Current Radiopharmaceuticals - Volume 16, Issue 1, 2023

Targeted Alpha Therapy (TAT) is considered an evolving therapeutic option for cancer cells, in which a carrier molecule labeling with an α-emitter radionuclide make the bond with a specific functional or molecular target. α-particles with high Linear Energy Transfer (LET) own an increased Relative Biological Effectiveness (RBE) over common β-emitting radionuclides. Normal tissue toxicity due to non-specific uptake of mother and daughter α-emitter radionuclides seems to be the main conflict in clinical applications. The present survey reviews the available preclinical and clinical studies investigating healthy tissue toxicity of the applicable α -emitters and particular strategies proposed for optimizing targeted alpha therapy success in cancer patients.

Radiation treatment has been advancing ever since the discovery of X-rays in 1895. The goal of radiotherapy is to shape the best isodose on the tumor volume while preserving normal tissues. There are three advantages: patient cure, organ preservation, and cost-effectiveness. Randomized trials in many various forms of cancer (including breast, prostate, and rectum) with a high degree of scientific proof confirmed radiotherapy's effectiveness and tolerance. Such accomplishments, critical to patients' quality of life, have been supported in the past. Radiopharmaceuticals were developed to diagnose and treat various disorders, including hyperthyroidism, bone discomfort, cancer of the thyroid gland, and other conditions like metastases, renal failure, and myocardial infarction and cerebral infarction perfusion. It is also possible to sterilize thermo-labile materials with a radioactive substance. This includes surgical dressings and a wide range of other medical supplies. Nuclear medicine provides various advantages, including tumor localization, safe diagnosis, no radiation buildup, and excellent treatment effectiveness. Nowadays, the field of nuclear pharmacy is focused on developing novel radioactive pharmaceutical substances that will be useful.

Introduction: With its suitable nuclear decay characteristics and large-scale production feasibility with adequate specific activity, 177Lu is regarded as an excellent radionuclide for developing bone pain palliation agent. Ethylenediamine-tetramethylene phosphonic acid (EDTMP) is a preferred carrier molecule for radiolanthanides, such as 177Lu. The present paper describes the synthesis of EDTMP and the development of a ready-to-use kit for the preparation of 177Lu-EDTMP and its quality control in accordance with the quality and safety criteria required for medicinal use. Material and Methods: EDTMP was synthesized by a modified Mannich-type reaction, and the structure was characterized using NMR and IR spectroscopy. Optimization of radiolabeling conditions was done with two different salt forms of EDTMP. The labeling yield was checked by paper chromatography with radiation detection. Kit was developed as a lyophilized mixture of EDTMP and sodium bicarbonate in a maximum volume of 5 mL. Labeling efficiency, radionuclidic purity, radiochemical purity, sterility, and pyrogenicity analysis were performed as the quality control of the labeled kit. Results: The analytical data for the structure determination and purity of the synthesized ligand were in agreement with authentic commercial samples used in radiopharmacy.177Lu-EDTMP complex was prepared using synthesized EDTMP ligand under optimized labeling conditions with high labelling yield (>99%). The radiolabeling yields of the EDTMP kit at room temperature after 30 min and 48 hours were 99.46% and 99.00%. Conclusion: The developed EDTMP kit enables an instant one-step preparation of the radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. This enables the routine production of the 177Lu-EDTMP in nuclear medicine clinics without requiring experienced staff.

