Production of Alpha-emitting

Radionuclides for Cancer

Therapy

Saed Mirzadeh

Medical Radioisotope Program Nuclear Material Processing Group

Nuclear Security and Isotope Technology Division

Knoxville-Oak Ridge Section of the American Institute of Chemical Engineers,

Thursday, November 10, 2016

2

Outline

• Background

• Availability of 225Ac/213Bi and 224Ra/212Pb generator systems

through natural decay of 229Th and 228Th • New Initiatives to Enhance Production of Ac-225

a. Direct production of 225Ac in a high energy proton accelerator

b. Reactor Production of 229Th at ORNL

High Flux Isotope Reactor (Nuclear Data)

c. Production of 229Th via low energy protons

(Nuclear Data)

• Xofigo, 1st approved “targeted” alpha therapy (TAT) for

treatment of advanced prostate cancer

• 227Ac production: larger scale pilot demonstration

3

Isotope production,

enrichment and

distribution began

at Oak Ridge just

after WWII

4

ORNL’s unique combination of radioisotope

research and production assets

• High Flux Isotope Reactor (HFIR)

– LWR, flux trap; 85 MW full power; peak thermal neutron flux of 2.1x1015 n.cm-2.s-1

• Hot Cell and Processing Facilities

– Five active nuclear facilities including REDC and one radiological facility

• On path to reestablishing enrichment capabilities

5

6

Alpha-Emitting and Other Novel

Therapeutic Medical Radioisotopes

Available from ORNL

Alpha emitters:

• Actinium-225/Bismuth-213

• Radium-224/Lead-212

• Actinium-227/Thorium-227/Radium-223

High-energy Beta emitter:

• Tungsten-188/Rhenium-188

Low-energy Beta emitter:

• Strontium-89

Nuclear Science

and Engineering

Isotopes

Sample of Ac-225 in glovebox at REDC. Ac-225 has medical applications in the treatment of leukemia and many other cancers.

7

Therapeutic Nuclear Medicine

• Targeted therapy – , , emitters delivered to diseased tissue

• Strategies – Molecular targeting: Monoclonal antibodies,

peptides, etc; 90Y, 177Lu, 213Bi

– Natural targeting: Thyroid (131I-), Bone(89SrCl2, 223RaCl2,

153Sm & 188Re Phosphate complexes, 117mSn-DTPA), Liver (90Y & 166Ho particles)

– Brachytherapy: Prostate cancer (103Pd, 125I, 131Cs), others

“Xofigo, 1st α-emitting

radioisotope

(223RaCl2), for

treatment of bone

cancer, received

approval from FDA

and European

Commission in 2013”

“Zevalin”,1st β-emitting

radioisotope (90Y-

Ibritumomab tiuxetan)

for treatment B cell non-

Hodgkin's lymphoma

Prostate Cancer Seed

8

Alpha-Emitters for Therapeutic

Applications

• Important attributes

– High linear energy transfer

– Half-life compatible with therapy

– Versatile Chemistry

– Availability

• Alpha-emitters of interest

– 212Bi (60 m) and 213Bi (46 m)

– 212Pb(10 h)/ 212Bi

– 225Ac(10 d)/ 213Bi

– 211At (7 h, accelerator produced)

– 223Ra (11 d)

– 227Th (19 d)/223Ra

Radioimmunotherapy

ORNL 225Ac /213Bi

Generator

9

Availability of 225Ac/213Bi and 224Ra/212Pb generator systems through

natural decay of 229Th and 228Th

• Radiochemical extraction from 229Th and 228Th sources

208Tl 3.1 m

208Pb stable

212Bi 60.6 m

212Po 0.3 s

216Po 0.145 s

212Pb 10.6 h

224Ra 3.66 d

220Rn 55.6 s

232U 68.9 y

228Th 1.91 y

64%

36%

209Bi stable

209Pb 3.3 h

213Po 3.7 s

213Bi 45.6 m

209Tl 2.2 m

225Ra 14.9 d

217At 32 ms

233U 1.59E5 y

229Th 7340 y

225Ac 10.0 d

221Fr 4.9 m

217Rn 0.5 ms

99.99% 97.8%

2.2%

233U/

229Th

232U/

228Th

10

11

Radioimmunotherapy (RIT) Concept

Radionuclide

Chelator

(or fullerene?) Linker

Method for Targeting Cancer

Cell Epitopes:

