Current radiopharmaceuticals最新文献

Background: The testis is one of the most radiosensitive tissues in pelvic radiotherapy, especially in prostate cancer. Febuxostat (FBX), as an inhibitor of xanthine oxidase, has anti-inflammatory, antioxidant, and anti-apoptosis properties.

Objectives: The aim of this research was to survey the protective effect of FBX against irradiation (IR)-induced testis damage via the attenuation of oxidative stress.

Methods: Male adult mice were randomly assigned into eight groups: control, FBX with three doses of 5, 10, and 15 mg/kg, IR with 6 Gy, IR + FBX (IR + FBX in three doses), respectively. In the IR + FBX groups, FBX was administrated for 8 consecutive days, and then mice were exposed to IR at a dose of 6 Gy on the 9th day. One day after irradiation, biochemical parameters were evaluated in the testis of animals, while histopathological assessment had been performed on 14th day.

Results: Irradiation led to the induction of testicular toxicity. FBX significantly protected histopathological alterations and decreased oxidative stress parameters in irradiated testis. Besides, FBX increased the diameter and germinal epithelial thickness of seminiferous tubules and Johnson's score in irradiated mice.

Conclusion: Data showed that FBX markedly protected testicular injury induced by IR by inhibiting oxidative stress and may be considered as an infertility inhibitor in cancer patients, especially prostate cancer.

Background: Breast cancer Auger electron therapy is a growing field of study in radioimmunotherapy and oncology research. Trastuzumab, a high affinity-binding monoclonal antibody against HER2/neu is which is over-expressed in breast tumors, is used in radiopharmaceutical development.

Objectives: In this work, the lethal effects of ¹¹¹In³⁺, ¹¹¹In-DTPA-trastuzumab and ¹¹¹In-trastuzumab coupled-nuclear localizing sequence peptide (¹¹¹In-DTPA-NLS-trastuzumab) on malignant cells were studied in vitro.

Methods: DTPA-NLS-trastuzumab was prepared using sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) conjugation with NLS peptide in the first step, followed by conjugation with diethylenetriaminepentaacetic acid (DTPA). Both DTPA-trastuzumab and DTPA- NLS-trastuzumab were labeled with ¹¹¹In followed by purification and quality control techniques. Sk-Br-3 (a HER2/neu+ cell line), was used in the cell viability assessment assay for ¹¹¹In, ¹¹¹In-DTPA-trastuzumab and ¹¹¹In-DTPA-NLS-trastuzumab (3.7 MBq) at 37 ºC. The cytotoxicity of the three species was studied using MTT and comet assay was utilized DNA damage detection.

Results: A significant radiochemical purity for ¹¹¹In-DTPA-NLS-trastuzumab (99.36% ± 0.30%, ITLC) at the DTPA:antibody ratio of 6.90 ± 0.34:1, was obtained. Significant cell viability difference was found for ¹¹¹In-DTPA-NLS-trastuzumab compared to the other treatments at two-time points. In addition, comet assay demonstrated significant DNA damage at 144 h using ¹¹¹In-DTPA- NLS-trastuzumab.

Conclusion: The results of cell viability and cell death using MTT assay and comet assay, respectively, demonstrate the NLS-peptide effectively facilitates ¹¹¹In-trastuzumab transport into the HER2/neu positive cancer cell nuclei to impose the radiotherapeutic effects of Auger electrons on DNA leading to cell death.

Aims: The aim of this retrospective study was to investigate SUVs variability with respect to lesion size, administered dose, and reconstruction algorithm.

Background: SUV_max and SUV_peak are influenced by technical factors as count statistics and reconstruction algorithms.

Objective: To fulfill the aim, we evaluated the SUVs variability with respect to lesion size, administered dose, and reconstruction algorithm (ordered - subset expectation _maximization plus point spread function option - OSEM+PSF, regularized Bayesian Penalized Likelihood - BPL) in a 5 - rings BGO PET/CT scanner.

Methods: Discovery IQ scanner (GE Healthcare, Milwaukee, Wisconsin, US) was used for list mode acquisition of 25 FDG patients, 12 injected with 3.7 MBq/kg (Standard Dose protocol - SD) and 13 injected with 1.8 MBq/kg (Low Dose protocol - LD). Each acquisition was reconstructed at different time/FOV with both OSEM+PSF algorithm and BPL using seven different beta factors. SUVs were calculated in 70 lesions and analysed in function of time/FOV and Beta. Image quality was evaluated as a coefficient of variation of the liver (CV - liver).

