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Kit based sirt agents
1. Kit Based SIRT Agents: Preparation And
Quality Control
Madhava B Mallia
Radiopharmaceuticals Division, Radiochemistry and Isotope Group
Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, INDIA
2. All options: Quick glance…
2
90Y-Glass microspheres
Therasphere®
90Y-resin microspheres
SIR-spheres®
166Ho-PLA microspheres
QuiremSpheres®
Images not to scale…
188ReN-DEDC/Lipiodol188Re-SSS/Lipiodol188Re-HDD/Lipiodol
131I-Lipiodol
6. Options...
6
188Re-HDD/Lipiodol
• Lee YS, Jeong JM, et al. Nucl Med Commun.
2002; 23(3):237-42.
• Paeng JC, Jeong JM, et al. J Nucl Med. 2003
Dec;44(12):2033-8.
ReN kit DEDC
kit
188ReN-DEDC/Lipiodol
• Boschi A, Uccelli L et al. Nucl Med Commun.
2004;25(7):691-9.
188Re-SSS/Lipiodol
• Nicolas Lepareur et al., International Journal of
Molecular Imaging, doi:10.1155/2012/278306
8. 188Re-HDD/Lipiodol...
• HDD evolved from TDD
TDD
(2,2,9,9-Tetramethyl-4,7-diaza-1,10-decanedithiol)
HTDD
(4-Hexadecyl-2,2,9,9-Tetramethyl-4,7-diaza-1,10-
decanedithiol)
8
Jeong JM, Kim YJ, Lee YS, Ko JI, Son M, Lee DS, Chung JK, Park
JH, Lee MC. Lipiodol solution of a lipophilic agent, (188)Re-TDD, for
the treatment of liver cancer. Nucl Med Biol. 2001;28(2):197-204.
Paeng JC, Jeong JM, Yoon CJ, Lee YS, Suh YG, Chung JW, Park JH,
Chung JK, Son M, Lee MC. Lipiodol solution of 188Re-HDD as a new
therapeutic agent for transhepatic arterial embolization in liver cancer:
preclinical study in a rabbit liver cancer model. J Nucl Med. 2003 ;
44(12):2033-8.
12. 12
Preparation: Up to 3 mL of freshly
eluted sodium 188Re-perrhenate
added to AHDD kit vial and heated at
100C for 1 h.
100C, 60 min
AHDD kit
1. Vortex (10 min)
2. Centrifuge (10 min)
3. Separate lipiodol layer
3 mL lipiodol
Preparation of 188Re-HDD/Lipiodol...
14. Centrifuge and separate lipiodol phase...
14
Aqueous
phase
Lipiodol
phase
Automated
procedure for
separation of
lipiodol phase!!
15. Quality control:188Re-HDD/Lipiodol...
15
Banka VK, Moon SH, Jeong JM, Seelam SR, Lee YS, Kim YJ, Lee DS, Chung JK. Development of 4-hexadecyl-4,7-diaza-1,10-decanedithiol (HDD) kit for
the preparation of the liver cancer therapeutic agent Re-188-HDD/lipiodol. Nucl Med Biol. 2015 Mar;42(3):317-22.
Spot the lipiodol extract
17. 188Re-SSS/Lipiodol...
• Garin et al...2004
• 188Re-(S2CPh)(S3CPh)2 complex 188Re-SSS complex
• Higher yield
• Higher extraction into lipiodol compared to 188Re-HDD
• Lower intestinal and urinary excretion compared to 188Re-HDD
17
Garin E, Noiret N, Malbert C, Lepareur N, Roucoux A, Caulet-Maugendre S, Moisan A, Lecloirec J, Herry JY, Bourguet P. Development and biodistribution of
188Re-SSS lipiodol following injection into the hepatic artery of healthy pigs. Eur J Nucl Med Mol Imaging. 2004 Apr;31(4):542-6.
19. Step 1
• Reconstitute vial 1 with 1-2 mL (max.) of freshly
eluted Na188ReO4
• Incubate vial 1 for 15 min at ambient temperature
Step 2
• Reconstitute vial 2 with 0.5 mL of physiological
serum/saline and transfer to vial 1
• Heat vial 1 at 100C for 30 min
19
Preparation of 188Re-SSS/Lipiodol...
1. Vortex (10 min)
2. Centrifuge (10 min)
3. Separate lipiodol layer
3 mL lipiodol
21. 21
Quality control:188Re-SSS/Lipiodol...