Antibody or Fragment, Peptide

Typical attachment to

amine group on Lysine

12

N

N

CO2HN

CO2H

CO2H

CO2HCO

2H

SCN

N N

N N

N N

CO2HHO

2C

HO2C

HO2C CO

2H

CO2H

SCN

N N

N N NCS

CO2H

CO2H

HO2C

CO2H

CHX-A'' DTPA c-DOTA

HEHA C82 Carboxymetallofullerene

O

O

O

N

H

O

O

O

O

H

O

O

O

O

HN SC

-

-

-

Polyaminocarboxylate (PAC) Chelators and

Fullerenes

13

MAb 201B Bi-213

Radioimmunotherapy treated control

Day 0

Day 1

Day 3

Day 5

Kennel and Mirzadeh, 2000

14

Kennel and Mirzadeh, 2000

15

225Ac - A Promising Isotope for α-Therapy

Table from: International Atomic Energy Agency. Technical Meeting Report

“Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy” IAEA, 24-

28 June 2013.

16

Treatment of Acute Myelogenous

Leukemia (AML) with Bismuth-213

Posterior

60-Minute

Summation

Rate/Minute

Dose 1 Dose 4

Patient No. 4

Courtesy of Actinium Pharmaceutical Inc. and Sloan Kettering Cancer Center, NY

17

Before

treatment

5 weeks post

2nd treatment

7 weeks post

3rd treatment

9 weeks post

4th treatment

5 weeks post

1st treatment

treatment continued to date : 5 cycles)

Overall survival:>23 months

Patient 6 – Glioblastoma grade IV (male, 59 y)

Peptide receptor α-therapy of glioblastoma with Bi-213 Courtesy of Alfred Morgenstern at ITU

18

Nanoparticles Platform for in-vivo Delivery of Radionuclides

19

In-vitro Release of 225

Ac, 221

Fr and 213

Bi from La(225

Ac)PO4 NPs

Dialysis Time, d

0 5 10 15 20 25 30

Radio

activity, %

10-2

10-1

100

101

102

225Ac

221Fr &

213Bi

Isotope Half-life

α-Energy

(MeV)

α-Recoil

Energy

(keV)

Recoil

Range

(nm)

225Ac 10 d 5.829 107 20

221Fr 4.9 m 6.341 116 22

217At 32.3 ms 7.067 130 24

213Bi 46 m 8.376 154 29

La

225Ac

LaPO4 Nanoparticles Platform for in-vivo Delivery of Actinium-225

20

GdPO4

Shells

LaGd(225Ac)

PO4 Core

Core/Shell Design of

LaGd(225Ac)nanoparticles

21

Lung

Liver

Spleen

MAb 201B-NP &

cold MAb

MAb 201B-NP MAb 14-NP control

SPECT/CT of 225AcLaPO4 Targeted Nanoparticles

22 xaaaaaaaaaaaa

Rationale for R&D related to

production of 225Ac

• The present supply of 225Ac is

insufficient for current medical

and research demands of ~6

Ci/year.

• ORNL has been the main supplier of 225Ac (via

decay of existing 229Th stock) since 1997, with

an annual budget of $1.8 M.

• 700-900 mCi of 225Ac is harvested annually

from 130–mCi 229Th stock at ORNL.

• 6-12 campaigns are performed per year, and

campaign 126 is currently underway α 10 d

β 15 d

α 7.9x103 y

α 1.6x105 y

229Th

233U

225Ac

225Ra

Background of Actinium-225 Production at ORNL

0

50

100

150

200

250

0

100

200

300

400

500

600

700

800

900

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

Nu

mb

er o

f sh

ipm

ent

Ac-

225

(m

Ci)

Year

Annual Production of Ac-225

Production Capacity Dispensed Amount Shipments

23

23

Growth and Decay of 225

Ra and 225

Ac Separated from 229

Th at 60 d(N

0 = 1 Ci

229Th)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 20 40 60 80 100 120 140

Time (d)A

cti

vit

y (

Ci)

225Ra

225Ac

Theoretical Ac-225 Yield from Ra-225 Decay

Time (days)

0 20 40 60 80

Rad

ioac

tiv

ity,

mC

i

0.1

1

10

100

Ra-225

Ac-225 (cont. growth)

Ac-225 separated and shipped at time-interval shown below

7 21 35 49

60

20

5

2

(At t=0, Ra activity = 60 mCi)

