Assessment of Cell Cytotoxicity and Comet Assay on HER2/neu Positive Cell Line Due to 111In Auger Electrons as DNA-Targeting Radioimmunoconjugate.

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.

Preparation and Biological Evaluation of 67Gallium- Labeled Iranian Hemiscorpius Lepturus Scorpion Venom.

BACKGROUND: The Hemiscorpius lepturus (H. lepturus) is a deadly scorpion species living in the southern Iran. OBJECTIVE: H. lepturus induces delayed toxicity symptoms and understanding the long term biodistribution/ biokinetic of the venom is of great interest in toxicology. METHODS: A Ga-67 labeled venom was prepared using a DOTA -conjugated venom followed by radiolabeling using 67GaCl3 at 40°C for 90 min. The purification of the radiolabeled venom was performed using size exclusion-chromatography (radiochemical purity 71%). The radiolabeled venom was stable in the final solution in the presence of human serum at 37°C for 72 hours. The tissue distribution was studied in blood, heart, liver, spleen, muscle, brain, kidney, intestine and skin tissues at the intervals of 1, 4, 24, 48 and 72 hours using tissue counting and SPECT imaging. RESULTS: The radiolabeled venom mixture obtained with an estimated molar activity of 0.52 MBq/µg. The main accumulation tissues during the first 72 hours were kidneys, blood, liver, intestines, stomach and skin, respectively. Therefore, it is likely that H. lepturus' clinical effects and renal toxicity are primary and caused by direct effects of the H. lepturus venom. CONCLUSION: The results have largely shown the direct clinical effects on the studied tissues during the 72-hour period and antivenom administration can strongly alleviate the toxicity effects as early as 72 hours in the management of the patients.

68Ga-radiolabeled bombesin-conjugated to trimethyl chitosan-coated superparamagnetic nanoparticles for molecular imaging: preparation, characterization and biological evaluation.

INTRODUCTION: Nowadays, nanoparticles (NPs) have attracted much attention in biomedical imaging due to their unique magnetic and optical characteristics. Superparamagnetic iron oxide nanoparticles (SPIONs) are the prosperous group of NPs with the capability to apply as magnetic resonance imaging (MRI) contrast agents. Radiolabeling of targeted SPIONs with positron emitters can develop dual positron emission tomography (PET)/MRI agents to achieve better diagnosis of clinical conditions. METHODS: In this work, N,N,N-trimethyl chitosan (TMC)-coated magnetic nanoparticles (MNPs) conjugated to S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) as a radioisotope chelator and bombesin (BN) as a targeting peptide (DOTA-BN-TMC-MNPs) were prepared and validated using fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), thermogravimetric analysis (TGA), vibrating sample magnetometer (VSM), and powder X-ray diffraction (PXRD) tests. Final NPs were radiolabeled with gallium-68 (68Ga) and evaluated in vitro and in vivo as a potential PET/MRI probe for breast cancer (BC) detection. RESULTS: The DOTA-BN-TMC-MNPs with a particle size between 20 and 30 nm were efficiently labeled with 68Ga (radiochemical purity higher than 98% using thin layer chromatography (TLC)). The radiolabeled NPs showed insignificant toxicity (>74% cell viability) and high affinity (IC50=8.79 µg/mL) for the gastrin-releasing peptide (GRP)-avid BC T-47D cells using competitive binding assay against 99mTc-hydrazinonicotinamide (HYNIC)-gamma-aminobutyric acid (GABA)-BN (7-14). PET and MRI showed visible uptake of NPs by T-47D tumors in xenograft mouse models. CONCLUSION: 68Ga-DOTA-BN-TMC-MNPs could be a potential diagnostic probe to detect BC using PET/MRI technique.

Optimized Production and Biological Evaluation of 68Ga-PDTMP as a New Agent for PET Bone Scanning.

INTRODUCTION: In this study, 68Ga-PDTMP was introduced as a novel agent for PET bone scanning. METHODS: 68Ga-PDTMP was prepared with radiochemical purity of higher than 98% at the optimized conditions. RESULTS: Stability tests showed no decrease in radiochemical purity, even after 120 min. The capacity binding of 76.3% ± 0.7% after 10 min incubation for 68Ga-PDTMP was observed. CONCLUSION: Biological studies in normal mice demonstrated that most of the remained activity is transmitted from blood into bones. The results show that 68Ga-PDTMP can be considered as a potential radiolabelled complex for PET bone scanning.

