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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1117-1123

Samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid: A novel agent for bone pain palliation therapy


1 Nuclear Science and Technology Research Institute, Tehran, Iran
2 Faculty of Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran

Date of Web Publication4-Jan-2017

Correspondence Address:
Hassan Yousefnia
Nuclear Science and Technology Research Institute, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.197534

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 > Abstract 

Aim: Various phosphonate ligands labeled with β-emitting radionuclides have shown good efficacy for bone pain palliation. In this study, a new agent for bone pain palliation has been developed.
Materials and Methods: Samarium-153-(4-[((bis(phosphonomethyl))carbamoyl)methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (153Sm-BPAMD) complex was prepared using BPAMD ligand and samarium-153 chloride. The effect of various parameters on the labeling yield of 153Sm-BPAMD including ligand concentration, pH, temperature, and reaction time were studied. Production of 153Sm was performed at a research reactor using 152Sm (n, γ)153Sm nuclear reaction. The radiochemical purity of the radiolabeled complex was checked by instant thin layer chromatography. Stability studies of the complex in the final preparation and the presence of human serum were performed up to 48 h. Partition coefficient and hydroxyapatite (HA) binding of the complex were investigated and biodistribution studies using single photon emission computed tomography (SPECT) and scarification were performed after injection of the complex to wild-type mice.
Results: 153Sm-BPAMD was prepared in a high radiochemical purity >98% and specific activity of 267 GBq/mmol at the optimal conditions. The complex demonstrated significant stability at the room temperature and in human serum at least for 48 h. HA binding assay demonstrated that at the amount of more than 5 mg, approximately, all radiolabeled complex was bind to HA. At the pH 7.4, log Po/w was − 1.86 ± 0.02. Both SPECT and scarification showed major accumulation of the labeled compound in the bone tissue.
Conclusions: The results show that 153Sm-BPAMD has interesting characteristics as an agent for bone pain palliation, however, further biological studies in other mammals are still needed.

Keywords: (4-[((bis(phosphonomethyl)) carbamoyl) methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid, bone metastases, bone pain palliation, samarium-153


How to cite this article:
Yousefnia H, Enayati R, Hosntalab M, Zolghadri S, Bahrami-Samani A. Samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid: A novel agent for bone pain palliation therapy. J Can Res Ther 2016;12:1117-23

How to cite this URL:
Yousefnia H, Enayati R, Hosntalab M, Zolghadri S, Bahrami-Samani A. Samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid: A novel agent for bone pain palliation therapy. J Can Res Ther [serial online] 2016 [cited 2017 Feb 24];12:1117-23. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1117/197534


 > Introduction Top


Skeletal metastases are unfortunately common and develops in up to 70% of patients with prostate and breast cancers, and in up to 30% of those with cancers of the lung, bladder, and thyroid.[1],[2] In patients who have progressive disease despite treatment, a systemic bone-avid radiopharmaceutical for the treatment of widespread bony metastases has potential benefit.[3] For this purpose, various phosphonate ligands labeled with β-emitting radionuclides have shown good efficacy for bone pain palliation.[4],[5]

Nowadays, bisphosphonate is widely used as the carriers in nuclear medicine for diagnosis and treatment. Some requirements and restrictions of the first generation phosphonates, like ethylenediaminetetra-methylenephosphonic acid (EDTMP) and hydroxyethanephosphonic acid, have encouraged the researcher to evaluate recently synthesized ligands with improved properties.[6] (4-[((bis(phosphonomethyl)) carbamoyl) methyl]-7,10-bis(carboxymethyl)-1, 4, 7, 10-tetraazacyclododec-1-yl) acetic acid (BPAMD) [Figure 1], as a new macrocyclic diphosphonate, in labeling with 68Ga, in first human studies showed promising results such as very high target-to-soft-tissue ratios and ultrafast clearance.[7] The DOTA-based bisphosphonate ligand BPAMD may also be suitable for the complexation with therapeutic radionuclides such as samarium-153 (153Sm).
Figure 1: Chemical structure of (4-[((bis(phosphonomethyl))carbamoyl) methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid

