Current Radiopharmaceuticals - Volume 14, Issue 1, 2021

Background: Breast cancer is the leading cause of cancer in women. 13% of breast cancer patients are at a distant stage and mortality is due to metastases rather than primary disease. The unique genetic structure and natural process of breast cancer make it a very suitable area for targeted therapies. Experimental tumor models are validated methods to examine the pathogenesis of cancer, the onset of the neoplastic process and progression. Objective: This study aims to review the current literature on experimental breast cancer models and to bring a new perspective to the use of these models in teranostic preclinical studies in terms of the imaging. Methods: Search for relevant literature from academic databases using keywords (Breast cancer, theranostic, preclinical imaging, tumor models, animal study, and tailored therapy) was conducted. The full text of the articles was reached and reviewed. Current scientific data has been reevaluated and compiled according to subtitles. Results and Conclusion: The development of animal models for breast cancer research has been done in the last century. Imaging methods used in breast cancer are used for tumor localization, quantification of tumor mass, imaging of genes and proteins, evaluation of tumor microenvironment, evaluation of tumor cell proliferation and metabolism and treatment response evaluation. Since human breast cancer is a heterogeneous group of diseases in terms of genetics and phenotype; it is not possible for a single model to adequately address all aspects of breast cancer biology. Considering that each model has advantages and disadvantages, the most suitable model should be chosen to verify the thesis of the study.

Background: Theranostic is a new field of medicine that combines diagnosis and patient- specific targeted treatment. In the theranostic approach, it is aimed to detect diseased cells by using targeted molecules using disease-specific biological pathways and then destroy them by cellular irradiation without damaging other tissues. Diagnostic tests guide the use of specific therapeutic agents by demonstrating the presence of the receptor/molecule on the target tissue. As the therapeutic agent is administered to patients who have a positive diagnostic test, the efficacy of treatment in these patients is largely guaranteed. As therapeutic efficacy can be predicted by therapeutic agents, it is also possible to monitor the response to treatment. Many diagnostic and therapeutic procedures in nuclear medicine are classified as theranostic. ¹³¹I treatment and scintigraphy are the best examples of the theranostic application. Likewise, ¹⁷⁷Lu / ⁹⁰Y octreotate for neuroendocrine tumors, ¹⁷⁷Lu PSMA for metastatic or treatment-resistant prostate cancer, ⁹⁰Y SIRT for metastatic liver cancer, and ²²³Ra for bone metastasis of prostate cancer are widely used. Moreover, nanoparticles are one of the most rapidly developing subjects of theranostics. Diagnostic and therapeutic agents that show fluorescent, ultrasonic, magnetic, radioactive, contrast, pharmacological drug or antibody properties are loaded into the nanoparticle to provide theranostic use. Methods: This article reviewed general aspects of preclinical models for theranostic research, and presented examples from the literature. Conclusion: To achieve successful results in rapidly accelerating personalized treatment research of today, the first step is to conduct appropriate preclinical studies.

Background: Theranostic oncology combines therapy and diagnosis and is a new field of medicine that specifically targets the disease by using targeted molecules to destroy the cancerous cells without damaging the surrounding healthy tissues. Objective: We aimed to develop a tool that exploits enzymatic TQ release from glucuronide (G) for the imaging and treatment of lung cancer. We added magnetic nanoparticles (MNP) to enable magnetic hyperthermia and MRI, as well as 131I to enable SPECT imaging and radionuclide therapy. Methods: A glucuronide derivative of thymoquinone (TQG) was enzymatically synthesized and conjugated with the synthesized MNP and then radioiodinated with 131I. New Zealand white rabbits were used in SPECT and MRI studies, while tumor modeling studies were performed on 6–7- week-old nude mice utilized with bioluminescence imaging. Results: Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectra confirmed the expected structures of TQG. The dimensions of nanoparticles were below 10 nm and they had rather polyhedral shapes. Nanoparticles were radioiodinated with 131I with over 95% yield. In imaging studies, in xenograft models, tumor volume was significantly reduced in TQGMNP-treated mice but not in non-treated mice. Among mice treated intravenously with TQGMNP, xenograft tumor models disappeared after 10 and 15 days, respectively. Conclusion: Our findings suggest that TQGMNP in solid, semi-solid and liquid formulations can be developed using different radiolabeling nuclides for applications in multimodality imaging (SPECT and MRI). By altering the characteristics of radionuclides, TQGMNP may ultimately be used not only for diagnosis but also for the treatment of various cancers as an in vitro diagnostic kit for the diagnosis of beta glucuronidase-rich cancers.