Point of spotting Solvent front
188Re-SSS complex
Rf = 0.6
(Representative TLC)
TLC plate - silica/aluminium 60 F254 gel plates (Merck, Darmstadt, Germany)
Sample - 188Re-SSS complex/lipiodol
Developing solvent – Petrolium ether/dichloromethane (6:4 v/v)
22. Extraction efficiency...
22
Labeling efficiency Final Yield
188Re-SSS/Lipiodol 97.3 ±2.1%. 87% ± 9.1
Garin E, Noiret N, Malbert C, Lepareur N, Roucoux A, Caulet-Maugendre S, Moisan A, Lecloirec J, Herry JY, Bourguet P. Development and biodistribution of
188Re-SSS lipiodol following injection into the hepatic artery of healthy pigs. Eur J Nucl Med Mol Imaging. 2004 Apr;31(4):542-6.
23. 188ReN-DEDC/Lipiodol...
Boschi A et al…2004
23
188ReN intermediate
Step 1
+
DEDC ligand
Step 2
188ReN-DEDC complex
• Higher yield
• Higher extraction into lipiodol compared to 188Re-HDD
• Lower intestinal and urinary excretion compared to 188Re-HDD
Features similar to 188Re-SSS complex
Boschi A, Uccelli L, Duatti A, Colamussi P, Cittanti C, Filice A, Rose AH, Martindale AA, Claringbold PG, Kearney D, Galeotti R, Turner JH, Giganti M. A kit formulation for
the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. Nucl Med Commun.
2004 Jul;25(7):691-9. Erratum in: Nucl Med Commun. 2004 Sep;25(9):983.
25. 25
Step 2Step 1
Glacial acetic acid (150 L)
+
Na188ReO4 (up to 3 mL)
KIT 1
Incubate for 30 min
at room
temperature
2 mL saline
KIT 2
1.5 mL of
reconstituted solution
from kit vial 2
KIT 1
80C, 20 min
KIT 1
3 mL lipiodol
KIT 1
1. Vortex (10 min)
2. Centrifuge (10 min)
3. Separate lipiodol
layer
Step 3
Preparation of 188ReN-DEDC/Lipiodol…
Average time for preparation: ~ 60 min
29. Making the kit more user friendly...
29
Step 1
Glacial acetic acid (150
L)
+
Na188ReO4 (up to 3 mL)
Incubate for
30 min at
room
temperature
KIT 1
Original method
DTCz 2 mg
SnCl2.2H2O 0.8 mg
Sodium oxalate 28 mg
pH 3 to 4
DTCz 2 mg
SnCl2.2H2O 0.8 mg
Sodium oxalate 28 mg
Oxalic acid xx mg
pH 3 to 4
Step 1
Modified method
KIT 1
Na188ReO4 (up to 3 mL)
Incubate for
5 min at
room
temperature
30. 30
Kinetics of formation of [188ReN]2+...
188ReN core
188ReO4
-
188ReN core
HPLC of [188ReN]2+ intermediate prepared using oxalate buffer kit
HPLC of [188ReN]2+ intermediate prepared by conventional method
Mallia MB, Chirayil V, Dash A. Improved freeze-dried kit for the preparation of (188)ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma.
Appl Radiat Isot. 2018 Jul;137:147-153.
31. 31
Step 2
2 mL saline
KIT 2
1.5 mL of
reconstituted solution
from kit vial 2
KIT 1
80C, 20 min
KIT 1
3 mL lipiodol
KIT 1
1. Vortex (10 min)
2. Centrifuge (10 min)
3. Separate lipiodol
layer
Step 3
Average time for preparation: ~ 35 min
Save 25 mins!!
188ReN-DEDC complex: Prepared by
conventional kit using glacial acetic acid
188ReN-DEDC complex: Prepared by
oxalate buffer kit
33. 188Re-HDD Vs 188Re-SSS Vs 188ReN-DEDC…
33
188Re-HDD 188Re-SSS 188ReN-DEDC
Commercial availability Yes Yes No (will be available in
India soon)
Manufacturer Seoul National University,
South Korea
Institute for
Radioelements (IRE),
Belgium
Radiopharmaceuticals
division, BARC
Cost ~$294 (in India) ---- ~$ 75 (proposed)
Volume limit (Na188ReO4) 3 mL 2 mL 3 mL
(lab tested up to 4 mL)
Extraction efficiency in
lipiodol (reported)
90.2% ± 2.6 87% ± 9.1 96% ± 3
Extraction efficiency in
lipiodol (Clinical practice,
India)
50 – 55% 65 – 75% 70 – 75%
34. • Rhenium-188 is generator produced
• Availability of freeze-dried kits (multiple options): On demand
preparation possible in hospital radiopharmacy
• No need to keep the patient in isolation
• Moderate to low cost compared to 90Y/166Ho – microsphere
therapy
34
188Re-SIRT Agents: Advantages…
35. 188Re-SIRT Agents: Challenges…
• Cost of 188W/188Re generator
• Limited 188Re-Radiopharmaceuticals for clinical practice
• Competition from TACE and other modalities
• “Too many cooks spoil the broth”: Too many nuclear medicine
centers for 188Re-therapy affects economic viability at individual
centers…
35