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Open Access Highly Accessed Research article

188Re radiopharmaceuticals for radiosynovectomy: evaluation and comparison of tin colloid, hydroxyapatite and tin-ferric hydroxide macroaggregates

Eduardo Savio1*, María Cristina Ures1, Patricia Zeledón2, Victoria Trindade1, Andrea Paolino1, Virginia Mockford1, Antonio Malanga3, Marcelo Fernández1 and Javier Gaudiano4

Author Affiliations

1 Cátedra de Radioquímica. Facultad de Química. Universidad de la República. Montevideo, Uruguay

2 Servicio de Medicina Nuclear. Hospital San Juan de Dios. San José de Costa Rica, Costa Rica

3 Cátedra de Farmacotecnia. Facultad de Química. Universidad de la República. Montevideo, Uruguay

4 Centro de Medicina Nuclear. Hospital de Clínicas. Facultad de Medicina. Universidad de la República. Montevideo, Uruguay

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BMC Nuclear Medicine 2004, 4:1  doi:10.1186/1471-2385-4-1

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2385/4/1


Received:7 November 2003
Accepted:30 January 2004
Published:30 January 2004

© 2004 Savio et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Abstract

Background

Radiosynovectomy is a therapy used to relieve pain and inflammation from rheumatoid arthritis and related diseases. In this study three 188Re particulate compounds were characterized according to their physico-chemical properties and their biological behavior in rabbits. The results were compared in order to establish which was the radiopharmaceutical that better fits the requirements of this kind of radiotherapy.

Methods

Three radiopharmaceutical formulations, tin colloid, hydroxyapatite particles (HA) and ferric hydroxide macroaggregates coated with tin colloid (FHMA), were physically characterized (number, volume and surface of the particles). For this purpose laser diffraction methodology was used. To evaluate cavity leakage of activity the following studies in New Zealand rabbits were performed: scintigraphic images for 48 hr after intraarticular injection of each radiopharmaceutical, biodistribution at 48 hr and urine samples collection during the first 24 hr post-radiopharmaceutical administration.

Results

Labeling procedures for 188Re-HA and 188Re-Sn-FHMA were labour intensive while 188Re-Sn was easily prepared. Furthermore, 188Re-Sn colloid offered the greatest surface area in the 2–10 microm range and was obtained with a radiochemical purity over 95%, while percentage of bound activity for 188Re-HA and 188Re-Sn-FHMA were 55% and 92% respectively. Stability was verified for the three radiopharmaceuticals for 24 hr. Scintigraphic studies and biodistribution in rabbits after intraarticular administration of the radiopharmaceuticals showed relevant activity only in the knee, this being over 90% of the residual activity in the whole body at 48 hr in every case. Renal elimination of 188Re-Sn colloid and 188Re-Sn-FHMA was detected by activity measurements in urine samples, during the first 12 hr post-radiopharmaceutical injection.

The percentage of activity retained in the knee was 69.1% for 188Re-Sn colloid, 55.1% for 188Re-Sn-FHMA and 33.6% for 188Re-HA.

Conclusion

The 188Re-Sn colloid was easy to prepare, minimum facilities were required, was stable for 24 hr and showed minimal leakage from the joint after intraarticular injection into the rabbit's knee. Furthermore, 188Re-Sn colloid has greater retention in the knee when it is compared with the other radiopharmaceuticals, so it could provide the best therapeutic effect/absorbed dose ratio for the patient.

