Objective: Many studies have attempted to assess the significance of the use of the β−-particle emitter praseodymium-142 (142Pr) in cancer treatment. As praseodymium oxide (Pr2O3) powder is not water soluble, it was dissolved in HCl solution and the resultant solution had to be pH adjusted to be in an injectable radiopharmaceutical form. Moreover, it was shown that the nanosized neodymium oxide (Nd2O3) induced massive vacuolization and cell death in non-small-cell lung cancer. In this work, the production of 142Pr was studied and water-dispersible nanosized Pr2O3 was proposed to improve the application of 142Pr in nuclear medicine.
Materials and methods: Data from different databases pertaining to the production of 142Pr were compared to evaluate the accuracy of the theoretical calculations. Water-dispersible nanosized Pr2O3 was prepared using a poly(ethylene glycol) (PEG) coating or PEGylation method as a successful mode of drug delivery. Radioactive 142Pr2O3 was produced via a 141Pr(n,γ)142Pr reaction by thermal neutron bombardment of the prepared sample.
Results: There was good agreement between the reported experimental data and the data based on nuclear model calculations. In addition, a small part of nano-Pr2O3 particles remained in suspension and most of them settled out of the water. Interestingly, the PEGylated Pr2O3 nanoparticles were water dispersible. After neutron bombardment of the sample, a stable colloidal 142Pr2O3 was formed.
Conclusion: The radioactive 142Pr2O3 decays to the stable 142Nd2O3. The suggested colloidal 142Pr2O3 as a multifunctional therapeutic agent could have dual roles in cancer treatment as a radiotherapeutic agent using nanosized 142Pr2O3 and as an autophagy-inducing agent using nanosized 142Nd2O3.
aDepartment of Medical Radiation Engineering, Science and Research Branch, Islamic Azad University
bJaber Ibn Hayyan Research Laboratories, Nuclear Science and Technology Research Institute, Tehran
cAgricultural, Medical and Industrial Research School, Nuclear Science and Technology Research Institute, Karaj, Iran
dFaculty of Engineering, University of Talca, Talca, Chile
eDepartment of Energy Science, Sungkyunkwan University, Suwon, South Korea
Correspondence to Mohamadreza K. Bakht, Department of Medical Radiation Engineering, Science and Research Branch, Islamic Azad University, PO Box 14515-775, Tehran, Iran Tel: +98 912 243 4026; fax: +98 214 486 9656; e-mail: email@example.com
Received June 29, 2012
Accepted September 22, 2012
Therapeutic radiopharmaceuticals are molecules designed to deliver therapeutic doses of ionizing radiation to diseased sites using therapeutic radionuclides mainly via β−-particle-emitting isotopes 1,2. It should be noted that radionuclide therapy demands a wide range of β energies, from 0.4 to about 2.3 MeV. For instance, l69Er (β−max=0.34 MeV), l53Sm (β−max=0.81 MeV) or l86Re (β−max=1.07 MeV), and 90Y (β−max=2.288 MeV) have been proposed for the treatment of small, medium, and large tumors, respectively 3. Praseodymium-142 (142Pr) [T1/2=19.12 h, β−max=2.162 MeV (96.3%), γ=1575 keV (3.7%)] decays to neodymium-142 (142Nd), and β−-emissions of 142Pr penetrate about 3 mm of soft tissue 4. Therefore, 142Pr can be utilized for high penetration of relatively large lesions, such as large tumors and inflamed joints 5–9.
Our recent review summarized studies that attempted to assess the significance of 142Pr usage in cancer treatment 10. In previous studies, 142Pr was produced by neutron irradiation of praseodymium oxide (Pr2O3) powder in nuclear reactors via the141Pr(n,γ) 142Pr reaction. Thereafter, radioactive Pr2O3 was dissolved in HCl solution by gentle warming. It is important to note that Pr2O3 bulk powder is not water soluble; hence, it should be dissolved in HCl solution and the resultant solution needs pH adjustment to be in an injectable radiopharmaceutical form 7–9.
