ra-224 microparticles free ra-224 ra-224 microparticles · 2019-05-10 · biodistribution of ra-224...
TRANSCRIPT
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
Larg
e bo
wel
Live
r
Femur
s
Sku
ll
Diaph
ragm
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
wel
Live
r
Femur
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