Background

Three principal diseases associated with synovia hypertrophy are rheumatoid arthritis, hemophilic joint disease (principally related to bleeding into the joint), and some cases of traumatic joint disorders. The number of hemophilic patients is relatively small. In contrast, rheumatoid arthritis affects 1–2% of the world's population with a preponderance of men over women [1,2]. Cellular recruitment and proliferation, with subsequent formation of synovial granulation tissue (pannus) and an increased secretion of synovial fluid characterize the inflammatory process. Progression of the disease leads to the destruction of the joint or loss of function. Surgery is the last option as a conventional technique for treating intractable joint disease after pharmacological therapies have failed, but removal of all the tissue is not frequently achieved and so there is high recurrence after 3 to 5 years [2]. Radiation synovectomy provides an interesting alternative because cartilage is relatively radioresistent, so a radioactive agent with effective soft tissue penetration can be administered directly into the joint, causing no harm to the adjacent cartilage. As beta radiation can penetrate only a few hundred cell diameters, microparticles labeled with beta emitting radionuclides are effective in treating the disease by radiation in confined spaces without endangering nearby normal tissues [2]. Radiopharmaceutical particle size must be small enough to be phagocyted by the superficial cells of the sinovium, but not so small as to facilitate a fast biological clearance by diffusion from the joint [2,3].

Many beta emitters, and many other particulate chemical compounds have been used as radiosynovectomy agents [4-6]. In this study 188Re is the chosen radionuclide as it is readily available on routine basis from the 188W/188Re generator. The radionuclide 188Re, has a β-ray emission of sufficient energy (2.11 MeV) to penetrate 5–10 mm of thickened synovial membrane, and its low-level γ-ray emission (155 keV) makes scintigraphic monitoring possible, without harming patients or practitioners. Its half-life (16.9 hr) is adequate in terms of obtaining an appropriate therapeutic effect or for handling of the agent, avoiding hazardous residual effects.

In this study, particulate chemical compounds such as tin colloid, hydroxyapatite particles and ferric hydroxide macroaggregates were compared from the physico-chemical and biological point of view.

The most important criteria of therapeutically useful radiolabeled microparticles are their physico-chemical characteristics such as size range, surface area and volume, insolubility in aqueous media and irreversible attachment of radionuclide to the particles [1,2,7]. The best method of particle size determination is electron microscopy and more recently laser scattering, both of which provide information on particle number, size and size distribution. The last of these is used in this study.

Radiopharmaceutical leakage from the knee was evaluated by the acquisition of scintigraphic images over 48 hr after intraarticular administration of the radiolabeled preparations to New Zealand rabbits. Biodistribution studies were also performed.

The results were compared in order to establish which was the radiopharmaceutical that best fits the requirements of this kind of therapy.

Methods

Radiopharmaceutical composition

Four radiopharmaceutical kits were prepared according to the following formulations:

188Re-Tin colloid [8]

• 15 mg SnCl2.2H2O

• 0.5 mL HCl 0.1 N

• N2 atmosphere

188Re-Hydroxyapatite particles (Indirect method) [1]

First step: preparation of 188Re-HEDP kit

• 10 mg HEDP (free acid)

• 3 mg gentisic acid

• 0.3 mg KReO4

• 3.8 mg SnCl2.2H2O

Second step: preparation of 188Re-Hydroxyapatite (HA) particles kit:

• 40 mg Hydroxyapatite (Ceramed, Type II, 20 um, CAT N° 157-2000)

• 650 μL 0.9% saline solution

• 50 μL of 20% Tween 80 (in water)

• 100 μL of SnCl2.2H2O solution (4 mg/mL)

• N2 atmosphere

188Re-Hydroxyapatite particles (Direct method) [9]

• 40 mg Hydroxyapatite (Ceramed, Type II, 20 μm, CAT N° 157-2000)

• 20 mg SnCl2.2H2O

• 13.7 mg K2C2O4.H2O

pH was adjusted to 1.5 with HCl 0.75 N

188Re-Ferric Hydroxide Macroaggregates, modified from Castro M, Portilla A. [10]

First step: preparation of 188Re-Tin colloid:

• 15 mg SnCl2.2H2O

• 0.5 mL HCl 0.1 N

• N2 atmosphere

Second step: preparation of 188Re-Ferric Hydroxide Macroaggregates (FHMA):

• 1.8 mL FeSO4.7H2O (7.36 mg/mL)

• 0.7 mL NaOH 0.1 N

• 1.1 mL 0.9% saline solution

• 0.6 mL PVP K30 (16 mg/mL)

• 3 mL PVP K30 (16 mg/mL) pH 8.5

All reagents used were analytical grade.