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Nowadays, radiopharmaceuticals with radionuclides such as 32P,89Sr,186Re,188Re,153Sm, and 177Lu are developed for the treatment of painful metastases. Among the therapeutic radionuclides,153Sm with the favorable radiation characteristics (t½=1.93 d, βmax = 0.81 MeV [20%], 0.71 MeV [49%], 0.64 MeV [30%], and γ =103 keV [30%]), is the most promising radionuclide for this purpose [8] and therefore,153Sm-EDTMP (lexidronam) is the most widely used bone pain palliative radiopharmaceutical in the United States.[9]

In this research, due to the interesting properties of BPAMD and 153Sm, the idea of developing a possible bone pain palliative agent,153Sm-BPAMD, was investigated. Radiolabeling, quality control, partition coefficient, hydroxyapatite (HA) binding assay and biodistribution studies using single photon emission computed tomography (SPECT), and scarification, after injection of the complex to wild-type mice are reported.


 > Materials and Methods Top


Production of 153Sm was performed at a research reactor using 152Sm (n, γ)153Sm nuclear reaction. Samarium-152 with a purity of >98% was obtained from ISOTEC Inc. BPAMD was purchased from ABX (Radeberg, Germany). All other chemical reagents were purchased from Sigma-Aldrich Chemical Co., U.K. Whatman No. 2 paper was obtained from Whatman (UK). Radiochromatography was performed by Whatman paper using a thin layer chromatography scanner, Bioscan AR2000, Paris, France. The activity of the samples was measured by a p-type coaxial high-purity germanium (HPGe) detector (model: EGPC 80–200R) coupled with a multichannel analyzer card system. Calculations were based on the 103 keV peak for 153Sm. All values were expressed as a mean ± standard deviation and the data were compared using Student's t-test. Animal studies were performed in accordance with the United Kingdom Biological Council's Guidelines on the Use of Living Animals in Scientific Investigations, second edition.

Production and quality control of samarium-153 chloride solution

153Sm was produced by neutron irradiation of 100 μg of enriched 152Sm2O3 (152Sm, 98.7% from ISOTEC Inc.) according to reported procedures [10] in a research reactor at a thermal neutron flux of 5 × 1013 n/cm 2/s for 5 d. The specific activity of the produced 153Sm was 819 mCi/mg. The irradiated target was dissolved in 200 μl of 1.0 M HCl, to prepare samarium-153 chloride (153SmCl3) and diluted to the appropriate volume with ultrapure water, to produce a stock solution. The mixture was filtered through a 0.22 μm biological filter and sent for use in the radiolabeling step. The radionuclidic purity of the solution was tested for the presence of other radionuclides using beta spectroscopy, as well as HPGe spectroscopy for the detection of various interfering beta and gamma emitting radionuclides. The radiochemical purity of the 153SmCl3 was checked using 2 solvent systems for instant thin layer chromatography (ITLC) (a) 10 mm diethylenetriaminepentaacetic acid DTPA pH 4 and (b) ammonium acetate 10%:Methanol (1:1).

Preparation of quality control of samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1, 4, 7, 10-tetraazacyclododec-1-yl) acetic acid

In order to obtain maximum complexation yields, several experiments were carried out and the effect of various parameters on the labeling yield of 153Sm-BPAMD including ligand concentration, pH, temperature, and reaction time were studied.

Briefly, 1 mg of BPAMD was dissolved in 1 ml pure water, and the aqueous solution was used for labeling studies. Typically, equal amounts (92.5 MBq) of 153SmCl3 (in 0.2 M HCl) were added to the 10 ml conical vials and dried under a flow of nitrogen. Distinct values of the complex ligands (100–400 nmol) were added to the samarium-containing vials. By varying pH (2–12) and temperature (50–100°C), the effect of these parameters was investigated based on ITLC results. The optimal procedure for the preparation of 153Sm-BPAMD complex with a high labeling yield was obtained.

For radio thin layer chromatography, a 5 µl sample of the final fraction was spotted on a chromatography Whatman No. 2 paper and developed in various mobile phase mixtures.

Stability studies

The stability of the complex was checked according to the conventional ITLC method. A sample of 153Sm-BPAMD (approximately, 37 MBq) was kept at the room temperature for 48 h while being checked by ITLC at time intervals in order to check stability in the final product using chromatography system. For serum stability studies, 37 MBq of labeled complex was added to 500 µl of freshly collected human serum and the resulting mixture was incubated at 37°C for 48 h, aliquots (5-µl) were analyzed by ITLC.

