Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent

;Devido às propriedades interessantes do ;177;Lu e da avidez tumoral das tetrafenil porfirinas (TPP), desenvolveu-se a ;177;Lu-tetrafenil porfirina como composto terapêutico potencial. ;177;Lu de atividade específica de 2,6-3 GBq/mg foi obtido por irradiação de amostra de Lu;2;O;3; com fluxo térmico de nêutrons de 4 × 10;13; n.cm;-2;.s;-1;. Sintetizou-se a tetrafenil porfirina e marcou-se com ;177;Lu. A pureza radioquímica do complexo foi estudada usando método de Cromatografia Instantânea de Camada Delgada ( ITLC). A estabilidade do complexo foi checada na formulação final e no ser humano por 48 h. A biodistribuição do composto marcado em órgãos vitais de ratos do tipo selvagem foi estudada por mais de 7 dias. A dose absorvida para cada órgão humano foi calculada pelo método da Dose Médica de Radiação Interna (MIRD). Estudo farmacocinético comparativo detalhado foi efetuado para o cátion ;177;Lu e para o [;177;Lu]-TPP. O complexo foi preparado com pureza radioquímica >;97±1% e atividade específica de 970-1000 MBq/mmol. Os dados de biodistribuição e os resultados dosimétricos mostraram que todos os tecidos receberam uma dose absorvida aproximadamente insignificante devido à rápida excreção do complexo pelo trato urinário. O [;177;Lu]-TPP pode ser um agente interessante de direcionamento do tumor devido à baixa captação pelo fígado e pela dose bem baixa absorvida, de, aproximadamente, 0,036 do corpo humano total.;Due to interesting therapeutic properties of ;177;Lu and tumor avidity of tetraphenyl porphyrins (TPPs), ;177;Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. ;177;Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu;2;O;3;sample with thermal neutron flux of 4 × 10;13; n.cm;-2;.s;-1;. Tetraphenyl porphyrin was synthetized and labeled with ;177;Lu. Radiochemical purity of the complex was studied using Instant thin layer chromatography (ITLC) method. Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied up to 7 d. The absorbed dose of each human organ was calculated by medical internal radiation dose (MIRD) method. A detailed comparative pharmacokinetic study was performed for ;177;Lu cation and [;177;Lu]-TPP. The complex was prepared with a radiochemical purity: >;97±1% and specific activity: 970-1000 MBq/mmol. Biodistribution data and dosimetric results showed that all tissues receive approximately an insignificant absorbed dose due to rapid excretion of the complex through the urinary tract. [;177;Lu]-TPP can be an interesting tumor targeting agent due to low liver uptake and very low absorbed dose of approximately 0.036 to the total body of human

The Role of Intermittent Energy Restriction Diet on Metabolic Profile and Weight Loss among Obese Adults

Obesity is a disease defined by an elevated body mass index (BMI), which is the result of excessive or abnormal accumulation of fat. Dietary intervention is fundamental and essential as the first-line treatment for obese patients, and the main rule of every dietary modification is calorie restriction and consequent weight loss. Intermittent energy restriction (IER) is a special type of diet consisting of intermittent pauses in eating. There are many variations of IER diets such as alternate-day fasting (ADF) and time-restricted feeding (TRF). In the literature, the IER diet is known as an effective method for bodyweight reduction. Furthermore, IER diets have a beneficial effect on systolic or diastolic pressure, lipid profile, and glucose homeostasis. In addition, IER diets are presented as being as efficient as a continuous energy restriction diet (CER) in losing weight and improving metabolic parameters. Thus, the IER diet could present an alternative option for those who cannot accept a constant food regimen