Background: Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used for targeted drug delivery systems due to their unique magnetic properties. Objective: In this study, it has been aimed to develop a novel targeted ^99mTc radiolabeled polymeric drug delivery system for Gemcitabine (GEM). Methods: Gemcitabine, an anticancer agent, was encapsulated into polymer nanoparticles (PLGA) together with iron oxide nanoparticles via double emulsion technique and then labeled with ^99mTc. SPIONs were synthesized by reduction–coprecipitation method and encapsulated with oleic acid for surface modification. Size distribution and the morphology of the synthesized nanoparticles were characterized by dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. The radiolabeling yield of SPION-PLGAGEM nanoparticles was determined via Thin Layer Radio Chromatography (TLRC). Cytotoxicity of GEM loaded SPION-PLGA was investigated on MDA-MB-231 and MCF7 breast cancer cells in vitro. Results: SEM images displayed that the average size of the drug-free nanoparticles was 40 nm and the size of the drug-loaded nanoparticles was 50 nm. The diameter of nanoparticles was determined as 366.6 nm by DLS, while zeta potential was found as 29 mV. SPION was successfully coated with PLGA, which was confirmed by FTIR. GEM encapsulation efficiency of SPION-PLGA was calculated as 4±0.16% by means of HPLC. Radiolabeling yield of SPION-PLGA-GEM nanoparticles was determined as 97.8±1.75% via TLRC. Cytotoxicity of GEM loaded SPION-PLGA was investigated on MDA-MB-231 and MCF7 breast cancer cells. SPION-PLGA-GEM showed high uptake on MCF-7, while the incorporation rate was increased for both cell lines with external magnetic field application. Conclusion: ^99mTc labeled SPION-PLGA nanoparticles loaded with GEM may overcome some of the obstacles in anti-cancer drug delivery because of their appropriate size, non-toxic, and superparamagnetic characteristics.

Background: Tumors are defined as abnormal tissue masses, and one of the most important factors leading to the growth of these abnormal tissue masses is Vascular Endothelial Growth Factor, which stimulates angiogenesis by releasing cells under hypoxic conditions. Hypoxia has a vital role in cancer therapy, thus it is important to monitor hypoxia. The hypoxia marker Pimonidazole (PIM) is a candidate biomarker of cancer aggressiveness. Objective: The study aimed to perform radioiodination of PIM with Iodine-131 (¹³¹I) to join a theranostic approach. For this purpose, PIM was derived as PIM-TOS to be able to be radioiodinated. Methods: PIM was derived via a tosylation reaction. Derivatization product (PIM-TOS) was radioiodinated by using iodogen method and was analyzed by High-Performance Liquid Chromatography and Liquid chromatography-mass spectrometry. Thin layer radiochromatography was utilized for its quality control studies. Results: PIM was derived successfully after the tosylation reaction. The radioiodination yield of PIM-TOS was over 85%. Conclusion: In the current study, radioiodination potential of PIM with ¹³¹I, as a potential theranostic hypoxia agent was investigated. Further experimental studies should be performed for developing a novel hypoxia probe including theranostics approaches.

Background: Gallium-68 is an ideal research and hospital-based PET radioisotope. The uptake mechanism of Gallium citrate is a combination of specific and non-specific processes, for example, vasodilatation, increased vascular permeability, plasma transferrin binding and lactoferrin and siderophores. Objective: In this study, by applying the ⁶⁸Ge/⁶⁸Ga generator product, a simple technique for the synthesis and quality control of 68Ga-citrate was introduced and was followed by preliminary animal studies. Methods: The synthesis of ⁶⁸Ga-citrate was performed with a cationic method using the Scintomics automated synthesis system (Scintomics GmbH GRP module 4V). Since the standard procedure for quality control (QC) was not available, the definition of chemical and radiochemical purity of ⁶⁸Ga-citrate was carried out according to the ICH Q2(R1) guideline. The standard QC tests were analysed with Scintomics 8100 radio-HPLC system equipped with a radioactivity detector. In this study, a New Zealand rabbit weighing 2520 g was used for PET/CT images. Results: ⁶⁸Ga-citrate synthesis was performed by a cationic method without using organic solvents. The labelling efficiency was found to be >98% . The HPLC method used to assess the radiochemical purity of ⁶⁸Ga -citrate was validated as rapid, accurate and reproducible enough to apply it to patients safely. The physiological distribution of ⁶⁸Ga-citrate was investigated in a healthy rabbit. The blood pool, liver, spleen, kidneys and growth plates were the most common sites of ⁶⁸Ga-citrate involvement.

Background: Extremity exposures may raise the risk of cancer induction among radiographers involved in the preparation and administration of technetium-99m labelled radiopharmaceuticals. Objective: To estimate finger doses on radiographers at a South African tertiary hospital. Methods: Adhesive tape was used to securely fix a calibrated thermoluminescent dosimeter (TLD) on fingertips and bases of ring and index fingers of both hands of five radiographers who prepared and administered technetium-99m labelled radiopharmaceuticals. Rubber gloves were worn to avoid TLD contamination. TLDs doses were read with a Harsaw TLD Reader (Model 3500) after a week. Results: Five radiographers prepared and administered technitium-99m labelled radiopharmaceuticals (activity range; 78.20 GBq - 132.78 GBq during a one-week measurement period). A radiographer handling 132.78 GBq received 4.74±0.52 mSv on both hands; 5.52, 4.55, 5.11 and 4.60 mSv on the fingertip of the index finger of the dominant hand (FIDH), fingertip of the ring finger of the dominant hand (FRDH), fingertip of the index finger of the non-dominant hand (FINDH) and fingertip of the ring finger of the non-dominant hand (FRNDH), respectively. The respective doses received on the finger bases were 4.50 mSv, 4.60, 4.21 and 3.48 mSv. The radiographer handling 78.20 GBq received 0.85±0.18 mSv on both hands, 1.04, 1.17, 0.77 and 1 mSv for the FIDH, FRDH, FINDH and FRNDH, respectively, while respective doses for the bases were 0.8, 0.9, 0.6 and 0.8 mSv. Conclusion: The extremity exposures were below the annual limit (500 mSv). However, the use of syringe shields could still reduce the finger doses further.