Equipment

• Dose calibrator system: Capintec Radioisotope Calibrator CRC 5

• Solid scintillation counter NaI(Tl) 3 × 3": EG&G ORTEC Multichannel Analyzer

• Particle size analyzer: Particle Size Analyzer Coulter ®

• Gammacamera: Sophy Camera DSX

Labeling procedure and quality control

The 188Re used in all formulations were eluted from a 188W/188Re generator (Oak Ridge Laboratories, United States).

188Re-Tin colloid

The 188Re-Sn colloid was labeled by the addition of 500 μCi (18.5 MBq) of 188ReO4- to the kit formulation described above, then it was autoclaved for 1 hour. pH was adjusted to 6.0 with the addition of NaOH 1.0 N.

Radiochemical purity was determined by paper chromatography (Whatmann 1) using 0.9% saline solution as the mobile phase. Radioactivity was measured with a NaI(Tl) solid scintillation counter.

188Re-Hydroxyapatite particles (Direct method)

40 mg of hydroxyapatite particles were mixed in a centrifuge tube with 13.7 mg K2C2O4.H2O and 20 mg SnCl2.2H2O with 0.3 mL of distilled water. 3 mCi (111 MBq) of 188ReO4- (contained in 0.4 mL) was added to the tube. The pH of the reaction mixture was made acidic (pH 1.5) by slow addition of HCl 0.75 N. The suspension was vortexed and incubated at room temperature for 1 hour. 1 mL of ascorbic acid (10 mg/mL) was added to the suspension at the end of the hour and was centrifuged at 2000 rpm for 2 minutes. Activity in supernatant and particles was measured in a dose calibrator system. The particles were washed twice with 2 mL of ascorbic acid. The activity of the particles and washings was also measured. The final suspension was made in ascorbic acid (10 mg/mL, pH 5).

The percentage of bound activity was determined by measuring the activity of both particles and supernatant solution in a dose calibrator. From these data the percentage of labeled particles yield was calculated.

188Re-Hydroxyapatite particles (Indirect method)

First step: preparation of 188Re-HEDP. 188Re-HEDP was prepared by adding 1 mL of a 188ReO4- solution (11 mCi / 414 MBq) to a vial containing the lyophilized HEDP kit formulation described above (pH ≈ 1). The solution was heated in a water bath for 10 minutes at 100°C.

Radiochemical purity of 188Re-HEDP was determined by the paper chromatography method using a solution of HEDP 0.01 M in saline/Whatmann 3 MM and acetone/Whatmann 1 to determine 188ReO4-, 188Re-HEDP and reduced hydrolyzed 188Re species respectively.

Second step: preparation of 188Re-HA. 188Re-Hydroxyapatite particles were prepared by sequential addition of the following materials to a centrifuge tube containing 40 mg of hydroxyapatite particles: 650 μL of N2-purged saline, 200 μL of 188Re-HEDP (4 mCi / 148 MBq), 50 μL of 20% Tween 80 in water and 100 μL of a N2-purged SnCl2.2H2O solution (4 mg/mL). The mixture was incubated for 1 hour at room temperature with occasional stirring. 4 mL of saline solution was added to the contents of the tube and then centrifuged at 2000 rpm for 4 minutes. The supernatant and the particles were separated. The 188Re-Hydroxyapatite particles were resuspended with 3 mL of saline solution.

The percentage of bound activity was determined by measuring the activity of both particles and supernatant solution in a dose calibrator. From these data the percentage of labeled particles yield was calculated.

188Re-Sn-Ferric Hydroxide Macroaggregates

First step: preparation of 188Re-Sn colloid: The 188Re-Sn colloid was labeled by the addition of 500 μCi (18.5 MBq) of 188ReO4- to the kit formulation described above, then it was autoclaved for 1 hour.