Results: SUVs were not considerably affected by time/FOV. However, SUVs were influenced by beta: differences were higher in small lesions (37% for SUV_max, 15% for SUV_peak) compared to larger ones (14% and 6%). CV - liver ranged from 6% with Beta-500 (LD and SD) to 13% with Beta- 200 (LD). CV - liver of BPL with Beta-350 (optimized for clinical practice in our institution) in LD was lower than CV - liver of OSEM+PSF in SD.

Conclusion: When a high sensitivity 5 - rings BGO PET/CT scanner is used with the same reconstruction algorithm, quantification by means of SUV_max and SUV_peak is a robust standard compared to the activity and scan duration. However, both SUVs and image quality are influenced by reconstruction algorithms and the related parameters should be considered to obtain the best compromise between detectability, quantification, and noise.

Clinical imaging equipment technological advancements offer insight into the evolution of mathematical techniques used to estimate parameters necessary to characterize the microvasculature and, thus, differentiate normal tissues from abnormal ones. These parameters are blood flow (F), capillary endothelial permeability surface area product (PS), vascular fraction (v_e), and extravascular extracellular space size (EES,v_e). There are a number of well-established approaches that exist in the literature; however, their analysis is restricted by complexity and is heavily influenced by noise. On the other hand, these characteristics can also be calculated using simpler and straightforward approaches such as Up-Slope Method (USM) and Graphical Analysis (GA). The review looks into the theoretical background and clinical uses of these methodologies, as well as the applicability of these techniques in various sections of the human body.

Background: ¹⁷⁷Lu-Dotatate is used in the treatment of somatostatin-receptor-positive inoperable progressive gastroenteropancreatic neuroendocrine tumors. A co-infusion of amino acids (AAs) is administered to prevent renal toxicity.

Objective: This study aimed to quantify the impact of two types of AA cocktails on the pharmacokinetics and toxicity of ¹⁷⁷Lu-Dotatate.

Methods: Four injections of 7400 MBq ¹⁷⁷Lu-Dotatate were given per patient with administration of either Primene® 10% (containing a cocktail of 20 AAs with 22g of Lysine and 16.8 g of Arginine) or Lysakare® (containing 25 g of Lysine and 25 g of Arginine). Nine blood samples were collected at each cycle. Radioactivity-time data were analyzed according to a population-based model using NONMEM (version 7.4.1). Renal and hematological toxicity was evaluated after each cycle.

Results: 1,678 ¹⁷⁷Lu-Dotatate plasma concentrations versus time were analyzed from 83 consecutive patients with Primene® (n= 45 pts) or Lysakare® (n= 36 pts). Population pharmacokinetic analysis showed that Primene® significantly increased the elimination rate constant of ¹⁷⁷Lu-Dotatate as opposed to Lysakare®. Primene® also significantly lowered Lutathera® plasma exposure (AUC) by 34%, whereas Lysakare® increased AUC by 7%. There was no renal toxicity in either case. Lymphopenia significantly correlated with AUC (p=0.021) with a trend towards higher toxicity with Lysakare®.

Conclusion: Unlike Primene®, Lysakare® does not increase ¹⁷⁷Lu-Dotatate elimination. This difference is associated with a significant impact on AUC. The latter parameter has a high interpatient variability but a low intrapatient variability, which could have important clinical implications for treatment tailoring.

Introduction: Pulmonary embolism (PE) can be diagnosed by perfusion lung scintigraphy using human albumin macroaggregates labelled ^99mTc (^99mTc-MAA). When PE is suspected, subcutaneous Low Molecular Weight Heparin (LMWH) should be administered even before the results of the PE diagnostic flowchart. In our study, we aimed to evaluate a possible interaction (in vitro interference) between ^99mTc-MAA and LMWH.

Methods: The reconstitution of MAA kit was performed according to the manufacturer's instruction. After labelling, we carried out the following preparations: a standard dose of ^99mTc-MAA alone, as control; ^99mTc-MAA and enoxaparin at different ratios. According to the manufacturer's instruction, the radiochemical purity was performed and evaluated immediately (T₀), after 15 and 30 minutes after incubation (T₁₅ and T₃₀).