Background: Early diagnosis of Parkinson's disease (PD) is of primary importance. The delayed (3-4 h after injection) Iodine-123-Metaiodobenzylguanidine (123I-mIBG) scintigraphy has been proven to be effective in early differential diagnosis for Lewy body disease. But early imaging (15-30 min after injection) has only been marginally studied for its possible diagnostic role. In this prospective study, a threshold for the early Heart-to-Mediastinum (H/M) count ratio has been investigated, obtaining a diagnostic accuracy analogous to conventional, delayed imaging. Methods: One hundred and eight patients with suspected Parkinson's disease (PD) were acquired after 15 and 240 minutes from the injection of 150-185 MBq of 123I-mIBG. The early and late H/M (He/Me and Hl/Ml) were evaluated by drawing Region-of-Interests on the heart and the upper half of the mediastinum. Optimal threshold (Youden index) and overall predictive performance were determined by receiver operating characteristic curve, classifying tentatively patients having an Hl/Ml lower than 1.6 as suffering from PD. Results: He/Me was not significantly different from Hl/Ml (p-value=0.835). The Area-under-curve was 0.935 (95% CI: 0.845-1.000). The He/Me optimal threshold was 1.66, with sensitivity, specificity, and diagnostic accuracy of 95.5% , 85.7 and 90.7% respectively. Conclusion: The He/Me Ratio is almost as accurate as the widely used delayed 123I-mIBG imaging, reducing the burden of delayed imaging but preserving the diagnostic accuracy of the method. Moreover the differential diagnosis in Parkinson's disease can be made in just 25 minutes against the 4 hours currently needed, lowering costs of the healthcare system and improving patients compliance.

Background: To compare visual and semi-quantitative analysis of brain [¹⁸F]Florbetaben PET images in Mild Cognitive Impairment (MCI) patients and relate this finding to the degree of ß-amyloid burden. Methods: A sample of 71 amnestic MCI patients (age 74 ± 7.3 years, Mini Mental State Examination 24.2 ± 5.3) underwent cerebral [¹⁸F]Florbetaben PET/CT. Images were visually scored as positive or negative independently by three certified readers blinded to clinical and neuropsychological assessment. Amyloid positivity was also assessed by semiquantitative approach by means of a previously published threshold (SUVr ≥ 1.3). Fleiss kappa coefficient was used to compare visual analysis (after consensus among readers) and semi-quantitative analysis. Statistical significance was taken at P<0.05. Results: After the consensus reading, 43/71 (60.6% ) patients were considered positive. Cases that were interpreted as visually positive had higher SUVr than visually negative patients (1.48 ± 0.19 vs 1.11 ± 0.09) (P<0.05). Agreement between visual analysis and semi-quantitative analysis was excellent (k=0.86, P<0.05). Disagreement occurred in 7/71 patients (9.9% ) (6 false positives and 1 false negative). Agreement between the two analyses was 90.0% (18/20) for SUVr < 1.1, 83% (24/29) for SUVr between 1.1 and 1.5, and 100% (22/22) for SUVr > 1.5 indicating lowest agreement for the group with intermediate amyloid burden. Conclusion: Inter-rater agreement of visual analysis of amyloid PET images is high. Agreement between visual analysis and SUVr semi-quantitative analysis decreases in the range of 1.1

Background: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder. Neuroimaging findings are commonly considered rather non-specific. To date, no neuroreceptorial brain imaging with ¹²³I-FP-CIT(DaTScan) is known in subjects with SSADH deficiency. Methods: A 30-year-old man gained our attention to rule out any potential nigrostriatal dopaminergic presynaptic pathway alterations in a clinical context of a γ-hydroxybutyric aciduria. He showed impossibility to the autonomous gait, head and trunk retropulsion, lower limbs strength deficit, verbal and upper limbs motor stereotypies and irregular eye tracking. Results: His brain MRI depicted basal ganglia signal abnormalities. Brain SPECT with DaTSCan images showed a global significant reduction of radiotracer uptake. Conclusions: The findings obtained by means of the ¹²³I-DaTScan brain SPECT may give rise to new concerns on pathophysiological aspects of the SSADH deficiency disorder that has never been investigated before, such as the nigrostriatal dopaminergic system’s functionality, encouraging further investigation.