Ra-224 microparticles Free Ra-224 Ra-224 microparticles · 2019-05-10 · BIODISTRIBUTION OF RA-224...

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BIODISTRIBUTION OF RA-224 AND ITS PROGENY PB-212 AFTER INTRAPERITONEAL INFUSION OF RA-224 LABELED MICROPARTICLES IN RATS Jesper Fonslet 1 , Carsten H. Nielsen 1,4 , Lotte K. Kristensen 1,4 , Ida S. Jorstad 2 , Kim Lindland 2 , Roy H. Larsen 2 , Øyvind S. Bruland 3 , Andreas Kjaer 1,4 and Tina B. Bønsdorff 2 1 Minerva Imaging, Copenhagen, Denmark 2 Oncoinvent, Oslo, Norway 3 Oslo University Hospital, Oslo, Norway 4 Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark High peritoneal retention of both Ra-224 and its progeny Pb-212 after IP injection of Ra-224 labeled CaCO 3 microparticles, was found in rats with assumed high translational value to the clinical setting SPECT and planar imaging demonstrated that distribution of the Ra-224 labeled microparticles occur to the entire peritoneal lumen in the animals. SPECT and CT revealed some clusters of the labeled microparticles Due to the short range of the therapeutically active alpha-particles, the clusters are not expected to have an impact on safety of the product Abstract # 3922 Conclusion Results Materials and methods Background and Objectives Fifteen female Wistar rats were infused IP with Ra-224-labeled microparticles (200-400 kBq, 100 mg CaCO 3 , 1 mL + 3 mL Plasmalyte flush) via a multi-hole pigtail catheter Four female Wistar rats were infused IP with free Ra-224 (200- 400 kBq, RaCl 2 ) as a reference for uptake of released Ra-224 The Ra-224 labeled microparticles were imaged using both planar gamma imaging, SPECT and CT to evaluate the distribution over time in the abdominal region Longitudinal ex vivo biodistribution was performed after microparticle infusion and organs were harvested for activity measurements Planar gamma imaging was successful in visualizing the IP distribution of microparticles, with the hotspots identified as aggregates both in SPECT and under visual inspection ex vivo. Bottom left shows a representative image with little aggregation in the SPECT. The planar gamma images of the same animal showed fairly uniform exposure top left. Bottom right shows high levels of aggregation seen in only one rat. In the planar gamma image top right, this shows as a very high contrast between hotspots and background. All three modalities, planar gamma imaging, SPECT and CT were able to visualize the microparticle distribution. The graph illustrates the method of measurement of both Ra-224 and Pb-212. Only the Pb-212 daughter has usable gamma emission. Therefore initial measurement of organs yield the Pb-212 activity present in the organs at the time of euthanasia. Remeasurement 48 hours post mortem, allowed the initial Pb- 212 to decay and the ingrowing Pb-212 to reach equilibrium with Ra-224. The second measurement represents therefore Ra-224. 0 2 4 6 8 0.0 0.5 1.0 Time (d) A Ra-224 Pb-212 ingrowth Pb-212 initial Pb-212 Ra-224 0 100 200 300 400 0.0 0.5 1.0 1.5 Femur Ra-224 uptake Time (h) Ra-224 %ID/g Both CT and SPECT images show distribution of the infused microparticles to the entire peritoneum albeit with local areas of high microparticle concentration Modest but evident systemic leakage of Ra-224 from the microparticles in the peritoneal cavity was observed Based on the bone uptake of Ra-224, the retention of Ra-224 in the peritoneal cavity was found to be > 87% at 24 hours and > 77% at 168 hours Redistribution of the progeny Pb-212 was observed as modest uptake in the kidneys Designed to be administered intra- peritoneally (IP) following cyto-reductive surgery Designed to confine radiation exposure to the peritoneal cavity while treating both the linings of the peritoneal surfaces and liquid volumes The distribution of the Ra-224 labeled microparticles was examined using planar gamma imaging, SPECT and CT The ex vivo biodistribution of Ra-224 and its progeny Pb-212 was determined Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femurs Skull Diaphragm Peritoneum IP fat 0 1 2 3 Ra-224 %ID/g Ra-224 microparticles 2 h 24h 96 h 168 h 336 h Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femurs Skull Diaphragm Peritoneum IP fat 0 1 2 3 Pb-212 %ID/g Ra-224 microparticles 2 h 24h 96 h 168 h 336 h 2 hours 24 hours 2 hours 24 hours 5 cm 5 cm In-111 setting Tl-201 setting 2 hours 2 hours This novel alpha-therapy Radspherin ® , consisting of bio- degradable radium-224-labeled calcium carbonate (CaCO 3 ) microparticles, was developed with the intent to treat micrometastases located in the abdominal cavity Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femur Scull Diaphragm Peritoneum Ip. Fat 0 1 2 3 Free Ra-224 Ra-224 %ID/g 24 hours 7 days Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femur Scull Diaphragm Peritoneum Ip. Fat 0 1 2 3 Ra-224 microparticles Ra-224 %ID/g 24 hours 7 days Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femur Scull Diaphragm Peritoneum Ip. Fat 0 1 2 3 Ra-224 microparticles Pb-212 %ID/g 24 hours 7 days Urine Blood Kidneys Spleen Stomach Small bowel Large bowel Liver Femur Scull Diaphragm Peritoneum Ip. Fat 0 1 2 3 Free Ra-224 Pb-212 %ID/g 24 hours 7 days

