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

A comparative study of preliminary dosimetry for human based on distribution data in rats with 111In, 90Y, 153Sm, and 177Lu labeled rituximab

Radio immunotherapy is one of the most important and effective therapies for B-cell non Hoddgkin’s lymphoma treatment. Today, anti CD-20 antibodies labeled with beta emitter radionuclides are used in radio immunotherapy. Various radionuclides for labeling anti CD-20 antibodies have been studied and developed for the treatment and diagnosis of malignancies. This paper describes the preparation, bio-distribution and absorbed dose rate of 111In, 90Y, 177Lu, and 153Sm labeled anti CD-20 antibodies (rituximab) in human organs, after injection to rats. The macro cyclic bifunctional chelating agent, N-succinimidyl-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA-NHS) for conjugation to antibody, was used to prepare DOTA-rituximab. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. Radio-labeling was performed at 40 °C for 24 hours. After the quality control studies, the final radioactive solution was injected intravenously into rats through their tail vein. The tissue uptakes of each injection were measured. Then we calculated S values for 177Lu and 153Sm by using specific absorbed fractions and data used in the manner of radio-labeled analysis and dosimetry for humans. The absorbed dose rate of each organ was calculated in the specific time by medical internal radiation dose method with linear approximation in the activity measurements

The development of radiogallium-acetylacetonate bis(thiosemicarbazone) complex for tumour imaging

BACKGROUND: Various radiometal complexes have been developed for tumour imaging, especially Ga-68 tracer. In this work, the development of a radiogallium bis(thiosemicarbazone) complex has been reported. MATERIAL AND METHODS: [67Ga]acetylacetonate bis(thio-semicarbazone) complex ([67Ga]AATS) was prepared starting with [67Ga]Gallium acetate and freshly prepared acetylacetonate bis(thiosemicarbazone) (AATS) for 30 min at 90ºC. The partition co-efficient and stability of the tracer was determined in final solution (25ºC) and the presence of human serum (37ºC) for up to 24 hours. The biodistribution of the labelled compound in wild-type and fibrosarcoma-bearing rodents were determined for up to 72 hours. RESULTS: The radiolabelled Ga complex was prepared to a high radiochemical purity (> 97%, HPLC) followed by initial biodistribution data with the significant tumour accumulation of the tracer at two hours, which is far higher than free Ga-67 cation, while the compound wash-out is significantly faster. CONCLUSION: The above-mentioned pharmacokinetic properties suggest an interesting radiogallium complex prepared by the PET Ga radioisotope, 68Ga, in accordance with the physical half life, for use in fibrosarcoma tumours and possibly in other malignancies

Preparation and quality control of 177Lu-[tris(1,10-phenanthroline) lutetium(III)] complex for therapy

The 177Lu-[tris(1,10-phenanthroline)lutetium(III)] complex (177Lu-PQ3) was prepared successfully with high radiochemical purity (> 99%). Lu-177 chloride was obtained by thermal neutron flux (4 × 1013 n.cm–2.s–1) of natural Lu2(NO3)3 sample, dissolved in acidic media. The radiochemical yield was checked by measuring the radiochemical purity of the 177Lu-PQ complex by ITLC (10 mM DTPA, pH = 5, as mobile phase). The final complex solution was injected intravenously into wild-type male rats and bio-distribution of the complex was checked for up to 48 hours. The dose limiting organs were shown to be the reticulu-endothelial system. The bio-distribution of the labelled compounds in tumour-bearing animals is under investigation. Nuclear Med Rev 2010; 13, 2: 49–5

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

IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for Drug Delivery

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000 ' s, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled 'Nanosized delivery systems for radiopharmaceuticals' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor

Razvoj radiomarkiranog β-humanog koriogonadotropina

-human chorionic gonadotropin (-hCG) was successively labeled with [67Ga] gallium chloride after conjugation with freshly prepared diethylenetriaminepentaacetic acid dianhydride (ccDTPA). After solid phase purification of the radiolabeled hormone, high performance liquid chromatography showed radiochemical purity higher than 95 % under optimized conditions (specific activity = 2223 TBq mM1, labeling efficiency 80 %). Preliminary in vivo studies (ID g1, %) in male wild-type rats showed marked gonadal uptake of the tracer after 240 minutes in agreement with the biodistribution studies and reported -hCG receptors. Target to blood ratios were 5.1 and 15.2 after 3 and 24 hours, respectively, while target to muscle ratios were 35 and 40 after 3 and 24 hours, respectively.Beta-humani korionski gonadotropin (beta-hCG) uspješno je markiran s [67Ga] galijevim kloridom nakon konjugacije sa svježe priređenim dianhidridom dietilentriaminpentaoctene kiseline (ccDTPA). Nakon čišćenja radiomarkiranog hormona na čvrstoj fazi, radiokemijska čistoća bila je prema HPLC veća od 95 % (specifična aktivnost = 22-23 TBq mM-1, učinkovitost markiranja 80 %). Preliminarni in vivo pokusi (ID g-1, %) na mužjacima divljeg tipa štakora pokazali su da obilježeni hormon značajno ulazi u gonade nakon 240 minuta, što je u suglasnosti s ispitivanjima biodistribucije i podacima o receptorima za beta-hCG. Omjer koncentracija u gonadama i krvi bio je 5,1, odnosno 15,2 nakon 3, odnosno 24 sata, dok je omjer koncentracija u gonadama i mišićima bio 35, odnosno 40 nakon 3, odnosno 24 sata

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