Development and evaluation of 89Zr-trastuzumab for clinical applications

Objective(s): Due to the suitable physical characteristics of 89Zr as a PET radionuclide and affinity of Trastuzumab monoclonal antibody against HER2, [89Zr]Zr-Trastuzumab was prepared and went through preclinical evaluations for ultimate human applications.Methods: 89Zr was produced by using 89Y(p,n)89Zr reaction at a 30 MeV cyclotron (radionuclide purity>99.9%, specific activity of 17 GBq/µg). p-SCN-Bn-Deferoxamine (DFO); was conjugated to trastuzumab, followed by labeling with 89Zr in oxalate form at optimized condition. Cell binding, internalization and, radioimmuno-activity assays were studied using HER2+ BT474 and HER2- CHO cell lines. Finally, the biodistribution of the radioimmunoconjugate was assessed in normal and HER2+ BT474 tumor-bearing mice using tissue counting and imaging at different intervals after injection. Also, a woman with HER2-positive metastatic breast cancer under treatment with Herceptin underwent both [89Zr]Zr-Trastuzumab and, [18F]FDG PET/CTs.Results: 89Zr was produced with high radionuclidic and radiochemical purities (>99%) and [89Zr]Zr-DFO-Trastuzumab was prepared with radiochemical purity of >98% and specific activity of 9.85 GBq/µmol. The radioimmunoconjugate was stable both in PBS buffer and in human serum for at least 48 h. The radioimmunoactivity assay demonstrated about 70% of [89Zr]Zr-DFO-Trastuzumab is bound to the BT474 cells at the number of 250×106 cells. Cell binding studies showed that about 28% of radioimmunoconjugate is attached to BT474 cells after 90 min. Internalization studies showed that 50% of [89Zr]Zr-Trastuzumab is internalized to BT474 cells only in 6 h. The biodistribution study of the labeled compound in normal mice demonstrated the same pattern of the monoclonal antibodies which is entirely different from the biodistribution of free 89Zr. Biodistribution and imaging studies in tumor-bearing mice showed the significant uptake values of [89Zr]Zr-Trastuzumab in tumor sites. [89Zr]Zr-Trastuzumab PET/CT revealed metastatic lesions documented previously with [18F]FDG PET/CT scan in a woman with breast cancer who was under treatment with Herceptin. Although the [18F]FDG PET/CT scan had better quality images, the valuable and unique advantage of [89Zr]Zr-Trastuzumab PET/CT is delineating HER2+ metastasis, which is essential in diagnosis and HER2-based treatments.Conclusion: The prepared [89Zr]Zr-Trastuzumab has a high potential radio-pharmaceutical for immune-PET imaging of the patients with HER2+ tumors

Optimized Production Assessment, Compartmental Modeling and Dosimetric Evaluation of 177Lu- PSMA-617 for Clinical Trials

177Lu-PSMA-617 was prepared at the optimized conditions (95°C, 15-18 µg peptide, 35-40 min; solid phase purification) using 177Lu obtained from 176Lu(n, γ)177Lu reaction(>98%, ITLC, HPLC, S.A. 22-24 TBq/mM) followed by stability (up to 48 h), biodistribution studies (up to 168 h), planar imaging, compartmental modeling and dosimetry estimations via Sparks’s extrapolation method in human organs. Kidney is the critical organ with the dose of 0.067 mGy/MBq and the radiopharmaceutical can be safely used in trials considering the human dose

Preparation and quality control of 177 Lu-chitosan for radiosynovectomy

ABSTRACT Introduction: Rheumatoid arthritis (RA) is the most common autoimmune disease, leading to the destruction of the joints and causing pain, disability, and immobility in the patients. Radiosynovectomy (RSV) has been applied as an effective treatment for the patients with resistant synovitis after failure of long-term pharmacotherapy and intra-articular steroid injection for more than 50 years. Several radiopharmaceuticals have been developed for RSV so far, but still development of new radiophamaceuticals is of crucial interest. In this research, the 177 Lu-chitosan complex ( 177 Lu-CHITO) was introduced as a new agent for RSV. Methods: 177 Lu was produced by irradiation of a natural Lu 2 O 3 target at a thermal neutron flux of approximately 4 × 1

Beneficial Effects of Anti-Inflammatory Diet in Modulating Gut Microbiota and Controlling Obesity

