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7/15/2015
1
Intrinsically Radiolabeled
Nanoparticles: An Emerging Paradigm
Weibo Cai, PhD
Associate Professor of Radiology, Medical Physics, & BME
University of Wisconsin - Madison, USA
Email: [email protected]
2015 AAPM Annual Meeting, Anaheim, CA
July 15, 2015
Nanoplatforms for Cancer Theranostics
• Different nanoplatforms (organic and inorganic)
• Step-by-step surface modifications
• Potential to revolutionize diagnosis and treatment
• Polymeric NPs
• Solid lipid NPs
• Dendrimers
• Liposomes
• Micelles
• Ferritin cages
• Porphysomes
• Others…
Fe3O4 Gold nano-shell/cage (Porous) Silica NPsCopper-based
(e.g. CuS)
Upconversion NPs Quantum DotsCarbon-based
(e.g. CNTs, GO)
Others…
Chen et al., J Nucl Med, 2014.
Small Animal Molecular Imaging
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Functionalization of MSN for Theranostics
HS-
MPS Mal-PEG5k-NH2
1) p-SCN-Bn-NOTA
2) Mal-PEG5k-SCM
TRC105-SH64Cu
1 2 3
456
mSiO2 mSiO2-SH mSiO2-PEG-NH2
64Cu-NOTA-mSiO2-PEG-TRC105 NOTA-mSiO2-PEG-TRC105 NOTA-mSiO2-PEG-Mal
Chen, Hong, et al., ACS Nano, 2013.
MSN: mesoporous silica (mSiO2) nanoparticles
Intrinsically Radiolabeled Nanoparticles
Goel et al., Small, 2014.
Shreya Goel
Intrinsically Radiolabeled Nanoparticles PEG-[64Cu]CuS
100 nm
GS-[198Au]Au
5 nm 25 nm
[198Au]Au Nanocages
20 nm
[64Cu]-QD580
Lymph
node
Paw
100 nm
[*As]-SPION@PEG
50 nm
[18F]-NaYF4:Gd,Yb,Er [64Cu]-porphysomes
100 nm
[18F]-Al2O3
20 nm
a b c g
d e f h
3
4
1
2
• Chelator-free (or no additional step) radiolabeling
• Takes advantages of the physical/chemical properties of
rationally selected nanoparticles for radiolabeling
• Could offer an easier, faster and more specific
radiolabeling possibility Goel et al., Small, 2014.
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Commonly Used Strategies
Hot-plus-Cold Precursors
Proton Beam Activation
Specific Trapping
Cation Exchange
CuCl2
Na2S
Sodium Citrate
“Cold” “Hot”
64CuCl2 +
15 min at 90 ºC
Hot-plus-Cold Precursors: [64Cu]CuS
100 nm
64Cu, t1/2=12.7 h
Imaging Therapy
Zhou et al., J Am Chem Soc, 2010.
20 nm
Cation Exchange: [64Cu]QD580
• 64Cu replace Zn and Cd
• High stability in vivo
• Self-illuminating property
• PET/optical dual-modlity
20 nm
TEM PET Optical
Sun et al., J Am Chem Soc, 2014.
CdSe@ZnS
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20 nm
Proton Beam Activation: [18F]Al2O3
Perez-Campana et al., Analyst, 2012.
a
b
c d
e f
g h
i
jOxygen atom
Metallicatom
13N atom
18F atom
Metal Oxide NP
13N-labeled Metal Oxide NP
18F-labeled Metal Oxide NP
Proton
k
• Al2O3 was activated by protons to get [18F]-Al2O3
• Nanostructure was found intact
• In vivo biodistribution study
Specific Trapping
http://mi.wisc.edu
Todd Jerry Jon Greg Hector
Cai Research Group UW Cyclotron Group
• In > 40 years, UW - Madison cyclotron group produced
>100 isotopes (mostly PET, led by Prof. R. Jerry Nickles)
• Current Director: Dr. Todd E. Barnhart
PET/MR Scanners
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69Ge (t½ = 39.05 h)
Chakravarty, Valdovinos, Chen et al., Adv Mater, 2014.
Hard to label due to existence of 69Ge as complex ions in aqueous medium
Labeling Inspired by 68Ge/68Ga Generators
69Ge PEG
SPION SPION@PAA
TEM images of SPION and SPION@PAA Autoradiograph of TLC plates
69Ge-SPION
(RF = 0)
Free 69Ge
(RF = 0.95)
69Ge-SPION Free 69Ge
Max.
Min.
Chakravarty, Valdovinos, Chen et al., Adv Mater, 2014.