Radiochemical purity was determined by paper chromatography (Whatmann 1) using 0.9% saline solution as the mobile phase. Radioactivity was measured with a NaI(Tl) solid scintillation counter.

pH was adjusted to 7 with NaOH 1.0 N.

Second step: preparation of 188Re-FHMA: 1 mL of 188Re-Sn colloid and 1.8 mL of ferrous sulfate solution (7.36 mg/mL) were mixed in a centrifuge tube, 0.7 mL of NaOH 0.1 N and 1.1 mL of saline solution were added. The contents of the tube were vortexed for 10 seconds. 0.6 mL of Polivinylpirrolidone (PVP) solution (16 mg/mL) were added, vortexed and centrifuged at 1400 rpm for 4 minutes.

The precipitate particles were separated and the labeled FHMA were washed as follows.

188Re-FHMA were mixed with 3 mL of a PVP solution (16 mg/mL, pH 8.5), vortexed and centrifuged at 1400 rpm for 4 minutes. The supernatant and the macroaggregate were separated and the activity of both was measured in a dose calibrator.

The 188Re-FHMA was resuspended in 1.5 mL of saline solution and 1.0 mL of phosphate buffer 0.2 M (pH 7.5).

The percentage of bound activity was determined by measuring the activity of both precipitate and supernatant solution in a dose calibrator system. From these data the percentage of FHMA labeled yield was calculated.

Physical characterization of the radiopharmaceuticals

Non-radioactive forms of the radiopharmaceuticals were prepared using tracer quantities of potassium perrhenate in saline solution in volumes and concentrations corresponding to those of generator eluate.

The number, volume and area of the radiopharmaceuticals particles were analyzed with a laser diffraction particle size analyzer. Particles size were grouped in the following ranges, <2 μm, 2–10 μm, 10–40 μm and >40 μm.

Stability studies

In vitro and in vivo stability studies were performed for the 188Re-Sn colloid, 188Re-HA particles (Direct method) and for the 188Re-Sn-FHMA.

In vitro stability studies

Each radiopharmaceutical was kept at room temperature or at 37°C for 2 and 24 hr after labeling. Stability of 188Re-Sn colloid, 188Re-HA particles and 188Re-Sn-FHMA was assessed in saline solution, ascorbic acid (pH 5)/human serum and saline solution/human serum, respectively. In every case the percentage of bound activity was measured.

In vivo stability studies

Urine samples were collected during the first 24 hr post-radiopharmaceutical administration.

Biodistribution in New Zealand adult male rabbits (4 kg weight) was performed. The animals were sacrificed with an overdose of sodium thiopenthal after 48 hr of intraarticular administration of 188Re-Sn colloid, 188Re-HA direct method and 188Re-Sn-FHMA (1 mCi/mL).

Knee joint, thyroid, heart, urinary bladder, gall bladder, liver, spleen, lungs, stomach, intestines, kidney, muscle, bone, blood and urine samples were collected and radioactivity was measured in a scintillation counter.

Scintigraphic studies

The New Zealand rabbits were anesthetized by intramuscular administration of 50 mg/kg of ketamine and 10 mg/mL of xilazine. Scintigraphic images were acquired with a Sophy Camera DSX, with medium energy collimator, at 0, 24 and 48 hr after intraarticular administration of each radiopharmaceutical.

Table 1. Radiopharmaceutical stability during 24 hr after labeling as percentage

Results

Labeling procedures

188Re-Sn colloid was obtained with a radiochemical purity over 95% and was stable for 24 hr, as was previously reported [11].

188Re-HA was labeled according to Chinol M. procedure [1]. The first step which consisted in 188Re-HEDP preparation, was successfully achieved (radiochemical purity over 99%). However in the second step the percentage of bound 188Re-HA was not higher than 5%. In consequence a second technique called "direct method" was adopted, similar to that described by Kothari et al [9] with minor modifications. In this case the percentage of bound activity was 55% (n = 3).