The radiochemical data are of considerable practical importance, particularly for the production of radiopharmaceuticals 11. This paper is divided into three parts: in the first part, the reported experimental data and the evaluated excitation functions for the production of 142Pr via the 141Pr(n,γ)142Pr reaction from different databases were compared to evaluate the accuracy of theoretical calculations. In the second part, water-dispersible nanosized Pr2O3 was proposed and prepared to improve the application of 142Pr in radionuclide therapy. Finally, PEGylated radioactive 142Pr2O3 was produced following thermal neutron irradiation of the prepared samples.
Materials and methods
The neutron capture cross-section data
Cross-sections are valuable for the production of radionuclides, especially for medical applications 11–13. In this study, neutron capture cross-sections were obtained from theoretical calculations and from different experimental databases (http://www-nds.iaea.org/exfor/) for the 141Pr(n,γ)142Pr reaction. The TALYS program simulates nuclear reactions 14 and TALYS-based Evaluated Nuclear Data Library (TENDL) is a nuclear data library that provides the output of the TALYS nuclear model code system for direct use (http://www.talys.eu/tendl-2011). In addition, the European Activation File (EAF) is the collection of nuclear data required to carry out inventory calculations of materials that have been activated following exposure to neutrons or charged particles 15.
Preparation of nanosized Pr2O3
All chemicals used were of AR/GR grade from reputed chemical manufacturers. Praseodymium(III) nitrate hexahydrate (99.9%; Sigma–Aldrich, Zwijndrecht, the Netherlands) was used as the precursor for the synthesis of nanosized Pr2O3. The preparation of Pr2O3 took place in a stainless-steel (316L) autoclave that could endure working temperature and pressure of 550°C and 610 atm, respectively. The concentration of Pr(NO3)3 was 0.05 mol/dm3, and the heating period was about 2 h. Synthesis was carried out at 500°C to accelerate the hydrolysis reactions and thus shorten the fabrication period. To maintain the safety margin, the 200 cm3 stainless-steel autoclave was loaded with only 60–80 cm3 of the solution.
After removing it from the furnace, the autoclave was quenched with cold water and the nanosized Pr2O3 particles were recovered from the discharged solution by means of high-speed centrifugation (Sigma 2K15C; Braun Biotech International, Göttingen, Germany) at 19 056g for about 60 min. The nanoparticles produced were then washed three times in the same centrifuge with ultrapure water and then dried at ambient temperature.
Transmission electronic microscopy
A suspension of Pr2O3 particles was visualized using a LEO 912AB TEM (Leo Electron Microscopy Ltd, Cambridge, UK). The suspensions were placed on a carbon-coated copper TEM grid, without staining, and allowed to air dry before transmission electronic microscopy (TEM) viewing.
Nanoparticles were characterized by X-ray diffraction (XRD) (Philips PW 1800; Philips, Eindhoven, The Netherlands). The scans were taken at a scanning rate of 1°/min in the 2θ range from 20 to 100°.
Poly(ethylene glycol) coating
For PEGylation or poly(ethylene glycol) (PEG) coating, a mixture of nanosized Pr2O3 (5 mg) and 10 ml aqueous solution of PEG 1000 (50 mg/ml) was stirred for about 24 h at ambient temperature. The mixture was then centrifuged and the PEGylated Pr2O3 nanoparticles produced were redispersed in 5 ml water. Finally, the nanosized Pr2O3 was dried in a vacuum oven at 100°C for 5 h.
Neutron irradiation of the targets
Two quartz tubes were charged with 7.19 mg of the PEGylated Pr2O3 nanoparticles and 5 mg of the bulk Pr2O3 powder in micron size. It should be noted that the masses of Pr2O3 in the two samples were equal (5 mg). The quartz tubes were flame-sealed under vacuum and cold-welded in an aluminium can. 142Pr was produced by the 141Pr(n,γ)142Pr reaction in a Tehran Research Reactor (TRR) via thermal neutron bombardment of the samples at a flux of 2.55×1013 neutrons/cm2/s for 5 days. TRR is an open pool-type reactor with a maximum thermal power of 5 MW 16. Finally, the can was opened inside a lead-shielded plant.