Results: We compared the radiochemical purity of ^99mTc-MAA with: (i) radiochemical purity of ^99mTc-MAA and enoxaparin (11 ratio), (ii) radiochemical purity of ^99mTc-MAA and enoxaparin (0.5 ratio), and (iii) radiochemical purity of ^99mTc-MAA and enoxaparin (ratio 2). No significant differences were found between all the measured parameters at each time point for each ratio. We also tested the stability of ^99mTc-MAA in physiological conditions (at 37°C in PBS): the initial radiochemical purity of ^99mTc-MAA was 99.78%. The values of 99mTc-MAA radiochemical purity were high in all conditions of possible interaction with LMWH, with values ranging from 98.00% at T0 to 95% at T₃₀.

Conclusion: We found no statistically significant change in the in vitro stability of ^99mTc-MAA in the presence of enoxaparin, excluding a possible direct interference. Future studies will be needed to check the ^99mTc-MAA stability under physiological conditions.

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 recent approval of radiopharmaceuticals for diagnosis and treatment of cancer is ushering nuclear medicine into a new era of theranostics and alpha therapy using radiopharmaceuticals labeled with ²²⁵Ac shows remarkable results in clinical trials. As such, reliable methods for the synthesis and quality control of ²²⁵Ac-radiopharmaceuticals are needed.

Objective: ²²⁵Ac-PSMA-617 is being used for targeted alpha therapy in patients with prostate cancer, and we had cause to synthesize the agent for preclinical use. However, technology transfer proved cumbersome owing to the paucity of information available on synthesizing and analyzing ²²⁵Ac-radiotherapeutics. To address this need, we describe a straightforward synthesis of ²²⁵Ac-PSMA- 617 as well as suitable approaches for quality control analysis using standard equipment in a modern PET Center.

Methods: PSMA-617 precursor was dissolved in 25 μL metal-free water (0.67 mg/mL) and combined with 500 μL 0.05M Tris buffer, pH 9. Actinium stock solution (~65 μCi in 15 μL) was added and the reaction was heated at 120°C for 40-50 min. The reaction was cooled and 0.6 mL gentisic acid solution (4 mg/mL in 0.2 M NH₄OAc) was added. To formulate the dose for injection, sterile saline, USP (8 mL) was added and the pH was adjusted by the addition of 100 μL 0.05 M Tris buffer (pH 9) to give a final pH of ~7.2. The final solution was filtered using a 0.22 μm GV sterile filter into a sterile dose vial. Radiochemical purity was determined by radio-TLC (eluent: 50mM Sodium Citrate, pH 5), and plates were analyzed using an AR2000 scanner.

Results: The method provided ²²⁵Ac-PSMA-617 in high radiochemical yield (57 ± 3 μCi, >99%) and radiochemical purity (98 ± 1%), formulated for preclinical studies (9 mL, pH = 7.2), n=3.

Conclusion: A straightforward synthesis of ²²⁵Ac-PSMA-617 is described that will facilitate production for (pre)clinical studies. The approach could also be applicable to the synthesis of other alpha radiotherapeutics incorporating ²²⁵Ac.

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: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated with a bifunctional chelator 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4- oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA) (hereafter referred to as Cell Death Indicator [CDI]), enters dead and dying cells and binds to 90kDa heat shock proteins (hsp90).

Objective: This study assesses stability, biodistribution, imaging, and radiation dosimetry of [68Ga]- Ga-CDI for positron emission tomography (PET).

Methods: Preparation of [⁶⁸Ga]Ga-CDI was performed as previously described. Product stability and stability in plasma were assessed using high-performance liquid chromatography. Biodistribution and imaging were conducted in ten healthy male Lewis rats at 1 and 2 h following intravenous [⁶⁸Ga]Ga-CDI injection. Human radiation dosimetry was estimated by extrapolation for a standard reference man and calculated with OLINDA/EXM 1.1.

Results: Radiochemical purity of [⁶⁸Ga]Ga-CDI averaged 93.8% in the product and 86.7% in plasma at 4 h post-synthesis. The highest concentration of [⁶⁸Ga]Ga-CDI is observed in the kidneys; [⁶⁸Ga]Ga-CDI is excreted in the urine, and mean retained activity was 32.4% and 21.4% at 1 and 2 h post-injection. Lower concentrations of [⁶⁸Ga]Ga-CDI were present in the small bowel and liver. PET CT was concordant and additionally demonstrated focal growth plate uptake. The effective dose for [⁶⁸Ga]Ga-CDI is 2.16E-02 mSv/MBq, and the urinary bladder wall received the highest dose (1.65E-02 mSv/Mbq).

Conclusion: [⁶⁸Ga] Ga-CDI is stable and has favourable biodistribution, imaging, and radiation dosimetry for imaging of dead and dying cells. Human studies are underway.