Development of a Radiolabeled Amlodipine Analog for L-type Calcium Channel Imaging.

PURPOSE: The non-invasive imaging and quantification of L-type calcium channels (also known as dihydropyridine channels) in living tissues is of great interest in diagnosis of congestive heart failure, myocardial hypertrophy, irritable bowel syndrome etc. METHODS: Technetium-99m labeled amlodipine conjugate ([99mTc]-DTPA-AMLO) was prepared starting freshly eluted (<1 h) 99mTechnetium pertechnetate (86.5 MBq) and conjugated DTPAAMLO at pH 5 in 30 min at room temperature in high radiochemical purity (>99%, RTLC; specific activity: 55-60 GBq/mmol). The calcium channel blockade activity (CCBA) and apoptosis/necrosis assay of DTPA-amlodipine conjugate evaluations were performed for the conjugate. Log P, stability, bio-distribution and imaging studies were performed for the tracer followed by biodistribution studies as well as imaging. RESULTS: The conjugate demonstrated low toxicity on MCF-7 cells and CCBA (at µm level) compared to the amlodipine. The tracer was stable up to 4 h in final production and presence of human serum and log P (-0.49) was consistent with a water soluble complex. The tracer was excreted through kidneys and liver as expected for dihydropyridines; excluding excretory organs, calcium channel rich smooth muscle cells; including colon, intestine and lungs which demonstrated significant uptake. SPECT images supported the bio-distribution data up to 4 h. CONCLUSION: significant uptake of [99mTc]-DTPA-AMLO was obtained in calcium channel rich organs. The complex can be a candidate for further SPECT imaging for L-type calcium channels.

Preclinical Evaluation of 68Ga-MAA from Commercial Available 99mTc-MAA Kit.

99mTc-Macroaggregated Albumin (99mTc-MAA) has been used as a perfusion agent. This study described development of the 68Ga-MAA via commercially available kits from Pars-Isotopes Company as a 99mTc-MAA kit. 68Ge/68Ga generator was eluted with suprapure HCl (0.6 M, 6 mL) in 0.5 mL fractions. The two fractions with the highest 68GaCl3 activity were generally used for labeling purposes. After labeling, the final product was centrifuged 2 times to purify the solution. Five rats were sacrificed at each exact time interval (from 15 min to 2 h post injection) and the percentage of injected dose per gram (%ID/g) of each organ was measured by direct counting from 11 harvested organs of rats. The RTLC showed that labeling yields before centrifuges were 90% and 95% for Pars-Isotopes and GE kits, respectively and after centrifuges, they became 100%. The microscopic size examination showed a shift in the particle sizes post centrifuges and the biodistribution data revealed the efficiency and benefits of centrifuges in terms of preventing the of liver and bone marrow uptakes especially for Pars-Isotopes kits. Our results showed that after centrifuges of the final product, the lung uptakes increased from 89% to more than 97% of %ID/g after 5 min post injections. The whole procedure took less than 25 min from elution to the final product. Since 99mTc-MAA remained longer than 68Ga-MAA in the lung and 68Ga-MAA showed better image qualities, using 68Ga-MAA is recommended.

Preclinical Study of 68Ga-DOTATOC: Biodistribution Assessment in Syrian Rats and Evaluation of Absorbed Dose in Human Organs.

OBJECTIVES: Gallium-68 DOTA-DPhe1-Tyr3-Octreotide (68Ga-DOTATOC) has been applied by several European centers for the treatment of a variety of human malignancies. Nevertheless, definitive dosimetric data are yet unavailable. According to the Society of Nuclear Medicine and Molecular Imaging, researchers are investigating the safety and efficacy of this radiotracer to meet Food and Drug Administration requirements. The aim of this study was to introduce the optimized procedure for 68Ga-DOTATOC preparation, using a novel germanium-68 (68Ge)/68Ga generator in Iran and evaluate the absorbed doses in numerous organs with high accuracy. METHODS: The optimized conditions for preparing the radiolabeled complex were determined via several experiments by changing the ligand concentration, pH, temperature and incubation time. Radiochemical purity of the complex was assessed, using high-performance liquid chromatography and instant thin-layer chromatography. The absorbed dose of human organs was evaluated, based on biodistribution studies on Syrian rats via Radiation Absorbed Dose Assessment Resource Method. RESULTS: 68Ga-DOTATOC was prepared with radiochemical purity of >98% and specific activity of 39.6 MBq/nmol. The complex demonstrated great stability at room temperature and in human serum at 37°C at least two hours after preparation. Significant uptake was observed in somatostatin receptor-positive tissues such as pancreatic and adrenal tissues (12.83 %ID/g and 0.91 %ID/g, respectively). Dose estimations in human organs showed that the pancreas, kidneys and adrenal glands received the maximum absorbed doses (0.105, 0.074 and 0.010 mGy/MBq, respectively). Also, the effective absorbed dose was estimated at 0.026 mSv/MBq for 68Ga-DOTATOC. CONCLUSION: The obtained results showed that 68Ga-DOTATOC can be considered as an effective agent for clinical PET imaging in Iran.