After irradiation of the samples, the bulk Pr2O3 sample was dissolved in HCl solution by gentle warming and the nanosized Pr2O3 sample was dissolved in deionized water. The samples were then analyzed using a liquid scintillation counter (LSC) and a high-purity germanium detector (HPGe). Radionuclide purity of the 142Pr samples was determined by high-resolution gamma ray spectrometry using an HPGe detector (Silena International 2000, Rome, Italy) coupled to a multichannel analyzer (MCA). The counting of β emissions of 142Pr was carried out using a LSC (Wallac 1220 Quantulus; PerkinElmer Life Sciences Inc., Boston, Massachusetts, USA) with two dual MCAs.
Calculation of activity
The value of radioactive atoms can be determined at time t as follows:
where σ is the neutron activation cross-section leading to the production of radioisotopes of interest, in barns; φ is the flux, in neutrons/cm2/s; t is the time of irradiation; λ is the decay constant; and A is the atomic weight of the target element. (Equation 1) clearly shows that growth of activity in a target under irradiation is exponential in nature and reaches a saturation value limited by the neutron flux in the reactor 17,18.
Excitation function of the 141Pr(n,γ)142Pr reaction
Natural praseodymium can be used to generate 142Pr by thermal neutron activation. The 141Pr(n,γ)142Pr process was determined as an advantageous reaction over the other possible reactions as the natural abundance of 141Pr is 100% 19; as a result, the target of this reaction does not need enriching. Figure 1 shows comparison between the reported experimental data from EXFOR database 20 and the evaluated excitation functions from TENDL (http://www.talys.eu/tendl-2011) and EAF 15 databases for the discussed reaction. At the energy range of thermal neutrons (0.025 eV), there is good agreement between the reported experimental data and the evaluated excitation functions based on nuclear model calculations via recent nuclear codes from various databases. Further, at this energy range, the excitation function reaches the cross-sectional value of about 7.5 b. Therefore, the natural praseodymium thermal neutron activation cross-section is reasonably high for medical applications in comparison with other high-energy β−-particle-emitting isotopes such as yttrium with a 1.2 b thermal neutron cross-section.
Nanosized Pr2O3 characterization
The XRD pattern of the nanosized Pr2O3 is shown in Fig. 2a. Most of the diffraction peaks of the X-ray are indexed to Pr2O3 and some of them are indexed to Pr6O11. In addition, energy-dispersive X-ray spectroscopy (EDX) analysis was performed to investigate the compositional analysis of the synthesized nanosized Pr2O3. It was observed that the atomic percentage of each element was close to the stoichiometric ratio of Pr2O3 materials (Pr : O=0.63 : 1). Thus, the synthesized nanosized Pr2O3 contains only praseodymium and O elements without other impurity elements, as confirmed by the XRD result. The morphology of the synthesized nanosized Pr2O3 was evaluated by TEM. TEM images showed that the synthesized Pr2O3 nanoparticles are mostly nanorods with an average diameter of 25–50 nm and length of 600–650 nm. In addition, it should be noted that particles with an average diameter of 25–50 nm were observed. TEM images of the obtained Pr2O3 nanorods are shown in Fig. 2b. Moreover, the morphology of the PEGylated nanosized Pr2O3 was assessed by TEM. Figure 2c shows the nanosized PEG-coated Pr2O3 rods surrounded by PEG.