Introduction: This study aimed to determine the critical organ doses in 223Ra, 89Sr, 153Sm, and 32P treatments via dosimetry using the phantoms. Material and Methods: The OpenDose was used to calculate S values (mGy MBq-1s-1) for bone surface, red bone marrow, urinary bladder wall, testes, ovaries, uterus, and kidneys using male (ICRP110AM) and female (ICRP110AF) phantoms. The cortical thoracic spine was modeled as metastasis. Moreover, the absorbed doses were computed via MIRD formalism according to the activities of 3.3, 148, 2220, and 370 MBq for ICRP110AM and 4.015, 148, 2701, and 370 MBq for ICRP110AF in 223Ra, 89Sr, 153Sm, and 32P treatments, respectively. Results: Whilst the maximum bone surface doses were found as 1.22E+02 and 8.51E+01 mGy at 32P treatment, the minimum bone surface doses were calculated as 8.42E-02 and 8.26E-02 mGy at 223Ra. In terms of the comparison of red bone marrow, urinary bladder wall, and kidney doses, 153Sm and 89Sr treatments showed maximum doses of 2.45E-03, 1.50E-03, 3.23E-07, 5.45E-06, 1.20E-01, 1.49E-01 mGy and the minimum doses with 3.46E-05, 1.99E-05, 6.33E-09, 8.77E-09, 1.19E-04, 1.15E-04 mGy, respectively. The maximum testes and ovaries-uterus doses were found as 6.17E-08, 7.40E-06, 3.46E-07 mGy in 153Sm treatment, and minimum testes and ovaries doses as 1.70E-09, 1.34E-07 mGy in 223Ra. The minimum uterus dose with 7.03E-09 mGy was determined in 89Sr treatment. Conclusion: It is observed that 223Ra produces low critical organ doses in the treatment of painful bone metastasis. Among the beta-emitting radionuclides, 89Sr stands out by showing optimal dosimetric results.

Background: Myelosuppression is common and threatening during tumor treatment. However, the effect of radiation on bone marrow activity, especially leukocyte count, has been underestimated in cervical cancer. The aim of this study was to evaluate the severity of radiotherapy- induced acute leukopenia and its relationship with intestinal toxicity. Methods: The clinical data of 59 patients who underwent conventional radiation alone for cervical cancer were retrospectively analyzed. The patients had normal leukocyte count on admission, and the blood cell count, gross tumor volume (GTV) dose, and intestinal toxicity were evaluated. Results: During radiotherapy (RT), 47 patients (79.7%) developed into leukopenia, with 38.3% mild and 61.7% moderate. The mean time for leukopenia was 9 days. Compared with leukopenianegative patients, leukopenia-positive ones had lower baseline leukocyte count, while neutrophil/ lymphocyte (NLR) and monocyte/lymphocyte (MLR) showed no significance. Logistic regression analysis indicated that excluding the factors for age, body mass index (BMI), TNM stage, surgery and GTV dose, baseline leukocyte count was an important independent predictor of leukopenia (OR=0.383). During RT, a significant reduction was found in leukocyte, neutrophil and lymphocyte count at week 2 while monocyte count after 2 weeks. Furthermore, NLR and MLR showed a significant and sustained upward trend. About 54.2% of patients had gastrointestinal symptoms. However, no significant relevance was noted between leukocyte count as well as NLR/MLR and intestinal toxicity, indicating leukopenia may not be the main factor causing and aggravating gastrointestinal reaction in cervical cancer. Conclusion: Our results suggest the underrated high prevalence and severity of leukopenia in cervical cancer patients receiving RT, and those with low baseline leukocyte count are more likely for leukopenia, for whom early prevention of infection may be needed during RT.