188Re-Sn-FHMA was first labeled according to the procedure used with 195Dy described by Castro M and Portilla A [10]. The percentage of bound activity obtained with this procedure was 1.2%. A technique in two steps introducing tin as a reducing agent improved the labeling yields to 91.8% (n = 3).

Physical characterization of the radiopharmaceuticals

There are no significant differences between the radiopharmaceuticals formulated taking into account number and volume of the particles that are in the critical range (less than 2 micrometers and over 40 micrometers) as can be seen in Table 2. However differences arise when we study the surface area of each formulation analyzed.

Table 2. Radiopharmaceutical particles distribution according to size, volume and surface

Stability studies

In vitro stability studies

Stability studies for 188Re-Sn were carried out in saline solution, showing that the radiopharmaceutical was stable for 24 hr at room temperature (Table 1).

For 188Re-HA the stability studies were carried out in human serum and ascorbic acid, showing that the radiopharmaceutical was stable for 24 hr at 37°C (Table 1).

Stability studies for 188Re-Sn-FHMA in saline solution and human serum were performed, showing that the radiopharmaceutical was stable for 24 hr at 37°C (Table 1).

In vivo stability studies

Renal elimination of 188Re-Sn colloid and 188Re-Sn-FHMA was detected by activity measurements in urine samples during the first 12 hr post-radiopharmaceutical injection.

Activities per gram of selected tissue/organs including the knee joint after 48 hr of the radiopharmaceutical intraarticular administration to New Zealand rabbits are shown in Table 3.

Table 3. Radiopharmaceutical biodistribution at 48 hr after injection

The percentage of activity retained in the knee joint for each radiopharmaceutical at 48 hr post injection was over 90% of residual activity in the whole body (Figure 1).

thumbnailFigure 1. Percentage of residual whole body activity in the knee joint at 48 hr post-administration.

Nevertheless the percentage of injected activity in the knee joint after 48 hr for each radiopharmaceutical was significantly different. The 188Re-Sn colloid had the highest percentage of retention in the knee joint (Figure 2).

thumbnailFigure 2. Percentage of injected activity in the knee joint at 48 hr post-administration.

Scintigraphic studies

The scintigraphic images of the rabbits, at 0, 24 and 48 hr post administration, indicate relevant activity only in the knee, and negligible activity in the rest of the organism for each formulation (Figure 3).

thumbnailFigure 3. Scintigraphic images at 0, 24 and 48 hr for 188Re-Sn, 188Re-Sn-FHMA and 188Re-HA.

Discussion

The labeling procedures for 188Re-HA and 188Re-Sn-FHMA included multiple centrifugation and separation steps. In both cases modifications from previous techniques had to be adopted to improve the percentage of bound activity to the particles. For 188Re-HA a two step procedure (used for Samarium-153 and Rhenium-186 labeled hydroxyapatite) [1] was discarded and a direct labeling technique was tried [9], that improved the percentage of bound activity from less than 5% to over 55%.

For the ferric hydroxide macroaggregates labeling a procedure originally developed for 195Dy was followed. This method did not succeed for 188Re (less than 2% of bound activity) because of the differences in reduction potentials of the two radionuclides. Therefore several reducing agents were tested and the best results were obtained with the two step procedure using tin to reduce the 188ReO4- prior to the labeling (coating) of the ferric hydroxide macroaggregate (over 90% of bound activity was obtained).

The labeling procedures for both 188Re-HA and 188Re-Sn-FHMA was time consuming and difficult to perform in a nuclear medicine facility in sterile conditions. On the other hand the 188Re-Sn colloid is easily labeled in sterile conditions with high radiochemical purity (over 95%) and was stable for a 48 hr period.