63

Production of 225AC from Decay of 229Th Production 225Ac from Decay of 229Th

24

• Direct production of 225Ac in a

high energy proton accelerator

• Reactor Production of 229Th at

ORNL High Flux Isotope Reactor

(Nuclear Data)

• Production of 229Th via low

energy protons (Nuclear Data)

New Initiatives to Enhance

Production of Ac-225

25

Direct production of 225

Ac in a proton accelerator

229Ra

4.0 m

228Ra

5.75 y

227Ra

42.2 m

226Ra

1600 y

225Ra

14.9 d

224Ra

3.66 d

225Ac

10.0 d

226Ac

29.4 h

227Ac

21.8 y

228Ac

6.15 h

229Ac

1.05 h

227Th

18.7 d

228Th

1.91 y

229Th

7340 y

230Th

7.54E4 y

231Th

25.5 h

232Th

1.4E10 y

228Pa

22 h

229Pa

1.4 d

232U

68.9 y

233U

1.59E5 y

n,

c

??

?

• Develop the processing chemistry

• Evaluate yields and impurities

• Construct and evaluate 225Ac/213Bi

Generator

• Provide Ac and generator to

selected customers for in vivo

evaluation

ORNL Contributions:

The new collaboration between ORNL, BNL and LANL aims at developing a plan for full-scale production and stable supply of 225Ac by irradiating 232Th targets in the BNL BLIP and LANL IPF, and target processing at ORNL

1st publication of tri-lab efforts: Griswold et al, Large Scale Accelerator Production of 225Ac: Effective Cross Sections for 78-192 MeV Protons Incident on 232Th Targets (in print, App. Rad. Isot., 2016)

26

Challenges Associated with Accelerator-Based

Production of 225Ac -- Complex Chemistry

Thorium Target Mass : 1-10 g – initial mass, 50-100 g – anticipated for Ci-level targets

Production of Radiolanthanides: Significant challenge to separate trivalent Ln-isotopes from 225Ac (specifically 140La and 141Ce)

Production of large quantities of fission products: In the 100-200 MeV proton energy range, for every mCi of 225Ac, 12.5 mCi of

fission products are produced

Timing: The 227Ac/225Ac ratio (~0.2% at EOB) gets worse with time

Toxicity: Biological toxicity of minute amount of 0.2% 227Ac in 225Ac is

not evaluated

27

232Th[p,x]227Ac

Incident Proton Energy (MeV)

50 100 150 200

Eff

ective

Cro

ss S

ectio

n (

mb

)

0

5

10

15

20

25

30

This Work

Ermolaev et al., 2012Gauvin et al., 1963Lefort et al., 1961

Engle et al., 2014

232Th[p,x]226Ac

50 100 150 200

Eff

ective

Cro

ss S

ectio

n (

mb

)

0

5

10

15

20

25

This WorkEngle et al., 2014

Gauvin et al., 1963Lefort et al., 1961

Titarenko et al., 2003

232Th[p,x]225Ac

50 100 150 200

Eff

ective

Cro

ss S

ectio

n (

mb

)

0

5

10

15

20

25

This Work

Ermolaev et al., 2012Gauvin et al., 1963Lefort et al., 1961

Weidner et al., 2012Titarenko et al., 2003

232Th[p,f]140Ba

Incident Proton Energy (MeV)

50 100 150 200

Eff

ectiv

e C

ross

Sec

tion

(mb)

5

10

15

20

25

30

35

40

This Work

Duijvestijn et al., 1999Holub et al., 1973

Engle et al., 2014Titarenko et al., 2003

Accelerator Production of 225Ac (cont.)

28

Chemical Process for Accelerator-Produced 225Ac

LANL

BNL

ORNL

29

Radionuclide

Yield at EOB

IPF: 250 µA, 90 MeV BNL: 100 µA, 192 MeV

(Ci) (GBq) (Ci) (GBq)

225Ac 1.5 5.6 × 101 1.5 5.7 × 101

226Ac N/M N/M 3.2 1.2 × 102

227Ac 2.7 × 10−3 1.0 × 10−1 3.1 × 10−3 1.1 × 10−1

227Th 6.3 2.3 × 102 1.9 7.0 × 101

228Th 2.2 × 10−1 8.1 × 100 8.0 × 10−2 2.8

99Mo 1.8 × 101 6.7 × 102 5.4 2.0 × 102

140Ba 3.1 1.2 × 102 4.6 × 10−1 1.7 × 101

139Ce 1.1 × 10−2 4.1 × 10−1 1.6 × 10−2 5.9 × 10−1

141Ce 1.4 5.2 × 101 3.5 × 10−1 1.3 × 101

143Ce 1.4 5.1 × 101 1.6 5.8 × 101

144Ce 9.0 × 10−2 3.5 3.3 × 10−2 1.2

For a 10 day irradiation of a 5 g cm−2 232Th target at IPF or BLIP, yield of 225Ac is ~1.5 Ci at EOB with ~0.2% contamination from 227Ac

