Current Radiopharmaceuticals - Volume 11, Issue 2, 2018

Background and Objective: Motion due to patient's breathing can introduce heavy bias in PET/CT, both in image quality and quantitation. This paper is a review of the main technical solutions available to manage movement in PET/CT studies: a) Respiratory Gated (RG), b) Motion Free (MF), c) End Expiration (EE), d) Banana Artefact Management (BAM) and e) Data Driven Gating (DDG). Methods: The most diffused solutions (RG, MF and EE) are based on LIST mode acquisition of a PET Field of View (4D FOV), centered on the anatomical region of interest; to link PET data not only to time and to spatial position but also to the corresponding breathing phase, the synchronized acquisition of the patient's breathing curve is performed by an external tracking device. Different commercial tools to track and to record patient breathing cycle are available to associate the internal organ motion with a measurable external parameter; for example these systems can measure the pressure on a chest elastic belt, the air flow trough patient nose, the breath-in and breath-out air temperature or the markers movement on the thorax/ abdominal region. Recently DDG techniques are developed to correct respiratory motion without the help of external motion tracking devices and to obtain a comparable result to that based on standard RG protocols. Results: The final result of an RG or DDG protocol is a sequence of 3D images showing organs and lesions movement; using the other motion management options a single 3D motion-free image is obtained without motion artefacts and degradation. Compared to the previously described options the BAM solution is not a real motion management protocol but just a Banana Artefact correction technique obtained using an Attenuation Correction Map calculated merging the Whole Body Helical CT with a Cine CT on the diaphragm area. Conclusion: The motion management in PET/CT imaging shows benefits in terms of image quality, quantification and lesion detectability and it is useful both in diagnostic and radiotherapy planning.

Background and Objective: Even though the benefits of radiation therapy are well established, it is important to recognize the broad spectrum of radiation-induced changes, particularly in the central nervous system. The possible damage to the brain parenchyma may have clinical consequences and in particular cognitive impairment might be one of the major complications of radiotherapy. To date, no studies have investigated the effects of focal radiation therapy on brain structure and function together with the assessment of their clinical outcomes at a long follow-up. Methods: In this prospective study, we evaluated in six patients the possible brain late effects after radiation therapy, using a standardized neuropsychological battery, MRI and 18F-FDG PET using SPM and semi-quantitative methods, in patients affected by cranial base tumors who underwent gamma knife or tomotherapy. Results: Neuropsychological examinations showed no cognitive impairment after the treatment. In all patients, both MRI assessment and 18F-FDG-PET did not reveal any local or distant anatomical and metabolic late effects. Conclusion: The present study support the safety of advanced radiation therapy techniques. 18F-FDGPET, using SPM and semi-quantitative methods, might be a valuable tool to evaluate the cerebral radiotoxicity in patients treated for brain neoplasms.

Background: In medical cyclotron facilities, 11C is produced according to the 14N(p,α)11C reaction and widely employed in studies of prostate and brain cancers by Positron Emission Tomography. It is known from literature that the 11C-target assembly shows a reduction in efficiency during time, meaning a decrease of activity produced at the end of bombardment. This effect might depend on aspects which are still not completely known. Objective: Possible causes of the loss of performance of the 11C-target assembly were addressed by Monte Carlo simulations. Methods: Geant4 was used to model the 11C-target assembly of a GE PETtrace cyclotron. The physical and transport parameters to be used in the energy range of medical applications were extracted from literature data and 11C routine productions. The Monte Carlo assessment of 11C saturation yield was performed varying several parameters such as the proton energy and the angle of the target assembly with respect to the proton beam. Results: The estimated 11C saturation yield is in agreement with IAEA data at the energy of interest, while it is about 35% greater than the experimental value. A more comprehensive modeling of the target system, including thermodynamic effect, is required. The energy absorbed in the inner layer of the target chamber was up to 46.5 J/mm2 under typical irradiation conditions. Conclusion: This study shows that Geant4 is potentially a useful tool to design and optimize targetry for PET radionuclide productions. Tests to choose the Geant4 physics libraries should be performed before using this tool with different energies and materials.