Aim: In the current study, we aimed to mitigate radiation-induced small intestinal toxicity using post-irradiation treatment with nano-micelle curcumin. Background: Small intestine is one of the most radiosensitive organs within the body. Wholebody exposure to an acute dose of ionizing radiation may lead to severe injuries to this tissue and may even cause death after some weeks. Objective: This study aimed to evaluate histopathological changes in the small intestine following whole-body irradiation and treatment with nanocurcumin. Materials and Methods: Forty male Nordic Medical Research Institute mice were grouped into control, treatment with 100 mg/kg nano-micelle curcumin, whole-body irradiation with cobalt-60 gamma-rays (dose rate of 60 cGy/min and a single dose of 7 Gy), and treatment with 100 mg/kg nano-micelle curcumin 1 day after whole-body irradiation for 4 weeks. Afterward, all mice were sacrificed for histopathological evaluation of their small intestinal tissues. Results: Irradiation led to severe damage to villi, crypts, glands as well as vessels, leading to bleeding. Administration of nano-micelle curcumin after whole-body irradiation showed a statistically significant improvement in radiation toxicity of the duodenum, jejunum and ileum (including a reduction in infiltration of polymorphonuclear cells, villi length shortening, goblet cells injury, Lieberkühn glands injury and bleeding). Although treatment with nano-micelle curcumin showed increased bleeding in the ileum for non-irradiated mice, its administration after irradiation was able to reduce radiation-induced bleeding in the ileum. Conclusion: Treatment with nano-micelle curcumin may be useful for mitigation of radiationinduced gastrointestinal system toxicity via suppression of inflammatory cells’ infiltration and protection against villi and crypt shortening.

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.

Background: Some compounds have been investigated to mitigate the effect of radiation on the lung, such as pneumonitis and fibrosis. Objective: This study aimed to examine the mitigation efficiency of Spirulina compared to the effect of Metformin. Methods: 25 male Wistar rats were allotted in five groups: control, Spirulina, Radiation, Radiation plus Spirulina, and Radiation plus Metformin. Rat chest regions were irradiated by 15 Gray (Gy) xradiation using aLINAC. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. Eighty days after irradiation, all rats were sacrificed, and their lung tissues were removed for histopathological, and biochemical assays. Results: The results demonstrated that irradiation increased MDA (Malondialdehyde) levels while suppressing the SOD (superoxide dismutase) and GPx(glutathione peroxidase) activity in the irradiated group. MDA levels in lung tissues were reduced with Metformin but not with Spirulina. Both Metformin and Spirulina increased the SOD and GPx activity in lung tissue. Moreover, histopathological evaluations showed extensive changes in the lung tissue including infiltration of lymph cells around the bronchioles and blood vessels, thickening of the alveolar wall, and the disruption of the alveolar structure, as well as accumulation of collagen fibers. Administration of Spirulina and Metformin significantly reduced pathological changes in lung tissue, although the effect of Metformin was greater than that of Spirulina. Conclusion: Spirulina could mitigate radiation-induced lung injury moderately, although Metformin is more effective than Spirulina as a mitigator agent.

Background: During a radiological or nuclear disaster, exposure to a high dose of ionizing radiation usually results in cardiovascular diseases such as heart failure, attack, and ischemia. Objective: The purpose of this study was to examine the mitigation effects of Spirulina in comparison to Metformin's. Methods: 25 male Wistar rats were randomly assigned to five groups (5 rats in each): for the control group, rats did not receive any intervention. In group 2, spirulina was administered orally to rats. In group 3, rats were irradiated to the chest region with 15 Gray(Gy) x-radiation. In groups 4 and 5, rats were irradiated in the same way as group 3. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. All rats were sacrificed after ten weeks, and their heart tissues were removed for histopathological and biochemical assays. Results: Results showed an elevation in Malondialdehyde (MDA) and decreasing superoxide dismutase (SOD) activity. Moreover, pathological changes of radiation were irregularities in the arrangement of myofibrils, proliferation, migration of mononuclear cells, vacuolation of the cytoplasm, and congestion. Administration of spirulina enhanced the SOD activity while did not affect MDA level and pathological change in heart tissue. Despite spirulina, metformin had a considerable effect on pathological lesions and decreased the level of MDA. Conclusion: Reactive oxygen species (ROS) may be involved in the late effects of radiationinduced heart injury, and scavenging these particles may contribute to reduced radiation side effects. Based on these results, Spirulina had no effect on radiation-induced cardiac damage, while metformin did. Higher Spirulina doses given over a longer period of time will likely have a greater heart-mitigate effect.