Preparation and preclinical evaluation of 68Ga-DOTA-amlodipine for L-type calcium channel imaging.

AIM: In order to develop a possible tracer for L-type calcium channel imaging, we here report the development of a Ga-68 amlodipine derivative for possible PET imaging. MATERIALS AND METHODS: Amlodipine DOTA conjugate was synthesized, characterized and went through calcium channel blockade, toxicity, apoptosis/necrosis tests. [68Ga] DOTA AMLO was prepared at optimized conditions followed by stability tests, partition coefficient determination and biodistribution studies using tissue counting and co incidence imaging up to 2 h. RESULTS: [68Ga] DOTA AMLO was prepared at pH 4-5 in 7-10 min at 95°C in high radiochemical purity (>99%, radio thin layer chromatography; specific activity: 1.9-2.1 GBq/mmol) and was stable up to 4 h with a log P of -0.94. Calcium channel rich tissues including myocardium, and tissues with smooth muscle cells such as colon, intestine, and lungs demonstrated significant uptake. Co incidence images supported the biodistribution data up to 2 h. CONCLUSIONS: The complex can be a candidate for further positron emission tomography imaging for L type calcium channels.

Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran.

During past 3 decades, nuclear medicine has flourished as vibrant and independent medical specialty in Iran. Since that time, more than 200 nuclear physicians have been trained and now practicing in nearly 158 centers throughout the country. In the same period, Tc-99m generators and variety of cold kits for conventional nuclear medicine were locally produced for the first time. Local production has continued to mature in robust manner while fulfilling international standards. To meet the ever-growing demand at the national level and with international achievements in mind, work for production of other Tc-99m-based peptides such as ubiquicidin, bombesin, octreotide, and more recently a kit formulation for Tc-99m TRODAT-1 for clinical use was introduced. Other than the Tehran Research Reactor, the oldest facility active in production of medical radioisotopes, there is one commercial and three hospital-based cyclotrons currently operational in the country. I-131 has been one of the oldest radioisotope produced in Iran and traditionally used for treatment of thyrotoxicosis and differentiated thyroid carcinoma. Since 2009, (131)I-meta-iodobenzylguanidine has been locally available for diagnostic applications. Gallium-67 citrate, thallium-201 thallous chloride, and Indium-111 in the form of DTPA and Oxine are among the early cyclotron-produced tracers available in Iran for about 2 decades. Rb-81/Kr-81m generator has been available for pulmonary ventilation studies since 1996. Experimental production of PET radiopharmaceuticals began in 1998. This work has culminated with development and optimization of the high-scale production line of (18)F-FDG shortly after installation of PET/CT scanner in 2012. In the field of therapy, other than the use of old timers such as I-131 and different forms of P-32, there has been quite a significant advancement in production and application of therapeutic radiopharmaceuticals in recent years. Application of (131)I-meta-iodobenzylguanidine for treatment of neuroblastoma, pheochromocytoma, and other neuroendocrine tumors has been steadily increasing in major academic university hospitals. Also (153)Sm-EDTMP, (177)Lu-EDTMP, (90)Y-citrate, (90)Y-hydroxyapatite colloid, (188/186)Re-sulfur colloid, and (188/186)Re-HEDP have been locally developed and now routinely available for bone pain palliation and radiosynovectomy. Cu-64 has been available to the nuclear medicine community for some time. With recent reports in diagnostic and therapeutic applications of this agent especially in the field of oncology, we anticipate an expansion in production and availability. The initiation of the production line for gallium-68 generator is one of the latest exciting developments. We are proud that Iran would be joining the club of few nations with production lines for this type of generator. There are also quite a number of SPECT and PET tracers at research and preclinical stage of development preliminarily introduced for possible future clinical applications. Availability of fluorine-18 tracers and gallium-68 generators would no doubt allow rapid dissemination of PET/CT practices in various parts of our large country even far from a cyclotron facility. Also, local production and availability of therapeutic radiopharmaceuticals are going to open exciting horizons in the field of nuclear medicine therapy. Given the available manpower, local infrastructure of SPECT imaging, and rapidly growing population, the production of Tc-99m generators and cold kit would continue to flourish in Iran.