Objective: The purpose of this study was to develop lipid-water based drug delivery system of Alendronate Sodium (ALD) in liquid and solid form obtained by using spray drying method and compare these two forms with radioactive cell culture studies. Methods: This study included the development of liquid and solid form obtained by spray drying method, radiolabelling of ALD with 99mTc, preparation of formulations containing 99mTc -ALD and evaluation of their permeability with Caco-2 cell. The liquid formulations have been developed by using various surfactants, co-surfactants, oil and water phases. Physicochemical characterizations like droplet size, polydispersity index (PDI) and zeta potential measurements and short term stability studies were investigated. Results: According to the measurement results, two oil in water formulations (F1-L and F2-L) were selected and spray dried with Buchi mini spray dryer apparatus to provide solid formulations (F1-S and F2-S). ALD was labeled with 99mTc and added to formulations. The effect of experimental conditions on radiolabeling efficiency of ALD and stability of all formulations containing 99mTc-ALD were investigated through Radio Thin Layer Chromatography (RTLC). It was observed that the labeling efficiency of ALD was greater than 90% and all formulations were found to be stable up to 6 h at room temperature. Permeability of radiolabeled ALD from all formulations was performed by using Caco-2 cells. According to the cell culture studies, permeability from spray dried formulations of ALD was found higher than liquid formulations. Conclusion: As a conclusion, spray dried formulations could be a promising drug delivery system for enhancing the permeability of ALD. Furthermore, this study is a good example of the use of radiolabeled compounds in drug development.

Background: Ionizing radiation induces DNA damage on normal cell results in apoptosis and cell deaths. Objectives: The radioprotective effects of cerium oxide nanoparticles (CNPs) on genotoxicity, apoptosis and necrosis induced by Ionizing Radiation (IR) in human healthy lymphocytes as highly radiosensitive cells were investigated. Materials and Methods: Lymphocytes were prepared from three volunteers and then treated with CNPs at different concentrations and exposed to IR at dose 1.5 Gy. The radioprotective effects of CNPs were assessed by micronucleus (MN) assay and flow cytometry. Interleukin-1 was quantified in treated samples. Results: It was found that CNPs reduced the percentage of MN induced by IR in lymphocytes up to 73%. CNPs treatment significantly reduced IR-induced apoptotic and necrotic incidences in human lymphocytes. CNPs significantly reduced IL-1β produced in cell environment exposed to IR. The present study demonstrated that CNPs may be an effective radioprotector against DNA damage and apoptosis induced by IR mainly through mitigation of pro-inflammatory process in lymphocytes. Conclusion: This result provides a new potential indication of CNPs for protection of normal cells during radiation therapy in the treatment of cancer or unwanted radiation exposure.

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.

Background and Objective: The future of medicine relies on the capability to forecast the future and in the development of new drugs. The same rationale is applied to radiopharmacy. In this direction the development of nano-radiopharmaceuticals represents the most effective glance of the future. Methods: In this manuscript we developed an efficient, rapid and direct methodology to label ultrasmall polymeric nanoparticle (10 to 12 nm) and regular polymeric nanoparticles (200 to 210 nm), both obtained by double emulsion technique, with Ga-68 in order to promote the development of PETnanoradiopharmaceuticals. Results: The results showed that the methodology is reliable and efficient to label both, polymeric small and ultra-small nanoparticles, with a labeling efficacy of over 90% in both cases. Also, the plasma stability as the bindings test corroborates the application and stability of the nanoparticles labeled with 68Ga. Conclusion: The results are preliminary and the data must be supported by animal biodistribution assay.