Radioactive nanosized Pr2O3
142Pr radioactivity of the samples was estimated by its characteristic 1575 keV photopeak. Figure 3a and b shows the spectrum of 142Pr using the gamma HPGe-MCA system and the LSC. To calculate the total activity of the samples, the data obtained by HPGe and LSC were used. A measure of 7.19 mg of the PEGylated Pr2O3 nanoparticles and 5 mg of the bulk Pr2O3 powder in micron size irradiated for 5 days at a flux of 2.55×1013 neutrons/cm2/s produced approximately the same activities. Table 1 shows the activity of Pr2O3 samples containing 4.15 mg of praseodymium, in GBq. Therefore, the Pr2O3 nanoparticles and the bulk Pr2O3 powder in micron size produced about 0.7 and 1.0 GBq/mg of 142Pr, respectively. It should be noted that the PEGylated nano-Pr2O3-specific activity was 30% less than that of the Pr2O3 powder because of the greater total molecular mass of the PEGylated nano-Pr2O3. Furthermore, Fig. 3c shows the curves of the decayed mass of 142Pr2O3 and the stable produced mass of 142Nd2O3. After a 19.12-h decay period, a mixture of radioactive Pr2O3 and stable neodymium oxide (Nd2O3) was formed.
Water solubility of Pr2O3
The sedimented mass of Pr2O3 in water was measured five times. Pr2O3 powder in micron size was insoluble in water. In fact, a suspension of Pr2O3 powder in micron size in water gave a heterogeneous fluid containing solid particles that were sufficiently large for sedimentation. As can be seen in Fig. 4a and b, 5 mg of Pr2O3 powder in 25 ml of deionized water completely sedimented in less than 5 min. In this suspension, sedimentation occurring because of the dispersed phase (
) is much denser than that due to the continuous phase.
In contrast, 3.75 of 5 mg nano-Pr2O3 in 25 ml of deionized water sedimented after 1 day (Fig. 4c). It can be said that the nano-Pr2O3 particles in water were kept in suspension by the action of physical forces on the particles themselves. Interestingly, 2.30 of 7.19 mg PEGylated Pr2O3 nanoparticles (containing 5 mg nano-Pr2O3) in 25 ml deionized water sedimented after 1 day. In fact, the PEGylated nano-Pr2O3 particles were water-dispersible and formed a stable colloidal PEGylated nano-Pr2O3 (Fig. 4a and d).
Lung cancer is the leading cause of cancer-related death in both men and women in the USA. Eighty-five percent of lung cancers are categorized as non-small-cell lung cancer 21. Chen et al. 22 showed that the nanosized Nd2O3 induced massive vacuolization and cell death in non-small-cell lung cancer NCI-H460 cells at a micromolar equivalent concentration range. In fact, nano-Nd2O3 could have implications for the treatment of non-small-cell lung tumors. It is interesting to note that radioactive 142Pr2O3 decays to stable 142Nd2O3 with a half-life of 19.12 h, whereas 90% of the dose (D90) is deposited in 2.65 days 6,10. In a very recent study, Di Pasqua et al. 23 evaluated the tumor accumulation of neutron-activatable holmium-containing mesoporous silica (166Ho-MCM-41) nanoparticles in an orthotopic non-small-cell lung cancer mouse model. Similar to 142Pr, 166Ho belongs to the lanthanide group and emits high-energy β−-particles (Emax=1.84 MeV) with a short half-life of 26.8 h. 166Ho-MCM-41 nanoparticles were administered intravenously to orthotopic non-small-cell lung cancer A549-luciferase tumor-bearing mice.
Furthermore, PEG is highly applicable in pharmacology as a result of its excellent water solubility and high biocompatibility. When PEG attaches to other molecules, it modulates the solubility of the attached molecules 24. PEGylation or PEG coating has proved to be a successful mode of drug delivery 25,26. For instance, Ishii et al. 27 prepared functionally PEGylated gold nanoparticles as colloidal biosensor systems. Moreover, the pioneering efforts by Professor Katti have demonstrated the enormous potential of radioactive gold nanoparticles in cancer treatment 17,28. However, so far, very little attention has been paid to the radioactive 142Pr. The findings of this study could pave the way for more clinical trials in the future.
Previously, radioactive Pr2O3 powder was dissolved in HCl solution as it is not water soluble. In addition, previous studies had to adjust the pH of the resultant solution to be in an injectable pharmaceutical form for therapeutic applications 7–9. With the proposed method detailed in this paper (Fig. 5a), radioactive Pr2O3 can be prepared in a stable colloidal form, thereby eliminating the time taken in radioactive laboratories for dissolving Pr2O3 in HCl solution as well as the challenges faced in pH adjustment.