Hydroxyapatite binding assay

HA binding assay was performed according to the procedure described previously,[11] with only a slight modification. In brief, to vials containing 5.0, 10.0, 15.0, 20.0, 25.0, and 50.0 mg of solid HA, 2 ml of saline solution of pH 7.4 were added and the mixtures were shaken for 2 h. Then, 50 µl of the radioactive preparation was added, and the mixtures were shaken for 24 h at room temperature. The suspensions were centrifuged, and two aliquots of the supernatant liquid were taken from each vial and the radioactivity was measured with a well-type counter. Test experiments were performed using a similar procedure, but in the absence of HA. The percentage binding of 153Sm to HA was calculated according to HB = 1− A/B × 100, where A is the mean radioactivity value of the supernatant sample under study and B is the mean total value of whole activity used.

Determination of partition coefficient

The partition coefficient of 153Sm-BPAMD was calculated followed by the determination of P (the ratio of specific activities of the organic and aqueous phases). A mixture of 1 ml of 1-octanol and 1 ml of isotonic acetate-buffered saline (pH = 7) containing approximately 3.7 MBq of the radiolabeled complex at 37°C was vortexed 1 min and left 5 min. Following centrifugation at >1200 ×g for 5 min, the octanol and aqueous phases were sampled and counted in an automatic well-type counter. A 500 µl sample of the octanol phase from this experiment was shaken again 2–3 times with fresh buffer samples. The reported log P values are the average of the second and third extractions from three to four independent measurements.

Biodistribution of samarium-153 chloride and radiolabeled complex in wild-type mice

The distribution of 153SmCl3 and radiolabeled complex (2, 4, 24, and 48 h) among tissues was determined in wild-type mice. The total amount of radioactivity injected into each animal was measured by counting the 1 ml syringe before and after injection in a dose calibrator with fixed geometry.

The animals were sacrificed using the animal care protocols at selected times after injection. Blood samples were rapidly taken from the rodent aorta after scarification. The tissues (heart, lung, intestine, skin, stomach, kidneys, spleen, liver, muscle, and bone) were weighed and rinsed with normal saline and their specific activities were determined with an HPGe detector equipped with a sample holder device as a percent of injected dose per gram of tissues.

Imaging of wild-type mice

Images were taken from normal wide-type mice 24 and 48 h after administration of the radiolabeled complex by a dual-head SPECT system. The mouse-to-high energy septa distance was 12 cm. The useful field of view was 540 mm × 400 mm.


 > Results Top


Production and quality control of samarium-153 chloride solution

The 153Sm radionuclide in specific activity of 30 GBq/mg and radionuclidic purity of >99.9% [Figure 2] was prepared for radiolabeling. The radioisotope was diluted and evaporated to obtain the desired pH and volume followed by sterile filtering. Radiochemical impurities in the 153Sm sample used in the radiolabeling step were checked by two solvent systems [Figure 3]; (a) a mixture of 10 mm DTPA solution (pH 5) as the mobile phase on Whatman No. 2 paper, the free samarium cation in 153Sm3+ form, was chelated with the polydentate eluting leading to the migration of the cation in 153Sm-DTPA form to higher Rf (Rf0.7), any other ionic species would lead to the observation of new radiopeaks, especially at the origin (Rf0.0–0.1), (b) a mixture of 10% ammonium acetate: Methanol (1:1) was used as another solvent system on the Whatman No. 2 paper,153Sm3+ remains at the origin using this system, while other ionic species would migrate to higher Rfs.
Figure 2: Gamma spectrum of samarium-153 chloride solution used in the radiolabeling

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Figure 3: Instant thin layer chromatography chromatograms of samarium-153 chloride solution in diethylenetriaminepentaacetic acid solution (pH 5) (left) and 10% ammonium acetate: Methanol (1:1) solution (right) using Whatman No. 2

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Labeling optimization studies

In order to obtain maximum complexation yield, several experiments were carried out by varying different reaction parameters such as ligand concentration, pH, and reaction time.

