Diagnostics Therapy
Real-time imaging
of disease Efficient delivery of
therapeutics
Theranostics
‘Theranosis’
Tumor Imaging
nanoparticle
Drug-carrying nanoparticle
Improved imaging for diagnosis
Drug delivery for therapy
Patient Tumor therapy
Theranostics
Imaging modalities : Anatomic vs Functional
CT(Computed Tomography)
MRI(Magnetic Resonance Imaging) PET(Positron Emission Tomography) Optical Imaging
Ultrasound sonography SPECT
Technique Resolution Depth Imaging agent Target Clinical Use MR 10-100m No limint Galolinium, dysprosium A, P, M Yes
iron oxide particle
CT 50 m No limit Iodine A, P Yes
Ultrasound 50 m Millimetres Micorbubbles A, P Yes PET 1-2 mm No limit 18F, 11C, 15O P, M Yes SPECT 1-2 mm No limit Tc, In chelates P, M Yes FRI 2-3 mm < 1 cm Photoproteins (GFP), P, M Development
NIR fluorochromes
FMT 1 mm < 10cm NIR fluorochromes P, M Development
BLI 1 M < 400 m Photoproteins (GFP) M No
Fluorochromes
Primary area that a given imaging modality interogates: A, anatomical; M, molecular P, physiological. BLI, bioluminescence imaging; CT, X-ray computed tomography; FMT, florescence-mediated molecular
tomography; FRI, fluorescence reflectance imaging; NIR, near-infrared; NR, magnetic resonance; PET, positron emission tomography; SPECT, single-photon emission computed tomography.
Table from Nature Reviews, Drug Discovery, (2003)
Imaging Modalities
Tissue contrast of CT vs MR : Anatomic Imaging
AP EP
T2WI
CT
MR
Autofluorescence and Selection of Dye for Optical Imaging
Current Opinion in Chemical Biology, 2003, 7, 626
The near-infrared region offers unique advantages for the imaging of pathophysiologic states.
Water and most naturally occurring fluorochromes do not absorb substantial amounts of energy in this region.
Near-infrared radiation penetrates tissues more efficiently.
X N+
X
N R' R
n
X = O, NR, C(CH3)2, S, Se R and R' = aklyl or aryl n = 0, 1, 2, 3, 4, or 5
Water soluble Photo-stable pH insensitive Tolerance in labeling
N N
SO3- SO3- SO3-
-O3S
Cy5.5
Near Infrared Fluorescent Dye: Cyanine Dye
Previous Works of NIRF Imaging Using FRET
Weissleder et. al., Radiology 2001, 221, 523 Nature Biotechnology , 1999,17, 375
Pro-Leu-Gly-Val-Arg
(MMP-2 specific cleavable linker)
MMP(2, 9, 12) Extracellular matrix
VEGF Tumor
Blood vessel Angiogenesis
Selection of Dyes and Gold Nanoparticles
Fluorescence Resonance Energy Transfer (FRET)
1 2
Self Quenching:
No Fluorescence
2 1’
N N
SO3- SO3- SO3-
-O3S
Cy5.5
Noble metal nanoparticles Excitation
Emission Energy transfer Excitation
to SPR of nanoparticles
10 nm ~ ∞ ~ 10 nm Quenching state
Emitting state
•Noble metal : Au, Ag, Pt, etc.
•SPR : surface plasmon resonance No emission
Gold Nanoprobe for Tumor Detection
MMP specific sequence Cleavage site
Peptide modified gold nanoparticle (20 nm)
Absorbance
Wavelength (nm)
400 500 600 700 800
Cell viability (%)
AuNP Conc. (μg/mL)
1 2 3 4
100 80 60 40 20 0 120 140
Angew. Chem. Int. Ed. 2008, 47, 2846
“Noninvasive” in vivo Molecular Imaging
Drug discovery and development -Reduce cost for drug evaluation
- Faster and more accurate evaluation of inhibitor dosing in human drug trials
Biodistribution
[ 18 F]FMISO [ 18 F]FLT
• VX-2 Tumor bearing Rabbit
• Three different radiopharmaceuticals in the same animal [ 18 F]FDG
Tumor Biology with PET
Lymphatic drainage Tumor tissue
Nanoparticle Tumor blood supply
Why Nanoparticles?
Tumor Blood Vessel Normal Blood Vessel
EPR effect (Enhanced Permeability And Retention)
Tumor blood vessel
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C.
Farokhzad, Rimona Margalit, and Robert Langer
Nanocarriers as an emerging platform for cancer therapy
Nanobased carriers for
cancer detection and
therapy
Nat. Nanotech.2007, 2, 751
Nanotechnology in Cancer Therapy
Nanoparticle Fabrication
In Vitro Stability
H2O PBS H2O
In Vivo Biodistribution
PBS
Passive Targeting
Active Targeting
Targeting moiety
Increase tumor cell selectivity - Stable in PBS
Nanoparticular Molecular Imaging Probes
