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Intrinsically Radiolabeled

Nanoparticles: An Emerging Paradigm

Weibo Cai, PhD

Associate Professor of Radiology, Medical Physics, & BME

University of Wisconsin - Madison, USA

Email: wcai@uwhealth.org

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

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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

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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