Development of [64Cu]-DOTA-PR81 radioimmunoconjugate for MUC-1 positive PET imaging.

OBJECTIVE: Breast cancer radioimmunoscintigraphy targeting MUC1 expression is a growing field of work in nuclear medicine research. PR81 is a monoclonal antibody that binds with high affinity to MUC1, which is over expressed on breast tumors. In this study, we report production, quality control and preclinical qualifications of a copper-64 labeled PR81 for PET imaging of breast cancer. METHODS: PR81 was conjugated with DOTA-NHS-ester and purified by molecular filtration followed by chelate:mAb ratio determination by spectrophotometric method. DOTA-PR81 was labeled with (64)Cu followed by radiochemical purity, in vitro stability, in vitro internalization and immunoreactivity determination. The tissue biodistribution of the (64)Cu-DOTA-PR81 and (64)Cu-DOTA-hIgG was evaluated in BALB/c mice with breast carcinoma tumors using tissue counting and imaging. RESULTS: The radiochemical purity of radioimmunoconjugate was >95±1.9% (ITLC) (specific activity; 4.6 µCi/µg). The average number of chelators per antibody was 3.4±0.3:1. The (64)Cu-DOTA-PR81 showed immunoreactivity towards MUC1 antigen and MCF7 cell line with significant in vitro stability (>89% in PBS and 78±0.5% in human serum) over 48 h. Maximum internalized activity of radiolabeled PR81 in 4-8 h was 81.5%. The biodistribution and scintigraphy studies showed the accumulation of the complex at the site of tumors with high sensitivity and specificity compared to control probes. CONCLUSION: The results showed that (64)Cu-DOTA-PR81 may be considered as a potential PET tracer for diagnosis and follow-up of MUC1 expression in oncology.

Preparation and Evaluation of (68)Ga-ECC as a PET Renal Imaging Agent.

PURPOSE: Development of a gallium-68-labeled renal tracer can be a good substitute for Tc-99m, a known SPECT tracer. In this study, effort was made to develop (68)Ga-ethylenecysteamine cysteine ((68)Ga-ECC). METHODS: Ga-ECC was prepared using generator-based (68)GaCl3 and ethylenecysteamine cysteine (ECC) at optimized conditions. Stability of the complex was checked in human serum followed by partition coefficient determination of the tracer. The biodistribution of the tracer in rats was studied using tissue counting and PET/CT imaging up to 120 min. RESULTS: Ga-ECC was prepared at optimized conditions in 15 min at 90 °C (radiochemical purity ≈97 ± 0.88 % ITLC, >99 % HPLC, specific activity: 210 ± 5 GBq/mM). (68)Ga-ECC was a water-soluble complex based on partition coefficient data (log P; -1.378) and was stable in the presence of human serum for 2 h at 37 °C. The biodistribution of the tracer demonstrated high kidney excretion of the tracer in 10-20 min. The SUVmax ratios of the liver to left kidney were 0.38 and 0.39 for 30 and 90 min, respectively, indicating high kidney uptake. CONCLUSION: Initial biodistribution results showed significant kidney and urinary excretion of the tracer comparable to that of the homologous (99m)Tc compound. The complex could be a possible PET kidney imaging agent with a fast imaging time.

Preparation, quality control and biodistribution assessment of ¹5³Sm-BPAMD as a novel agent for bone pain palliation therapy.