Transcript of Ra-224 microparticles Free Ra-224 Ra-224 microparticles · 2019-05-10 · BIODISTRIBUTION OF RA-224...

Page 1: Ra-224 microparticles Free Ra-224 Ra-224 microparticles · 2019-05-10 · BIODISTRIBUTION OF RA-224 AND ITS PROGENY PB-212 AFTER INTRAPERITONEAL INFUSION OF RA-224 LABELED MICROPARTICLES

BIODISTRIBUTION OF RA-224 AND ITS PROGENY PB-212 AFTER INTRAPERITONEAL INFUSION OF RA-224 LABELED MICROPARTICLES IN RATS

Jesper Fonslet1, Carsten H. Nielsen1,4, Lotte K. Kristensen1,4, Ida S. Jorstad2, Kim Lindland2, Roy H. Larsen2, Øyvind S. Bruland3, Andreas Kjaer1,4 and Tina B. Bønsdorff2

1Minerva Imaging, Copenhagen, Denmark2Oncoinvent, Oslo, Norway 3Oslo University Hospital, Oslo, Norway

4Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark

• High peritoneal retention of both Ra-224 and its progeny Pb-212 after IP injection of Ra-224 labeled CaCO3 microparticles, was found in rats with assumed high translational value to the clinical setting

• SPECT and planar imaging demonstrated that distribution of the Ra-224 labeled microparticles occur to the entire peritoneal lumen in the animals. SPECT and CT revealed some clusters of the labeled microparticles

• Due to the short range of the therapeutically active alpha-particles, the clusters are not expected to have an impact on safety of the product

Abstract # 3922

Conclusion

Results

Materials and methods

Background and Objectives

• Fifteen female Wistar rats were infused IP with Ra-224-labeled

microparticles (200-400 kBq, 100 mg CaCO3, 1 mL + 3 mL

Plasmalyte flush) via a multi-hole pigtail catheter

• Four female Wistar rats were infused IP with free Ra-224 (200-

400 kBq, RaCl2) as a reference for uptake of released Ra-224

• The Ra-224 labeled microparticles were imaged using both

planar gamma imaging, SPECT and CT to evaluate the

distribution over time in the abdominal region

• Longitudinal ex vivo biodistribution was performed after

microparticle infusion and organs were harvested for activity

measurementsPlanar gamma imaging was successful in visualizing the IP distribution of microparticles, with the hotspots identified as

aggregates both in SPECT and under visual inspection ex vivo. Bottom left shows a representative image with little

aggregation in the SPECT. The planar gamma images of the same animal showed fairly uniform exposure top left. Bottom

right shows high levels of aggregation seen in only one rat. In the planar gamma image top right, this shows as a very high

contrast between hotspots and background. All three modalities, planar gamma imaging, SPECT and CT were able to

visualize the microparticle distribution.