30

HPLC Separation of 225Ac from 140La and other

radiolanthanides, showing only major radioactive species

Ac-

225

Ra-

223

Ba-

140

La-1

40

Ce-

139

Ce-

141

Ce-

144

Eu-

154

Eu-

156

Gd-

153

Nb-

95

Nd-

147

Pm

-144

Pm

-148

Pm

-148

m

Pm

-149

Cs-

132

Cs-

134

Cs-

136

Cs-

137

Tb-

155

Tb-

160

Th-

227

Ru-

103

Ru-

106

Zr-

95

In-1

44m

Mn-

54

V-4

8

Be-

7

0

10

20

30

40

50

60

70

80

90

100

F01

F03

F05

F07

F09

F11

F13

F15

F17

F19

F21

F23

F25

F27

F29

F31

F33

F35

F37

F39

F41

F43

F45

F47

F49

F51

F53

F55

F57

F59

Radioisotopes

Rad

ioac

tivi

ty (

µC

i)

Column Fractions

31

0

10

20

30

40

50

60

70

80

90

100

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65

Ac-225

Ba-140

La-140

Ce-139

Ce-141

Ce-144

% 0.4M a-HIBA

% DI Water

% 1M HCl

Second HPLC Separation of 225Ac From 140La – Gradient and Chromatogram

DI H20

α-HIBA

1 M HCl Ce radioisotopes

225Ac

32

Reactor production of Th-229

1st term of cross-section refers to thermal and 2nd term to resonance integrals. The values

in parenthesis are fission cross-sections at thermal and epi-thermal neutrons, respectively

229Ra

4.0 m

228Ra

5.75 y

227Ra

42.2 m

226Ra

1600 y

225Ra

14.9 d

224Ra

3.66 d

225Ac

10.0 d

226Ac

29.4 h

227Ac

21.8 y

228Ac

6.15 h

229Ac

1.05 h

227Th

18.7 d

228Th

1.91 y

229Th

7880 y

230Th

7.54E4 y

226Th

31 m

n,

c

?

1500, 1400

(202, 210)

123,1014

( 0.3, ?)

63,970

(31,405)

1000, 1600 100,1700 890,1660

12, 29 100, 590 13, 280 36, ?457 ± 195

( 0.29,?)

223Ra

11.4 d

130, ?

(0.7, ?) (<5E-5, ?) (<2, ?)

90

88

135 141136 137 138 139 140

89

Neutron CrossSection (b)

,I

(f,I

f)

33

• Projected 229Th yield for 6 cycle irradiations: 18-23 mCi per g of 226Ra,

with 228Th and 227Ac contaminations of 3000 and 50 times larger.

• 20 mCi of 229Th will generate ~140 mCi of 225Ac per year

Reactor Production of Thorium-229, Hogle, et al., ARI, 114, 19-27 (2016)

IRRADIATION TIME (Days)

0 20 40 60 80

AC

TIV

ITY

(M

Bq

/g 2

26R

a)

10-2

10-1

100

101

102

103

104

Th-228

Ac-227

Ra-228

Th-229

Reactor Production of Thorium-229

34 xaaaaaaaaaaaa

Production of 229Th via Proton-induced Reactions on 232Th

Th-229 7880 y

Th-230 7.5×10

4 y

Th-232 1.4×10

10 y

Pa-229 1.5 d

Ac-229 63 m

Ra-229 4.0 m

(99.5%) α (0.5%)

β

β

(p,d) (p,pn)

(p,nt) (p,2nd) (p,3np)

(p,2n)

(p,4n)

(p,2p) (p,α) (p,pt)

(p,n3He)

(p,2d) (p,npd) (p,2n2p)

(p,p3He)

(p,2pd) (p,3pn)

Thorium Proton Bombardment Reaction Block Diagram

Various Excitation Functions for Proton Bombardment of 232

Th

Energy (MeV)

10 20 30 40

Cro

ss S

ectio

n (

mb

)