OBJECTIVE: Various phosphonate ligands labeled with ß(-)-emitting radionuclides have shown good efficacy for bone pain palliation. In this study, a new agent for bone pain palliation has been developed. METHODS: ¹5³Sm-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (¹5³Sm-BPAMD) complex was prepared using BPAMD ligand and ¹5³SmCl3. The effect of various parameters on the labeling yield of ¹5³Sm-BPAMD including ligand concentration, pH, temperature and reaction time were studied. Radiochemical purity of the radiolabeled complex was checked by instant thin layer chromatography (ITLC). Stability studies of the complex in the final preparation and in the presence of human serum were performed up to 48 h. Partition coefficient and hydroxyapatite (HA) binding of the complex were investigated and biodistribution studies (SPECT imaging and scarification) were performed after injection of the complex to Syrian mice up to 48 h post-injection. The biodistribution of the complex was compared with the biodistribution of the ¹5³Sm cation in the same type mice. RESULTS: ¹5³Sm-BPAMD was prepared in high radiochemical purity >98% and specific activity of 267 GBq/mmol at the optimal conditions. The complex demonstrated significant stability at room temperature and in human serum at least for 48 h. HA binding assay demonstrated that at the amount of more than 5 mg, approximately, all radiolabeled complex was bound to HA. At the pH 7.4, LogP o/w was -1.86 ± 0.02. Both SPECT and scarification showed major accumulation of the labeled compound in the bone tissue. CONCLUSION: The results show that ¹5³Sm-BPAMD has interesting characteristics as an agent for bone pain palliation; however, further biological studies in other mammals are still needed.

Comparison of estimated human dose of (68)Ga-MAA with (99m)Tc-MAA based on rat data.

OBJECTIVE: (99m)Tc macroaggregated albumin ((99m)Tc-MAA) that had been used as a perfusion agent has been evaluated. In this study, we tried to estimate human absorbed dose of 68Ga-MAA via commercially available kit from Pars-Isotopes, based on biodistribution data in wild-type rats, and compare our estimation with the available absorbed dose data from (99m)Tc-MAA. METHODS: For biodistribution of 68Ga-MAA, three rats were sacrificed at each selected times after injection (15, 30, 45, 60, and 120 min) and the percentage of injected dose per gram of each organ was measured by direct counting from rats data from 11 harvested organs. The medical internal radiation dose formulation was applied to extrapolate from rats to human and to project the absorbed radiation dose for various organs in humans. RESULTS: The biodistribution data for 68Ga-MAA showed that the most of the activity was taken up by the lung (more than 97 %) in no time. Our dose prediction shows that a 185-MBq injection of 68Ga-MAA into humans might result in an estimated absorbed dose of 4.31 mGy in the whole body. The highest absorbed doses are observed in the adrenals, spleen, pancreas, and red marrow with 0.36, 0.34, 0.26, and 0.19 mGy, respectively. CONCLUSION: Since the (99m)Tc-MAA remains longer than 68Ga-MAA in the lung and 68Ga-MAA has good image qualities and results in lower amounts of dose delivery to the critical organs such as gonads, red marrow, and adrenals, the use of 68Ga-MAA is recommended.

Development of Protective Immunity against Inactivated Iranian Isolate of Foot-and-Mouth Disease Virus Type O/IRN/2007 Using Gamma Ray-Irradiated Vaccine on BALB/c Mice and Guinea Pigs.

OBJECTIVES: Foot-and-mouth disease virus (FMDV) causes a highly contagious disease in cloven-hoofed animals and is the most damaging disease of livestock worldwide, leading to great economic losses. The aim of this research was the inactivation of FMDV type O/IRN/1/2007 to produce a gamma ray-irradiated (GRI) vaccine in order to immunize mice and guinea pigs. METHODS: In this research, the Iranian isolated FMDV type O/IRN/1/2007 was irradiated by gamma ray to prepare an inactivated whole virus antigen and formulated as a GRI vaccine with unaltered antigenic characteristics. Immune responses against this vaccine were evaluated on mice and guinea pigs. RESULTS: The comparison of the immune responses between the GRI vaccine and conventional vaccine did not show any significant difference in neutralizing antibody titer, memory spleen T lymphocytes or IFN-γ, IL-4, IL-2 and IL-10 concentrations (p > 0.05). In contrast, there were significant differences in all of the evaluated immune factors between the two vaccinated groups of mice and negative control mice (p < 0.05). The protective dose 50 for the conventional and GRI vaccines obtained were 6.28 and 7.07, respectively, which indicated the high potency of both vaccines. CONCLUSION: GRI vaccine is suitable for both routine vaccination and control of FMDV in emergency outbreaks.

Absorbed dose assessment of (177)Lu-zoledronate and (177)Lu-EDTMP for human based on biodistribution data in rats.