It has been well established in previous works [8] that radiopharmaceutical particle size must be small enough to be phagocyted by the superficial cells of the sinovium (<40 μm) but not so small as to facilitate fast biological clearance by diffusion from the joint (>2 μm). For each of the radiopharmaceuticals tested, the activity remaining in the knee joint at 48 hr represented over 90% of the activity detected in the whole body, with no significant levels being detected in other tissues or organs, including liver and spleen.

Therefore any radiopharmaceutical not remaining in the knee joint must be rapidly excreted. This was confirmed by activity renal clearance during the first 12 hr, probably associated with very small particles, much less than 2 μm.

However the percentage of injected activity in the knee joint was significantly different for the preparations tested. The 188Re-Sn colloid had the highest retention (69.5%) followed by 188Re-Sn-FHMA (55.1%) and finally 188Re-HA particles (33.6%) (Figure 2).

Both 188Re-Sn colloid and 188Re-HA particle results were in agreement with the distribution percentage according to the surface area criteria (Table 2). It can be seen for the tin colloid that the greatest percentage surface area corresponds to the 2 to 10 micrometers range. 188Re-HA had the biggest loss of the injected activity because 53% of the surface area corresponds to particles of less than 2 μm which could leak from the joint.

Nevertheless apparently anomalous values were obtained for 188Re-Sn-FHMA distribution (surface area criteria, Table 2) where only 22% of the particle surface corresponds to the range lower than 2 μm and the residual activity in the knee was 55% instead of 80%. The ferric hydroxide radiopharmaceutical is actually a macroaggregate coated by a tin colloid as it was observed by electronic microscopy of HSA microspheres labeled with 188Re [12]. The macroaggregate labeling (coating) may be achieved by a combination of the reduction of 188ReO4- by tin and a particle surface related co precipitation effect of a ferric hydroxide macroaggregate with a tin colloid. The dissociation of 188Re-Sn from the ferric hydroxide macroaggregate could happen in a certain range, and as a consequence we postulated that the fraction smaller than 2 μm could leak from the joint. So actually the leakage of 188Re-Sn-FHMA would be by ferric hydroxide macroaggregates smaller than 2 micrometers and the 188Re-Sn colloid dissociated with a size of less than 2 μm.

We found that the range from 2 to 10 micrometers was the optimum because the particles were phagocyted and remained in the target area for at least 48 hr.

From the point of view of the radiological security of the patient, the best radiopharmaceutical is that one with a greater percentage of the injected dose retained in the joint because a smaller activity amount had to be injected to obtain the desired radiation dose. This fact takes into account radioprotection principles for the patient in order to minimize absorbed dose. The three formulations tested had rapid renal clearance and showed negligible retention in other tissues or organs other than the knee. Therefore 188Re-Sn which had the greatest retention in the knee (69.1%) was the radiopharmaceutical that could give the desired effect with the lowest absorbed dose in the patient's whole body.

Conclusions

188Re-Sn could be selected as the best formulation for synovectomy therapy taking into account ease of labeling procedure, kit formulation, minimum facilities required, suitable physical and biological characteristics and the lowest absorbed dose for the patient. Because of this the highest benefit/risk relation was found for 188Re-Sn in comparison with 188Re-Sn-FHMA and 188Re-HA.

Competing interests

None declared.

Authors' contributions

ES planned the study, coordinated it and drafted the manuscript.

MCU participated in the design of the radiopharmaceutical, carried out pharmaceutical experiments and drafted the manuscript.

PZ carried out pharmaceutical experiments and also drafted the manuscript.

VT carried out pharmaceutical experiments.

AP carried out the scintigraphic studies.

VM carried out pharmaceutical experiments.

AM performed the Coulter Analizer determinations.

MF performed the experimental animal studies.

JG was responsible for scintigraphic studies.

All authors read and approved the final manuscript.

Acknowledgements

The authors wish to thank:

- PEDECIBA Química for its financial support.

- Dr. Mercedes Mendoza de García (Fundación Cardioinfantil, Instituto de Cardiología. Bogotá, Colombia) for her collaboration.

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