Current Radiopharmaceuticals - Volume 15, Issue 1, 2022

Background: Cancer is one of the diseases causing society’s fears as a stigma of death and pain. Head and Neck Squamous Cell Carcinoma (HNSCC) is a group of malignant neoplasms of different locations in this region of the human body. It is one of the leading causes of morbidity and mortality in Brazil, because these malignant neoplasias, in most cases, are diagnosed in late phases. Surgical excision, chemotherapy and radiotherapy encompass the forefront of antineoplastic therapy; however, the numerous side effects associated with these therapeutic modalities are well known. Some treatments present enough potential to help or replace conventional treatments, such as Magnetic Hyperthermia and Photodynamic Therapy. Such approaches require the development of new materials at the nanoscale, able to carry out the loading of their active components while presenting characteristics of biocompatibility mandatory for biomedical applications. Objective: This work aims to make a bibliographical review of HNSCC treatments. Recent techniques proven effective in other types of cancer were highlighted and raised discussion and reflections on current methods and possibilities of enhancing the treatment of HNSCC. Methods: The study was based on bibliometric research between the years 2008 and 2019 using the following keywords: Cancer, Head and Neck Cancer, Chemotherapy, Radiotherapy, Photodynamic Therapy, and Hyperthermia. Results: A total of 5.151.725 articles were found, 3.712.670 about cancer, 175.470 on Head and Neck Cancer, 398.736 on Radiotherapy, 760.497 on Chemotherapy, 53.830 on Hyperthermia, and 50.522 on Photodynamic Therapy. Conclusion: The analysis shows that there is still much room for expanding research, especially for alternative therapies since most of the studies still focus on conventional treatments and on the quest to overcome their side effects. The scientific community needs to keep looking for more effective therapies generating fewer side effects for the patient. Currently, the so-called alternative therapies are being used in combination with the conventional ones, but the association of these new therapies shows great potential, in other types of cancer, to improve the treatment efficacy.

Background: Advances in the peaceful applications of ionizing radiation have brought in its wake the inevitable concern about radioactivity. Almost a decade ago, an infamous unprecedented radiological exposure incident occurred in Delhi, which has not only some positive aspects for imbibing good practices to emulate but also lessons learnt to further improvise the overall management, respectively. Objective: The Mayapuri incident at Delhi exposed the lack of awareness and laxity on the part of University of Delhi authorities in disposing of the Cobalt Irradiator, and the further insecure handling of the orphan radioactive source. Since an occurrence like this was unparalleled, it was necessary to flag all interlinked issues and put in place a technology management system that should address them. Methods: The methodology includes an in-depth discussion about the good practices and lessons learnt of the then-existing techno-legal systems and the response mechanism to the Mayapuri radiological incident from various departments of repute, both governmental as well as non-governmental. Result and Conclusion: The present article attempts to intensify pragmatic approaches to proactively avert and thwart ‘orphan source’ incidents like the Mayapuri radiological incident, so that threat to the society is minimal, and putting in place enhanced medical preparedness measures for the management of radiation casualties caused by ignorance, negligence, incompetence, accident, or malicious intention.

Background: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a β- emitting radioimmunoconjugate (⁹⁰Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. Methods: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50-fold excess of DOTA and then labelled with 90Y3+. The ⁹⁰Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the ⁹⁰Y-DOTA-nimotuzumab stability was evaluated in human plasma. Results: The radioimmunoconjugate ⁹⁰Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. Conclusions: The optimized conditions for a mild and easy preparation of ⁹⁰Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for β- radio-guided surgery.

