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RADIOPARTICLES FOR RADIOSINOVECTOMY

Radiosynovectomy is a radiation therapy for treating rheumatoid arthritis by injecting beta-emitting radionuclides into the synovial tissue. This article explores the ideal radionuclides, particulate carriers, and production methods for effective radiosynovectomy.

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RADIOPARTICLES FOR RADIOSINOVECTOMY

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  1. RADIOPARTICLES FOR RADIOSINOVECTOMY María Graciela Argüelles Centro Atómico Ezeiza, Comisión Nacional de Energía Atómica Buenos Aires, República Argentina

  2. Rheumatoid arthritis • It is an ubiquitous incapacitating disease that places substantial demands on health care resources. • It affects 1% to 2% of the population worldwide, with a woman -to- man prevalence ratio of 3:1. • The characteristic disease manifestations of RA are joint pain, swelling and reduced mobility as a result of the synovial tissue inflammation,

  3. Rheumatoid arthritis any synovial joint in the body can be affected by the disease.

  4. Rheumatoid arthritis Pannus can be considered the most destructive element affecting joints in the patient with rheumatoid arthritis. It can attack articular cartilage and destroy it.

  5. Radiosynovectomy • It consists of intra-articular injection of beta-emitting radionuclide in colloidal or particulate form, which comes into contact with synovium. Phagocytic cells absorb some of the injected dose, which is transmitted to the synovium. • If the amount of radioactivity injected is large enough the tissue will be destroyed. Regenerated tissue will be asymptomatic for 2-5 years. • Compared with surgical synovectomy, the radiation therapy is simpler and less traumatic, hospitalization time is shorter; cost is lower and duration of relief is comparable.

  6. RADIONUCLIDE Ideal radionuclide Pure beta-emitter or beta emitter with minimal gamma emissions. 5 mm < Tissue penetration < 10 mm Short half-life Low cost Chemically pure Non-toxic

  7. Radionuclides Used for Radiation Synovectomy

  8. PARTICULATE CARRIER Ideal particulate carrier It must be taken up by synovial tissue. It must form a stable complex with radionuclide. It must be prepared easily and reproducibly. Non-toxic. Non- allergenic.

  9. Finally, any biologically induced degradation of the agent should ideally release the radionuclide in a chemical form that rapidly egresses from the body.

  10. Radionuclides production Experimental

  11. SAMARIUM-153 PRODUCTION Target material Thermal neutron flux Irradiation time Specific activity 152Sm (98.7 %) nitrate 7.1013 n/cm2s 36 hours 5-10 Gbq/mg

  12. HOLMIUM-166 PRODUCTION Target material Thermal neutron flux Irradiation time Specific activity 165Ho (100 %) nitrate 1.1013 n/cm2s 20 hours 4-5 Gbq/mg

  13. Nuclear purity control Multichannel analyzer with HPGe detector. Gamma ray spectrum was identical to published nuclear data.

  14. PARTICLES PREPARATION Albumin microspheres • The microspheres were obtained by heat denaturalization of a human serum albumin (HSA) emulsion in vegetable oil. A 10 % human albumin solution and olive oil were used. • The HSA solution was added, drop by drop, into the olive oil stirring vigorously. • The emulsion was heated up to 140 -160°C for one hour. • The suspension was cooled and diluted with n-hexane. It was filtrated with mesh 200 in order to discard the particles over 75 µm. The supernatant was filtered thorough membrane filter. • The microspheres were rinsed with acetone and dried.

  15. Particles size measurement It was performed using a optical microscope with micrometric ocular.

  16. Size Distribution Of Microspheres

  17. Electronic microscopy photographies

  18. Hydroxyapatite particles Ca(NO3)2(NH4)2HPO4 A voluminous precipitate was formed. It was allowed to settle and the supernatant solution was discharged. pH 12

  19. Hydroxyapatite particles The precipitate was rinsed with hot water, dried at 150 °C and heated for an hour at 240 °C to remove the ammonium nitrate. By strong heating at 800 °C for an hour, the product becomes largely anhydrous and hardened. The synthesis yield was always greater than 80%.

  20. Size Distribution Of HA Microparticles

  21. Labelling with 153Sm • Labelling was done in two steps: • 153Sm-citrate was prepared by adding sufficient citric acid to the 153SmCl3 solution to give a concentration of 15 mg/ml citric acid in 0,1 N HCl. • The radioactive solution was added to the particulate suspension (20 mg) stirring continuously (30 min, 37 °C). • Radiolabelled particles were rinsed with saline and separated by centrifugation (5 min at 1000 rpm) and labelling efficiency was determined. • The microspheres were resuspended in 2 ml of saline.

  22. Labelling efficiency The radioactive mixture was transferred to a centrifuge tube using 4 ml of saline to rinse, centrifuged at 1000 rpm for 5 minutes. The supernatant was then transferred to another tube. Measurements of radioactivity were made and labelling efficiency was calculated as percentage of initial activity.

  23. 3 days n = 6 6 days n = 6 Cumulative Leakage * 153Sm-HA 153Sm-citrate 0.14+0.13 37.2+1.2 0.32+0.20 42.3+1.0 In vitro stability Stability of the labelled particles was studied in normal saline and 1% albumin solution, at 36°C over 48 hours. Albumin microspheres retained less than 80% of the initial activity after 48 h incubation. HA particles retained radiactivity for 6 days. EXTRA-ARTICULAR LEAKAGE * Blood, liver, kidneys, lungs, bone, urine.

  24. PLA particles HoCl3Acetylacetone Complex Ho(AcAc)3 pH 7 Evaporation Technique Complex + PLA Microsparticles X-ray fluorescence and energy dispersive spectrometry were used to determine the presence of Ho in the particles and complex stoichiometry.

  25. PLA particles The particle size distribution of microspheres was determined by electronic microscopy. Its diameter range was 20 µm.

  26. 166HoCl3 solution FeSO4solution Coprecipitation 166Ho(OH)3 / Fe(OH)3 Macroaggregates were washed twice with PVP solution. Particles were resuspended in saline and sterilized. Obtention Efficiency > 90 %. HOLMIUM-166 FERRIC HYDROXIDE MACROAGGREGATES

  27. Quality control • Radiochemical purity: • ITLC / SG – EDTA • Rf Ho3+ : 1.0 • Rf particles : 0.0 • Size: • light microscopy • serial filtration • In vitro stability: • Saline • EDTA solution • Pharmacological control : • Toxicity • Sterility • Pyrogenicity

  28. Animal model • - Normal New Zealand Rabbits • - Rabbits with antigen-induced arthritis • 0 weeks: intradermic injection of ovoalbumin • 3 weeks: intradermic injection of ovoalbumin

  29. Animal model • 6 weeks: intra-articular injection of ovoalbumin • 7 weeks : synovitis symptoms • Intra-articular injection of 166Ho-FHMA • Gamma camera imaging

  30. Gamma camera images 4 h p.i. Zoom 1.0 Zoom 4.0

  31. Gamma camera images 24 h p.i. Marker 99mTc Zoom 1.0 Body scan

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