fluorescence and Gold Nanoparticle Improve sensitivity negative sensing/ molecular beacon When a fluorophore is placed near a particle, fluorescence can be altered depending upon the field strength (i.e., the distance from the particle).

12. Distance control by polymer layer with 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- (PAH/PSS) GNP- PAH GNP GNP- (PAH/PSS)- PAHCy

13. Fluorophore 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 ICG Cypate

14. Distance from GNP surface (nm) Cypate fluorescence at various distance from GNP surface ** Control (Without GNP) *

15. Utilizing Both Quenching and Enhancement in One Entity? Fluorescence Distance from NGP surface

16. Optical Contrast Agent, NanoPPET(NanometalParticlePlasmonEnergy Transfer) (with Drs. Nantz and Achilefu) Long Linker for fluorescence enhancement NGP Short Linker for fluorescence quenching Molecule for cancer target Structure to be cleaved by Cancer secreting enzyme Fluorophore Fluorescence Excitation Light

17. Em Ex Ex Em Em Ex Em Ex Cancer cell The complex being delivered to the cancer Fluorescence quenched

18. Cancer cell Some complexes targeting cancer cell Some are washed out by blood stream

19. Cancer cell Enzyme from cancer cell cleave short spacer

20. Ex Ex Em Em Em Ex Cancer cell Short spacer is cut off -> long spacer determines the distance -> Fluorescence enhanced

22. Urokinase Sensitive Short Spacer: Quenching and Restoring Our Short Spacer is GGGRGG, 2.5 nm (theoretical estimation) Fluorescence Quenching by GNP Restoration of Fluorescence by Cleaving Spacer by Urokinase (UPA) Samples in 0.01M PBS buffer; Cypate Conc., 12.8 µM; GNP size, 10 nm; GNP concentration, 3.0 nM

23. Fluorescence with Long Spacers Long spacers and their estimated lengths by molecular simulation Cypate at 3.8 µM in water; GNP size, 10 nm

24. Nano-entity as Target Specific Thermal Guide

25. 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

26. AEM Field Generator & Probe Generator Probe of Common Configuration (Dimension, 51x92x38 cm Power, 12.5 kW, Wt: 80 kg Frequency, 35-100, 135-400 kHz)

27. Effect of Particle Size and Concentration on Heating Size Concentration Experimental Conditions: 1 ml sample; 300 KHz; ~3 KW; 5 minutes; solenoid coil.

28. Probe Configurations vs. Field Distributions Pancake Solenoid (most commonly used) Sandwich

29. Goldcoated magnetic nanoparticle for both optical detectionand hyperthermia (and for x-ray& MRI contrast) Spacer Biocompatible polymer layer Fluorophore -> for cancer detection Tumor specific biomolecules -> for tumor target Tumor Specific Dual-functional Nano-entity

30. Nanoparticle/Temperature Sensitive Polymer for Hyperthermia and sustained drug release Injection of PF127/MNP/anticancer drug mixture into tumor Instant gel formation at body temperature Hyperthermia and sustained drug release Sustained drug release heat

31. To me, Dr. Chance was: • Ｃｕｒｉｏｕｓ • Positive • Research/Work • Communicate with Anyone • Minimally Materialistic • Help Others behind the Scene

32. Primo Vascular System Brain, Spine Skin Brain BHD Skin BHD Blood vessel Skin BHC Organ surface Intravascular BHD Lymph Organ surface BHC