PET/MRI in Normal BALB/c Mice
Bioditribution Pattern
Sentinal Lymph Node Mapping
2 h
Lymph
node
Paw
0.5 h 2 h
10 0
%ID
/g
10 0
%ID
/g
0.5 h 12 h 36 h
Lymph nodes
PET T2* MRI
69G
e-S
PIO
N@
PE
G
Fre
e
69G
e
Kidney
Liver
0.5 h
2 h 24 h
0 h
0 h
2 h
0 5 10 15 20 250
20
40
60
80
100
69G
e la
be
ling
yie
ld (
%)
Incubation time (h)
SPION@PAA
SPION@dSiO2
CuS
Negative control
Rubel
Chakravarty
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Chelator-Free Synthesis of PET/MRI Agent
Feng Chen Lymph nodes
Pre-injection 2.5 h
10 %ID/g
0 %ID/g
Lymph
node
Paw
2.5 h 15 h
*As
SPION *As-SPION
Chen, Ellison, et al., Angew Chem Int Ed Engl, 2013.
Rieffel et al., Adv Mater, 2015.
Hexamodal Imaging with Nanoparticles
Self-
Assembly
DLS TEM PoP
Rieffel et al., Adv Mater, 2015.
FL UC PET PET/CT CL PA
In V
ivo
P
han
tom
Hexamodal Imaging with Nanoparticles
FL: fluorescence UC: upconversion CT: computed tomography
PET: positron emission tomography CL: Cerenkov luminescence
PA: photoacoustic
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Rieffel et al., Adv Mater, 2015.
Direct Comparison of Imaging Techniques
• Self-assembly of 2 active imaging components (PoP & UCNPs)
• FL (and PA) provided unique information on the self-assembly status
• PET and CT provided the deepest imaging capabilities
• CL and UC imaging was effective for imaging at intermediate depths,
significantly better than FL
• Such simple yet higher-order multimodal imaging agents can facilitate
the development of integrated imaging systems
Iron Oxide Decorated MoS2 Nanosheets
Prof. Zhuang Liu Liu et al., ACS Nano, 2015.
LA: lipoic acid
Non-Invasive Quantitative PET Imaging
Liu et al., ACS Nano, 2015.
Serum Stability Serial PET Imaging
4T1 Tumor Uptake Biodistribution
Sixiang Shi
7/15/2015
8
Multimodal Image-Guided PTT
Liu et al., ACS Nano, 2015.
Photoacoustic Tomography (PAT)
• Deeper signal penetration than other optical methods
• Inherently real-time imaging, suitable for imaging
dynamic processes without sacrificing spatial resolution
• In the USA alone, digestive diseases are implicated in
upwards of 100 million ambulatory care visits annually
Kinetically Frozen Micellar Naphthalocyanines
Prof. Jonathan F. Lovell
University at Buffalo Zhang et al., Nat Nanotechnol, 2014.
F127 (PEO-PPO-PEO)
Nc (logP of > 8)
50nm
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Multispectral Nanonaps & PAT Imaging
Zhang et al., Nat Nanotechnol, 2014.
Absorbance Oral Gavage
Depth Encoded PAT Intestinal ROI Analysis
Seamless 64Cu-Labeling
Zhang et al., Nat Nanotechnol, 2014.
Dual-Modality In Vivo PAT/PET Imaging
Zhang et al., Nat Nanotechnol, 2014.
PAT
PET
5 mm
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Chelator-Free 89Zr-Labeling of MSN
Chen, Goel, et al., ACS Nano, Revision.
MSN: mesoporous silica (mSiO2) nanoparticles
MSN: A Versatile Radiolabeling Platform
MSN or HMSN
111In
(2.8 d)
90Y
(64 h)
177Lu
(6.6 d)
Others…
89Zr
(78.5 h)
68Ga
(68 m)
45Ti
(185 m)
72As
(26 h)
64Cu
(12.7 h)
44Sc
(4 h)
Intrinsically Radiolabeled Nanoparticles
Mostly used
New combinations
Great potential
Early stage
7/15/2015
11
Acknowledgements
• UW - Madison Cyclotron Group – Prof. R. Jerry Nickles
– Dr. Todd E. Barnhart
– Dr. Jonathan W. Engle
– Dr. Gregory W. Severin
– Hector F. Valdovinos & Stephen A. Graves
• UW - Madison Imaging Facility – Prof. Jamey P. Weichert
– Mohammed Farhoud & Justin Jeffery
• Dr. Xiaoyuan Chen (NIBIB)
• Prof. Sanjiv S. Gambhir (Stanford)
• Prof. George Wilding (UW)
• Prof. Thomas M. Grist (UW)
• Prof. Shaoqin Gong (UW)
• Prof. Xudong Wang (UW)
• Prof. Glenn Liu (UW)
• Prof. Mark E. Burkard (UW)
• Dr. Timothy A. Hacker (UW)
• Prof. Zhuang Liu (Soochow University)
• Prof. Jianfeng Cai (USF)
• Prof. Jonathan F. Lovell (U Buffalo)
• UW Startup Fund & Internal Grants
• Susan G. Komen for the Cure
• DOD Breast Cancer Research Program
• DOD Prostate Cancer Research Program
• UW-Madison/Milwaukee Intercampus
Research Incentive Grants Program
• Elsa U. Pardee Foundation
• NIH (NIBIB & NCI)
• American Cancer Society
• TRACON Pharmaceuticals, Inc.
• Altor BioScience Corporation
• Promega
• Thermo Fisher Scientific