Radioactive 142Pr2O3 as a radiotherapeutic agent decays to stable 142Nd2O3 with a half-life of 19.12 h 4. In contrast, it has been shown by Chen et al. 22 that nano-Nd2O3 as an autophagy-inducing agent could induce massive vacuolization and cell death in non-small-cell lung cancer NCI-H460 cells at a micromolar equivalent concentration range. Therefore, the proposed colloidal 142Pr2O3 as a multifunctional agent could have dual roles in cancer treatment: as a radiotherapeutic agent and as an autophagy-inducing agent (Fig. 5b).
It should be remembered that the growth of activity in a target under irradiation reaches a saturation value limited by the neutron flux in the reactor 17,18. Therefore, the proposed autophagy-inducing function of the formed nano-142Nd2O3 could be more technically feasible by increasing the neutron flux during thermal neutron bombardment of the nano-Pr2O3 sample. Furthermore, there are some alternative routes for the production of 142Pr. It is noteworthy that the cyclotron-produced 142Pr could have much higher specific activity 19. Generally, the principal advantage of accelerator-produced radioisotopes is their high specific activities 29. Therefore, future studies on the current topic using cyclotron-produced 142Pr are recommended.
Chemotherapy and external beam radiotherapy have done little to reduce the number of deaths among patients suffering from lung cancer; hence, therapy using targeted therapeutic radionuclides such as 142Pr and 166Ho is being explored as a new treatment option 30. In addition, current progress in radionuclide therapy has revealed the possibility of designing tumor-targeted carriers that can deliver radionuclide payloads to a specific site or in a molecularly selective manner to improve the efficacy and safety of cancer therapy 31. Formerly, Chen et al. 22 suggested a magnetic drug-targeting method to deliver nano-Nd2O3 to lung tumors. In addition, nano-142Pr2O3 could be conjugated with other chemotherapeutic drugs, such as drugs that induce apoptosis, to improve its therapeutic characteristics while minimizing its toxicity. It should be noted that, although no targeting moieties were attached to the surface of the particles used by Di Pasqua et al. 23, tumor accumulation of 166Ho-MCM-41 was exceptionally high after intravenous injection. Therefore, further research should be conducted to investigate the appropriate method to deliver nano-142Pr2O3 to lung tumors.
The β−-particle emitter 142Pr [T1/2=19.12 h, β−max=2.162 MeV (96.3%), γ=1575 keV (3.7%)] as a radiotherapeutic radioisotope decays to 142Nd. In this study, the existing nuclear data for the production of radioactive 142Pr through 141Pr(n,γ)142Pr reaction were evaluated. In addition, it was observed that a small part of nano-Pr2O3 particles remained in suspension and most of them clumped together and settled out of the water. Interestingly, the PEGylated Pr2O3 nanoparticles were water dispersible. Consequently, after neutron bombardment of the PEGylated 141Pr2O3 nanoparticles a stable colloidal 142Pr2O3 was formed. Briefly, the recommended colloidal radioactive Pr2O3 as a multifunctional therapeutic agent could have dual roles in cancer treatment: as a radiotherapeutic agent by nanosized 142Pr2O3 and as an autophagy-inducing agent using nanosized 142Nd2O3.
Claudio Tenreiro was financially supported by the World Class University (WCU) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-2008-10029). In addition, the authors express their sincere appreciation to Seyed V. Banihashemian of Jaber Ibn Hayyan Research Laboratories, Nuclear Science and Technology Research Institute, Tehran, Iran, for his technical assistance, helpful suggestions, and radiation monitoring during the experimentation. Finally, the authors thank Mohsen Sadeghpour-Motlagh of the Department of Material Science and Engineering, Tabriz University, Tabriz, Iran, for his technical assistance during TEM imaging.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
autophagy; cancer therapy; nano praseodymium oxide; non-small-cell lung cancer; poly(ethylene glycol); radioisotope production