Optimized Production of 188Re-HYNIC-Bombesin: New Therapeutic Agent for GRPR Targeting.

Purpose: One of the most interesting methods to deliver therapeutic doses of ionizing radiation to tumor sites is radiolabeled compounds. Bombesin peptide binds to gastrin-releasing peptide receptors (GRPRs) with great affinity. Through its appropriate physical characteristics and accessibility as the 188W/188Re generator, 188Re can be effectively used to develop a therapeutic radio complex. In this study, 188Re-HYNIC-BBN was prepared under optimal conditions. Methods: Optimization of the effective parameters on 188Re-HYNIC-BBN radio-labeling yield like ligand concentration, pH, reaction time, and temperature were performed. The final product's radiochemical purity was measured by RTLC and HPLC. The stability of the radio-complex was checked in PBS buffer (4 °C) and human blood serum (37 °C). The partition coefficient of the final radio-complex was studied using standard procedure. Finally, the biodistribution of 188Re-HYNIC-BBN and free 188Re in different organs of the rats were compared in various intervals. Results: The final product was prepared with a specific activity of 7.11 TBq/mmol and radiochemical purity > 95% at the optimized conditions (pH = 4-5, reaction time = 45 min, temp = 95℃). This radio-complex was found to be stable in PBS and blood serum over 24 h. LogPo/w was - 1.78, showing the high hydrophilic nature of the radio-complex. The biodistribution of 188Re-HYNIC-BBN demonstrated the fast clearance of the radio-peptide from the blood circulation. The most portion of the radioactivity was excreted from the body via the urinary tract and the remaining activity was accumulated in GRPR-expressing organs. Conclusion: The special characteristics of the complex introduce 188Re-HYNIC-BBN as a new therapeutic agent for targeting GRPRs, however, more biological data is still needed.

Estimation of Human Absorbed Dose of 188Re-Hynic-Bombesin Based on Biodistribution Data in Rats.

BACKGROUND: HYNIC-Bombesin (BBN) is a potential peptide for targeted radionuclide therapy in gastrin-releasing peptide receptor (GRPr)-positive malignancies. The 188Re-HYNICBBN is a promising radiopharmaceutical for use in prostate cancer therapy. OBJECTIVE: The aim of this study was to estimate the absorbed dose due to 188Re-HYNIC-BBN radio-complex in human organs based on bio-distribution data of rats. METHODS: In this research, using bio-distribution data of 188Re-HYNIC-BBN in rats, its radiation absorbed dose of the adult human was calculated for different organs based on the MIRD dose calculation method. RESULTS: A considerable equivalent dose amount of 188Re-Hynic-BBN (0.093 mGy/MBq) was accumulated in the prostate. Moreover, all other tissues except for the kidneys and pancreas approximately received insignificant absorbed doses. CONCLUSION: Since the acceptable absorbed dose for the complex was observed in the prostate, 188Re-Hynic-Bombesin can be regarded as a new potential agent for prostate cancer therapy.

The radio-europium impurities in [153Sm]-EDTMP production: a review of isolation methods.

Many human cancers predominantly metastasize to the bone which causes bone pain and other symptoms. However, the management of bone metastases is challenging. Radionuclide therapy using low-energy beta-emitting radionuclides has yielded encouraging results. The aim of this therapy is to deliver the maximum dose to the metastatic sites but a minimal dose to the normal tissue. Samarium-153 [153Sm]Sm-Ethylenediamine tetramethylene phosphonate (EDTMP) is an FDA and European Medicine Agency approved (Quadramet) radionuclide and is widely used for bone pain palliation. 153Sm is reactor produced, and the presence of europium impurities is thus unavoidable. This in turn causes an increase in the hospital radioactive waste burden and in radiation absorbed doses to the patients, and therefore it is a concern. The effective removal of these impurities is thus highly desirable before its administration to the patients. In this article, we present a detailed review of the various methods described in the literature for separation of 153Sm and Eu, that is solvent extraction, ion-exchange chromatography, electrochromatography, electrochemical separation and supported ionic liquid phase.

Preparation and Dosimetry Evaluation of a Carrier- Free 90Y Labeled DOTMP as a Promising Agent for Bone Marrow Ablation.