The graph illustrates the method

of measurement of both Ra-224

and Pb-212. Only the Pb-212

daughter has usable gamma

emission. Therefore initial

measurement of organs yield the

Pb-212 activity present in the

organs at the time of euthanasia.

Remeasurement 48 hours post

mortem, allowed the initial Pb-

212 to decay and the ingrowing

Pb-212 to reach equilibrium with

Ra-224. The second

measurement represents

therefore Ra-224.0 2 4 6 8

0.0

0.5

1.0

Time (d)

A

Ra-224

Pb-212 ingrowth

Pb-212 initial

Pb-2

12

Ra-2

24

0 100 200 300 400

0.0

0.5

1.0

1.5

Femur Ra-224 uptake

Time (h)

Ra-2

24 %

ID/g

• Both CT and SPECT images show distribution of the infused microparticles to the

entire peritoneum albeit with local areas of high microparticle concentration

• Modest but evident systemic leakage of Ra-224 from the microparticles in the

peritoneal cavity was observed

• Based on the bone uptake of Ra-224, the retention of Ra-224 in the peritoneal

cavity was found to be > 87% at 24 hours and > 77% at 168 hours

• Redistribution of the progeny Pb-212 was observed as modest uptake in the

kidneys

• Designed to be administered intra-

peritoneally (IP) following cyto-reductive

surgery

• Designed to confine radiation exposure

to the peritoneal cavity while treating

both the linings of the peritoneal surfaces

and liquid volumes

• The distribution of the Ra-224 labeled

microparticles was examined using

planar gamma imaging, SPECT and CT

• The ex vivo biodistribution of Ra-224 and

its progeny Pb-212 was determined

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

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e bo

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Live

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s

Sku

ll

Diaph

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Per

itone

umIP

fat

0

1

2

3

Ra-2

24

%ID

/g

Ra-224 microparticles

2 h

24h

96 h

168 h

336 h

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

Larg

e bo

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Live

r

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s

Sku

ll

Diaph

ragm

Per

itone

umIP

fat

0

1

2

3

Pb

-21

2 %

ID/g

Ra-224 microparticles

2 h

24h

96 h

168 h

336 h

2 hours 24 hours 2 hours 24 hours

5 cm5 cm

In-1

11

set

tin

gTl

-20

1 s

etti

ng

2 hours 2 hours

• This novel alpha-therapy Radspherin®, consisting of bio-

degradable radium-224-labeled calcium carbonate (CaCO3)

microparticles, was developed with the intent to treat

micrometastases located in the abdominal cavity

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

Larg

e bo

wel

Live

r

Femur

Scu

ll

Diaph

ragm

Per

itone

um

Ip. F

at0

1

2

3Free Ra-224

Ra

-224 %

ID/g

24 hours

7 days

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

Larg

e bo

wel

Live

r

Femur

Scu

ll

Diaph

ragm

Per

itone

um

Ip. F

at0

1

2

3Ra-224 microparticles

Ra

-224 %

ID/g

24 hours

7 days

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

Larg

e bo

wel

Live

r

Femur

Scu

ll

Diaph

ragm

Per

itone

um

Ip. F

at0

1

2

3Ra-224 microparticles

Pb

-21

2 %

ID/g

24 hours

7 days

Urin

e

Blood

Kidne

ys

Splee

n

Sto

mac

h

Sm

all b

owel

Larg

e bo

wel

Live

r

Femur

Scu

ll

Diaph

ragm

Per

itone

um

Ip. F

at0

1

2

3Free Ra-224

Pb

-21

2 %

ID/g

24 hours

7 days