Background and Objective: Gallium-68 is a PET isotope available in each nuclear medicine departments, even those not equipped with a cyclotron, since it is easily obtained by eluting compact and transportable generator system. The preparation of Ga-68 DOTA-labeled compounds is performed by remotely controlled automated systems developed in order to ensure production efficiency, reproducibility of the results, fast reaction time, to facilitate the synthesis and minimize the radiation exposure. Many automatic synthesis systems are available on the radiopharmaceutical market, however, they requires some technical adaptations for routine use. We reported the [68Ga]Ga-DOTA-TOC production by automated cassette-based theranostic synthesizer system used in combination with a disposable GMP grade cassette system for cationic purification. Methods: The synthesizer is integrated with the 68Ge/68Ga generator systems and it allows to perform elution, eluate purification and radiolabeling in about 38 minutes. We have performed in 2 year (January 2016 - January 2018) over 100 [68Ga]Ga-DOTA-TOC preparations. Results: The average synthesis yield of radiopharmaceutical production was 54.4 ± 2.3 % and the radiochemical purity average was found 96.94 ± 0.74 %. Only three [68Ga]Ga-DOTA-TOC preparations have failed. Conclusion: The methodology and the adopted technical solutions allowed to obtain a high quality radiopharmaceutical product as required by the European Pharmacopoeia.

Objective: The present study had determine the impact of prolonged storage in a cartridge or syringe on the quality of the [18F]-radiopharmaceuticals used in our center [18F]fludeoxyglucose and [18F]fluorocholine). [18F]-radiopharmaceuticals registered as ready-to-use drugs are prepared in multidose flasks. When the change of packaging must be made extemporaneously for the preparation of patient unit doses in a syringe or cartridge, this is under the responsibility of radiopharmacists. As drug quality in medical devices (syringe or cartridge) is not evaluated during the marketing authorization of such radiopharmaceuticals, an evaluation of drug stability in such devices seems interesting. In addition, if there are difficulties in patient care (placement of the catheter, lack of personal, etc.) or equipment problems (technical issue with the automated dispenser delaying the delivery of the prepared dose), the contact time of [18F]-radiopharmaceuticals with the medical devices (cartridge or syringe) increases. Methods: Appearance, pH, radiochemical purity, sterility and endotoxin tests were made according the current European Pharmacopoeia. Adsorption tests were made according the literature. Results: There was no drug absorption of [18F]fludeoxyglucose or [18F]fluorocholine after 1.5h, which may be related to their hydrophilic nature. No drug radiolysis was observed even after dilution of the radiopharmaceuticals (appearance, pH, and radiochemical purity were unchanged). No impurity from medical devices (cartridge or syringe) was observed, and microbiological aspects remained in specification of the current European Pharmacopoeia. Conclusion: These radiopharmaceuticals repackaged in plastic medical devices retained their quality after dispensing and prolonged storage.

Background: 223Ra was the first therapeutic alpha-emitting radionuclide registered for clinical practice. This radionuclide is targeting actively bone-forming cells, and it is approved for treating metastatic skeletal disease in prostate cancer. 18F-PET is used to detect skeletal metastatic disease based on osteoblastic activity. The aim of this study was to analyze, if 18F-PET can be used assessing the results of 223Ra therapy, and to report final median overall survival in a total of 773 therapy cycles. Methods: A 161 men with castration-resistant prostate cancer were included in a single institution study (Protocol#: PA14-0848) and they received a total of 773 223Ra therapy cycles. Results: The median overall survival (95% CI) was 12.4 (9.1, 16.1) months in patient population. Interim Na18F-PET imaging was applied in 14 patients at baseline, after 3 cycles and after 6 cycles. TLF10 (skeletal disease burden at SUV-values >10 on Na18F -PET) were calculated in all these PET studies, and there was no significant association between change in TLF10 after 3 cycles and TLF10 after 6 cycles (p=0.20). Conclusion: From these results, we conclude that interim imaging does not help in assessing the final outcome of 223Ra therapy. The survival benefit of 223Ra therapy alone is more than a year in a high-risk group of advanced prostate cancer.