BACKGROUND AND OBJECTIVE: Skeletal uptake of 90Y-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethylene-phosphonate (DOTMP) is used to deliver high doses of this radiopharmaceutical to the bone marrow. METHODS: In this research, carrier-free (c.f.) 90Y was obtained from an electrochemical 90Sr/90Y generator. The c.f. 90Y was mixed with 300 µL of DOTMP (20 mg/mL) and incubated under stirring conditions at room temperature for 45 min. RESULTS: The [90Y]Y-DOTMP that was obtained under optimized reaction conditions had high radiochemical purities (>98%). Moreover, the radiolabeled complex exhibited excellent stability at room temperature, as well as in human serum. The biodistribution studies in rats showed the favorable selective skeletal uptake with rapid clearance from the blood, albeit with insignificant accumulation of activity in other non-target organs for the radiolabeled complex. Also, the present work has utilized the Monte Carlo codes MCNP-4C to simulate the depth dose profile for 90Y in a mice femur bone and compared with that produced by 153Sm and 177Lu. CONCLUSION: The results show that the absorbed dose produced by 90Y in the bone marrow is higher than 153Sm and 177Lu per 1MBq of the injected activity.

Production, quality control, and determination of human absorbed dose of no carrier added 177 Lu-risedronate for bone pain palliation therapy.

In this study, the radiocomplexation of risedronic acid, a potent bisphosphonate with a no carrier added (NCA) 177 Lu, was investigated and followed by quality control studies, biodistribution evaluation, and dosimetry study for human based on biodistribution data in Wistar rats. The moderate energy ß- emitter, 177 Lu (T½  = 6.7 days, Eßmax  = 497 keV), has been considered as a potential agent for development of bone-seeking radiopharmaceuticals. Because the specific activity of the radiolabeled carrier molecules should be high, the NCA radionuclides have an effective role in nuclear medicine. Many researchers illustrated an NCA 177 Lu production; among these separation techniques, extraction chromatography has been considered more capable than other methods. The NCA 177 Lu was produced with specific activity of 48 Ci/mg and radionuclidic purity of 99.99% by the irradiation of enriched 176 Yb target in thermal neutron flux of 4 × 1013  n·cm-2 ·s-1 for 14 days. The NCA 177 Lu was mixed to a desired amount of sodium risedronate (15 mg/mL, 200 µL) and incubated with stirring at 95°C for 30 minutes. The radiochemical purity of 177 Lu-risedronate was determined by radio thin-layer chromatography, and high radiochemical purities (>97%) were obtained under optimized reaction conditions. The complex was injected to Wistar rats, and complex biodistribution was performed 4 hours to 7 days postinjections showing high bone uptake (9.8% ± 0.24% ID/g at 48 hours postinjection). Also, modeling the radiation dose delivery by RADAR software for the absorbed dose evaluation of each human organ showed a major accumulation of the radiocomplex in bone tissue.

Production and quality control 177Lu (NCA)-DOTMP as a potential agent for bone pain palliation.

Skeletal uptake of radiolabeled-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetramethylene phosphoric acid (e.g., 177Lu-DOTMP) complex, is used for bone pain palliation. The moderate energy of ß-emitting 177Lu (T½ = 6.7 d, Eßmax = 497keV) has been considered as a potential radionuclide for development of the bone-seeking radiopharmaceutical. Since the specific activity of the radiolabeled carrier molecules should be high, the "no-carrier-added radionuclides" have sig-nificant roles in nuclear medicine. Many researchers illustrated no-carrier-added 177Lu production; among these separation techniques such as ion exchange chromatography, reversed phase ion-pair, and electrochemical method, extraction chromatography has been considered more capable than other methods. In order to optimize the conditions, some effective factors on separation of Lu/Yb were investigated by EXC. The NCA 177Lu, produced by this method, was mixed with 300 µl of DOTMP solution (20 mg in 1 mL of 0.5 M NaHCO3, pH = 8) and incu-bated under stirring at room temperature for 45 min. Radiochemical purity of the 177Lu-DOTMP complex was determined using radio-thin-layer chromatography (RTLC) method. The complex was injected to wild-type rats and biodistribution was then studied for seven days. The NCA 177Lu was produced with specific activ-ity of 48 Ci/mg and with a radinuclidic purity of 99.99% through irradiation of enriched 176Yb target (1 mg) in a thermal neutron flux of 4 × 1013 n.cm-2.s-1 for 14 days. 177Lu-DOTMP was obtained with high radiochemical purities (> 98%) under optimized reaction conditions. The radiolabeled complex exhibited excellent stability at room temperature. Biodistribution of the radiolabeled complex studies in rats showed favorable selective skeletal uptake with rapid clearance from blood along with insignificant accumulation within the other nontargeted organs.