0

100

200

300

400

500

232Th[p,3n]

230Pa (Morgenstern, 2009)

232Th[p,3n]

230Pa

232Th[p,x]

229Th

232Th[p,n]

232Pa

232Th[p,4n]

229Pa

232Th[p,5n]

230Pa

Channel Number

150 200 250 300 350

Cou

nts

1e+2

1e+3

1e+4

1e+5

-Ray Spectrum of Purified Pa Fraction

(Th230-2, PaPPT-T5, 6/15/2011)

X-rays of Th (228 Pa,

229 Pa & 230 Pa)

140 keV, 99 Mo

129 keV, 228 Pa

93 keV

108 keV

35

Production of 229Th via Proton-induced Reactions on 232Th

• Excitation function for the 232Th[p,4n]229Pa reaction has been measured with

good precision; excitation function peaks at 28 MeV, 150 mb.

• Measurements of thick target production show cross section is dominated by

the following two reactions: 232Th[p,4n]229Pa(1.5 d, EC)229Th 232Th[p,α]225Ac(63 m, β)229Th

• Irradiating 1 gram of 232Th (~0.5 mm) for 1 year at 100 µA of 35 MeV

protons and exiting at 25 MeV would yield ~28 mg of 229Th (5.6 mCi).

• Additional nuclear data for short-lived 229Ac is necessary to determine

cross section of 232Th[p,α]229Ac reaction

• The thick target yield from 230Th target expected to be 3-5 times greater

than from 232Th target

Future Work

Summary

36

227Ac production: larger

scale pilot demonstration

• 227Ac is made via irradiation

of 226Ra targets at HFIR 226Ra 227Ra

227Ac

n

2,000 yrs

22 yrs

42 min

Building 3047 cleanup • ORNL entered into a production

R&D phase shortly after hosting

the 2013 International TAT

conference

Preliminary feasibility R&D was

followed by two years of

1st 50-mg 226Ra pellet

1st HFIR Rabbit containing 2 Ra pellets

37

Xofigo, 1st

approved “targeted” alpha therapy

(TAT) for treatment of advanced prostate

cancer

• Prostate cancer is the second leading cause of cancer death in American men, behind

lung cancer

• 223Ra targets new bone growth, like Ca

• 223Ra is derived from an 227Ac generator Ac-227

Th-227

Ra-223

↓21.8 yrs

18.7 days

11.4 days

β

↓

α (5.9 MeV)

α (5.7 MeV)225Ra Biodistribution

Ra-225 Biodistribution

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

skull femur sternum kidney spleen liver

%ID

/g

day 1

day 3

day 6

day 9

day 14

day 19

Kennel and Mirzadeh, 2005

38

Ra-226 target design

• Up to 13 pellets can be stacked in a welded-aluminum rabbit for irradiation at HFIR

• Total RaCO3/Al volume: ~1.3 cm3

• Total Ra-226 mass: 0.7 g (0.749 g of RaCO3)

• aluminum mass: 2.748 g

• Ra-226 mass limit based on heat calculations and the target temperature during irradiation (dose rates will limit Ra-226 mass per target to about 600 mg)

Figure 5. Configuration of 13 RaO/Al pellets for irradiation at HFIR. Some of the components

include; 1) finned aluminum rabbit, 2) rabbit end caps (aluminum), 3) fill material – aluminum

foil or quartz wool, and 4) radium oxide pellets (13) – 0.250” diameter and 0.125” thick.

39

New HFIR-HT rabbit design

• Changes were made to the rabbit design to facilitate the in-cell welding process

• The bottom cap will be EB-welded outside of the hot cell • The circumference of the top cap will be welded first

under a helium cover gas • The plug will be welded after evacuating the chamber

and backfilling with high-purity helium (twice)

• Body is aluminum alloy 6061 • End caps are 4047

aluminum (required for welding)

40

TEAM

Rose Boll Roy Copping Sandra Davern David Denton Kevin Gaddis Greg Groover Justin Griswold Suzanne Hogle sm Karen Murphy Allison Owen Shelly Van Cleve Lance Wyant Dominic Giuliano (Design and Manufacturing) Richard Howard (Heat Calculations) Steve Owens (Thermodynamic Measurements)

Students:

Joseph Wright

David O’Neil

Mark Moore

Dan Stracener (Project Manger, accelerator produced Ac-225 and Ac-227) John Krueger (Oversight) s)