Labeling yield increased with increasing BPAMD concentration and reached above 98% by adding 200 µl (346 nmol) of the ligand. It was observed that at the temperature range of 90–100°C, the maximum complexation yield would be achievable. The effect of variation of pH on complexation was also studied by varying the pH of the reaction mixture from 2 to 12 using 1 M HCl or 2 M NaOH solution. Maximum yield was observed at pH 5–7 while decreased beyond this range. The reaction mixture was incubated at 100°C temperature for different time periods, and 75 min incubation was found to be adequate to yield maximum complexation.

Based on the obtained results, the optimal procedure for the preparation of 153Sm-BPAMD complex with a high labeling yield is as follows:

1 mg of BPAMD was dissolved in 1 ml pure water, and the aqueous solution was used for labeling studies. 92.5 MBq of 153SmCl3 were added to the 10 ml conical vials and dried under a flow of nitrogen. 200 µl (346 nmol) of the stock solution was added to the samarium-containing vials, and the pH was adjusted to 5.5. The mixture was incubated for 75 min at 100°C.

Different chromatographic systems were used for the detection of the radiolabeled compound from the free cation. The best ITLC mobile phase was considered by Whatman No. 2 paper using NH4 OH:MeOH:H2O (0.2:2:4). Using this mixture, free cation remains at the origin of the paper as a single peak, while the radiolabeled compound migrates to higher Rf (0.7) [Figure 4]. ITLC studies approved the production of a single radiolabeled compound.
Figure 4: Instant thin layer chromatography of samarium-153 chloride (left) and samarium-153-(4-[((bis(phosphonomethyl)) carbamoyl) methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (right) in NH4OH:MeOH: H2O(0.2:2:4) as mobile phase on Whatman No. 2 papers

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Stability tests

The chemical stability of 153Sm-BPAMD was high enough to perform further studies. Incubation of labeled complex in freshly prepared human serum for 48 h at 37°C showed no loss of 153Sm from the complex. The radiochemical purity of the complex remained >97% for 48 h under physiologic conditions.

Hydroxyapatite binding assay

HA assay demonstrated high capacity binding for 153Sm-BPAMD to HA. Even at 5 mg amount of HA, more than 93% binding was observed. At further amounts of HA, approximately, all radiolabeled complex was bind to HA [Figure 5].
Figure 5: Hydroxyapatite binding assay for samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl)methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid at 37°C in 24 h

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Partition coefficient of samarium-153-(4-[((bis (phosphonomethyl))carbamoyl)methyl]-7,10-bis (carboxymethyl)-1, 4, 7, 10-tetraazacyclododec-1-yl) acetic acid

The partition coefficient (Po/w) was calculated by dividing the counts in the octanol phase by those in the buffer, and the results expressed as log Po/w. The average value from three to four independent measurements for 153Sm-BPAMD was −1.86 ± 0.02 which highlight the strong hydrophilic nature of the complex as expected from the chemical formula [Figure 1]. The water solubility of the radiocomplex leads to less unnecessary uptakes in tissues including liver, fat, and faster kidney wash-out.

Biodistribution of samarium-153 chloride and radiolabeled complex in wild-type mice

Biodistribution study was performed for free Sm 3+. As shown in [Figure 6], for 153Sm cation, the biodistribution was mainly accumulated in the liver, kidney, and bone.
Figure 6: Biodistribution of samarium-153 chloride in wild-type mice after 2, 4, 24, and 48 h postinjection

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The distribution of injected dose in mice organs up to 48 h after injection of 153Sm-BPAMD (150 µCi/100 µl) solution was determined. The radiolabeled compound biodistribution is also demonstrated in [Figure 7].
Figure 7: Biodistribution of samarium-153-(4-[((bis (phosphonomethyl))carbamoyl)methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid in wild-type mice after 2, 4, 24, and 48 h postinjection

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Imaging of wild-type mice

SPECT images were taken from normal wide-type mice 24 and 48 h after administration of the radiolabeled complex [Figure 8]. Imaging in the wild-type mice showed a distinct accumulation of the radiotracer in the skeletal region 24 and 48 h after injection.
Figure 8: Single photon emission computed tomography images of samarium-153-(4-[((bis(phosphonomethyl)) carbamoyl) methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid in wild-type rats 24 h (a) and 48 h (b) postinjection

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 > Discussion Top


ITLC using a mixture of NH4 OH:MeOH: H2O(0.2:2:4) showed that the complex is majorly prepared in 75 min with above 98% radiochemical purity; the remaining is possibly attributed to other in ionic species which cannot react with BPAMD.