Background: Fluorine-18 is one of the promising radiotracers that can report target specific information related to its physiology to understand the disease status through the PET modality. In the current study, the radiochemical synthesis, purification, and molecular docking studies of fluorine-18 (18F) radiolabeled coumarin-triazole hybrid have been performed. Objective: To develop target specific fluorine-18 radiotracer for the diagnosis in oncology. Methods: GE Tracer-lab FX2N module with few modifications in the line connections was used for the radiosynthesis and purification of target molecule [¹⁸F]SG-2, 4-((2,6-dimethylmorpholino) methyl)-7-((1-(4-(fluoro-¹⁸F) benzyl)-1H-1,2,3-triazol-4-yl) oxy)-2H-chromen-2-one, through the nucleophilic radiofluorination mechanism. The radiochemical purity was measured by HPLC, and TLC analytical methods. The kryptofix levels were also evaluated by using the TLC method. The residual solvents like DMF, ethanol were measured using GC. The Schrödinger drug discovery suite 2018 was used to study the protein and ligand interactions. Results: The quality control parameters revealed the purity, chemical identity, and limits of residual solvents. The radiochemical purity was 95.5 ± 2.3%, and dimethylformamide solvent limit was 89 ± 3 ppm. The molecular docking results had suggested that the cold target molecule has made strong electronic interactions and showed the possible pharmacokinetic (ADME) properties with galectin-1 protein. Overall, these results showed that [[¹⁸F]SG-2 radiolabeling with 18F radionuclide was feasible, and support of molecular docking studies suggest possible interactions with Galectin- 1. Conclusion: we reported a feasibility study for labeling coumarin-triazole hybrid with fluorine-18 through aromatic nucleophilic fluorination reaction (SNAr).

Background: Radiotherapy is used as one of the most effective regimens for cancer treatment, while radioresistance is a major drawback in cancer treatment. Objectives: This study aimed to evaluate the sensitizing effect of olanzapine (OLA) with X-ray on glioblastoma (U-87 MG) cells death. Methods: The synergistic killing effect of OLA with ionizing radiation (IR) on glioma was evaluated by colony formation assay. The generations of reactive oxygen species (ROS) and protein carbonyl (PC) as oxidized proteins were determined in OLA-treated and irradiated cells. Results: Results of this study showed that OLA reduced the number of colonies in irradiated glioma cells.OLA elevated ROS and PC levels in irradiated cells. The synergistic killing effect of OLA with IR in U-87 MG cells was observed at concentrations of 1 μM and 20 μM of OLA. The maximum radiosensitizing effect of OLA was observed at a concentration of 20 μM. Conclusion: The present study demonstrates that OLA has a radiosensitizing effect on cell death induced by IR in glioma cells.

Background: Due to the suitable nuclear decay characteristics, ¹⁷⁷Lu is an attractive radionuclide for various therapeutic applications. The non-carrier added form of¹⁷⁷Lu has drawn much attention because of its high specific activity needed in radiolabeling studies. There have been several separation methods for NCA¹⁷⁷Lu production. Objectives: Among the various separation methods, the electro-amalgamation separation method has got a large potential for large scale production. Li presence is a significant problem in this separation method, which seriously affects the radiolabeling efficiency. Methods: In this study, Li was separated from the final product of electro-amalgamation separation by adding an ion-exchange chromatography column to the separation process. Results: NCA ¹⁷⁷Lu was obtained by 84.09% ELM separation yield, 99.9% radionuclide purity and, 65 Ci/g specific activity. Then, ¹⁷⁷Lu (¹⁷⁷LuCl3 chemical form) was separated from Li using the ion exchange chromatography method by a separation yield of 94%. The obtained results of the radiolabeling efficacy studies showed that the radiochemical purity and radio-complex stability were significantly increased by separating NCA ¹⁷⁷Lu from Li. Conclusion: This new separation setup consisting of two steps allows using ¹⁷⁷Lu of such a favorable quality for labeling studies.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor– avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1- R, which is a candidate for being labeled with a PET isotope and used for imaging purposes. Objective: Here, we report the development and validation results of a semi-manual procedure to label [Lys40,Nle14(Ahx-NODAGA)NH2]exendin-4, with Ga-68. Methods: A⁶⁸Ge/⁶⁸Ga Generator (GalliaPharma®, Eckert and Ziegler) was eluted with 0.1M HCl on an automated synthesis module (Scintomics GRP®). The peptide contained in the kit vial (Radioisotope Center POLATOM) in different amounts (10-20-30 μg) was reconstituted with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethansulfonic acid (HEPES) solution and ⁶⁸GaCl3 (400–900 MBq), followed by 10 min incubation at 95°C. The reaction solution was then purified through an Oasis HLB column. The radiopharmaceutical product was tested for quality controls (CQs) in accordance with the European Pharmacopoeia standards. Results: The synthesis of [⁶⁸Ga]Ga-NODAGA-Exendin-4 provided optimal results with 10 μg of peptide, getting the best radiochemical yield (23.53 ± 2.4%), molar activity (100 GBq/μmol) and radiochemical purity (91.69%). Conclusion: The study developed an imaging tool [⁶⁸Ga]Ga-NODAGA-Exendin-4, avoiding pharmacological effects of exendin-4, for the clinical community.