Obesity has consistently been associated with an increased risk of metabolic abnormalities such as diabetes, hyperlipidemia, and cardiovascular diseases, as well as the development of several types of cancer. In recent decades, unfortunately, the rate of overweight/obesity has increased significantly among adults and children. A growing body of evidence shows that there is a relationship between metabolic disorders such as obesity and the composition of the gut microbiota. Additionally, inflammation is considered to be a driving force in the obesity–gut microbiota connection. Therefore, it seems that anti-inflammatory nutrients, foods, and/or diets can play an essential role in the management of obesity by affecting the intestinal flora and controlling inflammatory responses. In this review, we describe the links between the gut microbiota, obesity, and inflammation, and summarize the benefits of anti-inflammatory diets in preventing obesity

Preliminary Dosimetry Study of 67Ga-AATS for Human Based on Biodistribution Data in Rats

Introduction Gallium-67 (67Ga) has been used as a radionuclide for imaging a variety of solid tumors since 1969. Since then use of various gallium-based radiotracers has been reported. Recently, 67Ga-labeled acetylacetate bis(thiosemicarbazones) (67Ga-AATS) complex with significant tumor accumulation and fast blood clearance has been employed. Materials and Methods In this study, the absorbed dose of 67Ga-AATS in each human organ was evaluated and compared with 67Ga-citrate as the most commonly used form of 67Ga in nuclear medicine. 67Ga was produced via 68Zn(p,2n)67Ga reaction at 30 MeV cyclotron. Moreover, 67Ga-AATS was produced by adding 50 µl of AATS to absolute ethanol (1 mg/ml) in a gallium-containing vial at 80-90 °C. The absorbed dose of each human organ was calculated, using RADAR method, based on biodistribution data in Wistar rats. Results According to the results, 67Ga-AATS was produced with radionuclidic and radiochemical purity higher than 99% and 93%, respectively. The highest absorbed dose was reported in the bone surface (0.401 mGy/MBq), whereas the whole-body absorbed dose was 0.092 mGy/MBq. Conclusion The absorbed dose of each human organ was comparable with the absorbed dose received by each organ after 67Ga-citrate injection. Considering this interesting finding and the significant tumor uptake, it seems that 67Ga-AATS can be used as an appropriate SPECT tracer

Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as a bone pain palliation agent

Objective(s): Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although 177Lutriethylene tetramine hexa methylene phosphonic acid (abbreviated as 177Lu- TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of 177Lu-TTHMP have been investigated and compared with the previously reported data. Methods: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the 177Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. Results: 177Lu was prepared with 2.6-3 GBq/mg specific activity and radionuclide purity of 99.98%. 177Lu-TTHMP was successfully prepared with high radiochemical purity (>99%). The complex showed rapid bone uptake, while accumulation in other organs was insignificant. Dosimetric results showed that all tissues received almost insignificant absorbed doses in comparison with bone tissues. Conclusion: Based on the obtained results, this radiopharmaceutical can be a good candidate for bone pain palliation therapy in skeletal metastases

The effect of silver nanoparticles on ovarian histopathological changes in mice treated with isoniazid

The study attempts to evaluate the effects of silver nanoparticles on preventing the destruction of ovarian tissue in mice treated with isoniazid. In this experiment, 40 adult female rats were randomly divided into 5 groups (n=8) including: control group (no treatment), sham group (0.2 mg / kg normal saline), experimental group 1 (50mg / kg Ison-iazid), experimental group 2 (50mg / kg Isoniazid and 0.25mg/kg silver nanoparticles) and the experimental group 3 (50mg / kg isoniazid and 0.50mg / kg silver nanoparticles). All injections were prescribed for 15 days and Isoniazid and silver nano-particles were received orally and intraperitoneally, respectively. All the animals were operated on and their ovarian tissues were removed and placed in 10% formalin solution. Then H & E staining was performed for histological studies. In experimental groups 1, 2 and 3, reduction in the number of secondary follicles and corpus luteum was obse-rved in comparison with the control group. There was a significant increase in the number of primordial and graafian follicles in experimental group 3 when it was compared with isoniazid group. In addition, a significant increase was observed in the number of primary monolayer follicles in experimental groups 2 and 3 in comparison with the experi-mental group 1. It should be assumed that by the utilization of the minimum dose of the silver nanoparticles, its toxic effects on the ovarian tissue could be ignored. Therefore, the minimum dose of the silver nanoparticles can reduce the isoniazid effects on ovarian tissue