The free cation is mainly soluble in water and it can be excreted via the urinary tract. Low blood radioactivity content demonstrates the rapid removal of 153Sm from the circulation after injection. Since the metallic 153Sm is transferred in plasma in protein bond form, the liver radioactivity uptake of the cation is high (more than 3%) and the maximum uptake is seen in 4 h (about 4%). The liver radioactivity uptake of the cation is comparable to other radiolanthanides such as Yb, Sm, and Tb.[12] Spleen also has significant 153Sm uptake possibly related to the reticuloendothelial system. Muscle and skin do not demonstrate significant 153Sm uptake was in accordance with other cations accumulation. A bone uptake is observed for 153Sm which remains almost constant after 4 h (1%).

Based on the results obtained from the biodistribution study of the labeled complex, it was clearly concluded that the major portion of the injected activity of the complex was transferred from blood circulation into bones. The significant excretion of the radioactivity is observed for kidneys as anticipated due to the water solubility of the compound, the major route of excretion for the labeled compound is through the urinary tract. The liver, however, plays no significant role in metabolism (<0.6%) and also lower GI (intestines, colon) uptake is observed. The removal of 153Sm-BPAMD from the circulation after injection occurs very fast.

The importance of an ideal bone-avid radiopharmaceutical, especially with therapeutic applications, relays on the accumulation of the complex in bone compared to the critical organs such as liver and kidneys since the radiation imposed to these organs, as well as secondary irradiation to the neighboring organs are important in developing a therapeutic agent. Therefore, for such radiopharmaceuticals, clearance from blood, accumulation in bone, and the ratio of accumulated activity in bone: Critical organs are parameters which should be considered. The ratios of bone/nontarget organs for the radiolabeled complex are presented in [Table 1].
Table 1: Target/nontarget ratios for 153Sm-BPAMD in different time intervals

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For a better comparison, a comparative study of vital organs uptake for 153Sm-BPAMD and 153SmCl3 has been shown in [Figure 9]. The result demonstrates different kinetic pattern for both species, especially for vital organs.
Figure 9: Comparative activity of blood, liver, kidney, and bone for samarium-153 chloride and samarium-153-(4-[((bis(phosphonomethyl)) carbamoyl)methyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid in wild-type mice 2–48 h postinjection

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Low blood radioactivity content for both species demonstrates the rapid removal of 153Sm and labeled complex from the circulation after injection, however,153Sm-BPAMD has a lesser amount in all time intervals.

153Sm cation is accumulated in the liver in the first 4 h postinjection (4%), while the accumulation of 153Sm-BPAMD in the liver is negligible all time after injection (<0.6%).

Since both species are water soluble and excreted from the kidneys, the activity of the kidneys for 153Sm and the labeled compound is significant, especially in early hours. The activity of kidneys, for both of 153Sm-BPAMD complex and a free cation, decreases slightly after injection until 48 h.

For 153Sm-BPAMD, the major radioactivity is accumulated in bones as expected for a bone-avid agent. Bone activity for 153Sm cation is rather low all time intervals after injection.


 > Conclusions Top


The radiolabeled 153Sm complex was prepared in high radiochemical purity (>98%, ITLC) and specific activity of 267 GBq/mmol. Labeling and quality control took 75 min. The complex demonstrated significant stability at the room temperature and in human serum at least for 48 h. HA binding assay demonstrated at the amount of more than 5 mg, approximately, all radiolabeled complex was bind to HA. At the pH.7.4, log Po/w was −1.86 ± 0.02. The final preparation was administered to wild-type mice, and biodistribution of the complex was checked until 48 h postinjection. Both SPECT and scarification showed major accumulation of the labeled compound in the bone tissue. All tissues approximately have insignificant uptake in comparison with bone tissue. The results show that 153Sm-BPAMD has interesting characteristics as an agent for bone pain palliation, however further biological studies in other mammals are still needed.

Financial support and sponsorship

Nuclear Science and Technology Research Institute, Tehran, Iran.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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