Background: The synthesis of ²²⁵Actinium derivatives was afforded by using PSMA- 617, DOTATATE peptides, and EDTMP ligand. Detailed experiments, quality control (QC), and stability studies were also well described. The radiolabelling reactions were performed in mild conditions with desirable radiochemical yields and high radiochemical purities. Methods: PSMA-617, DOTATATE were radiolabelled with ²²⁵Actinium in 0.1 M HCl in the presence of ascorbate buffer solution and passed through the C-18 light cartridge for purification and the product was eluted by ethanol-water solution. EDTMP was also radiolabelled with ²²⁵Actinium without using any stabilizer and purification step. All products were well analyzed by R-TLC and R-HPLC. The stability of those compounds was also studied within the validity period of time. Results: ²²⁵Ac-DOTATATE and 225Ac-PSMA-617 were obtained at the same condition. The radiochemical yield of 225Ac-DOTATATE was less than²²⁵Ac-PSMA 617. The stability experiments indicating decay daughters of ²²⁵Actinium appeared after T0 +1 h due to the recoil effect radiolysis. On the other hand, ²²⁵Ac-EDTMP was more stable than DOTA-peptide radiolabelled compounds. ²²⁵Ac-EDTMP was produced with more than 95% radiochemical yield and 99% radiochemical purity. Conclusion: A detailed chemistry study was presented for the synthesis of ²²⁵Actinium derivatives in mild conditions with absolute radiochemical purities and high yields. The experimental results showed that ²²⁵Ac-EDTMP could be a suitable radiopharmaceutical alternative for bone metastases arising from primer tumors as a cocktail therapy.

Background: The choice of mice strain can significantly influence the physiological distribution and may lead to an inadequate assessment of the radiopharmaceutical properties. Objective: This work aims to present how the legal requirements that apply to radiopharmaceuticals contained in the various guidelines determine the choice of the mouse strain for quality control and preclinical studies and affect the results of physiological distribution. Methods: Swiss and BALB/c mice were chosen as commonly used strains in experiments for research and quality control purposes. Radiopharmaceuticals, i.e., preparations containing one or more radioactive isotopes in their composition, are subject to the same legal regulations at every stage of the research, development and routine quality control as all other medicines. Therefore, in vivo experiments are to be carried out to confirm the pharmacological properties and safety. Moreover, if a radiopharmaceutical's chemical structure is unknown or complex and impossible to be determined by physicochemical methods, an analysis of physiological distribution in a rodent animal model needs to be performed. Results: In our studies, thirty-six mice (Swiss n=18, BALB/c n=18) were randomly divided into six groups and injected with the following radiopharmaceuticals: [^99mTc]Tc-Colloid, [^99mTc]Tc-DTPA and [^99mTc]Tc-EHIDA. Measurement of physiological distribution was conducted following the requirements of European Pharmacopoeia (Ph. Eur.) monograph 0689, internal instructions and the United States Pharmacopeia (USP) monograph. Additionally, at preclinical studies, ten mice (Swiss n=5, BALB/c n=5) were injected with the new tracer [^99mTc]Tc-PSMA-T4, and its physiological distribution has been compared. The p-value <0.05 proved the statistical significance of the radiopharmaceutical physiological distribution. Conclusion: We claim that mice strain choice can significantly influence the physiological distribution and may lead to inaccurate quality control results and incomprehensible interpretation of the results from preclinical in vivo studies of a new radiopharmaceutical.