Over the past few decades, several bone-seeking radiopharmaceuticals including various bisphosphonate ligands and ß-emitting radionuclides have been developed for bone pain palliation. Recently, (177)Lu was successfully labeled with zoledronic acid ((177)Lu-ZLD) as a new generation potential bisphosphonate and demonstrated significant accumulation in bone tissue. In this work, the absorbed dose to each organ of human for (177)Lu-ZLD and (177)Lu-ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP;as the only clinically bone pain palliation agent) was investigated based on biodistribution data in rats by medical internal radiation dosimetry (MIRD) method. (177)Lu-ZLD and (177)Lu-EDTMP were prepared in high radiochemical purity (>99%, instant thin layer chromatography (ITLC)) at the optimized condition. The biodistribution of the complexes demonstrated fast blood clearance and major accumulation in the bone tissue. The highest absorbed dose for both (177)Lu-ZLD and (177)Lu-EDTMP is observed in trabecular bone surface with 12.173 and 10.019 mSv/MBq, respectively. The results showed that (177)Lu-ZLD has better characteristics compared to (177)Lu-EDTMP and can be a good candidate for bone pain palliation.

Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent / Produção, controle de qualidade, avaliação de biodistribuição e avaliação da dose preliminar de [177Lu] -tetra complexo fenil porfirina como um possível agente terapêutico

Due to interesting therapeutic properties of ¹⁷⁷Lu and tumor avidity of tetraphenyl porphyrins (TPPs), ¹⁷⁷Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. ¹⁷⁷Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu₂O₃sample with thermal neutron flux of 4 × 10¹³ n.cm^-2.s^-1. Tetraphenyl porphyrin was synthetized and labeled with ¹⁷⁷Lu. 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 ¹⁷⁷Lu cation and [¹⁷⁷Lu]-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. [¹⁷⁷Lu]-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...

Devido às propriedades interessantes do ¹⁷⁷Lu e da avidez tumoral das tetrafenil porfirinas (TPP), desenvolveu-se a ¹⁷⁷Lu-tetrafenil porfirina como composto terapêutico potencial. ¹⁷⁷Lu de atividade específica de 2,6-3 GBq/mg foi obtido por irradiação de amostra de Lu₂O₃ com fluxo térmico de nêutrons de 4 × 10¹³ n.cm^-2.s^-1. Sintetizou-se a tetrafenil porfirina e marcou-se com ¹⁷⁷Lu. 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 ¹⁷⁷Lu e para o [¹⁷⁷Lu]-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 [¹⁷⁷Lu]-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...

Estimated human absorbed dose for (68)Ga-ECC based on mice data: comparison with (67)Ga-ECC.

OBJECTIVE: Nowadays, the efficacies of (68)Ga-based tracers are comparable to that of (18)F-based agents and have stimulated researchers to investigate the potential of (68)Ga-based positron emission tomography (PET) imaging agents. In this study, the human absorbed dose of (68)Ga labeled with ethylenecysteamine cysteine (68)Ga-ECC and (67)Ga-ECC was estimated based on biodistribution data in mice by the medical internal radiation dose (MIRD) method. METHODS: For biodistribution of (67)Ga/(68)Ga-ECC, three mice were killed by CO2 asphyxiation at each selected times after injection (15, 30, 45, 60, 120 min for (68)Ga-ECC and 0.5, 2 and 48 h for (67)Ga-ECC), and then the tissue (heart, lung, brain, intestine, skin, stomach, kidneys, liver, muscle and bone) was removed. RESULTS: (68)Ga-ECC as a new PET renal imaging agent was prepared with radiochemical purity of >97 % in less than 30 min. The biodistribution data for (68)Ga-ECC showed that the most of the activity extracted from the urinary tract very fast. Comparison between human absorbed dose estimation for these two agents indicated that the absorbed dose of the most organs after injection of (67)Ga-ECC is approximately tenfold higher than the amount after (68)Ga-ECC injection. CONCLUSION: The results showed that (68)Ga-ECC is a more appropriate agent rather than (67)Ga-ECC and generally can be a good candidate for PET renal imaging applications.

Assessment of human effective absorbed dose of 67 Ga-ECC based on biodistribution rat data.

OBJECTIVE: In a diagnostic context, determination of absorbed dose is required before the introduction of a new radiopharmaceutical to the market to obtain marketing authorization from the relevant agencies. In this work, the absorbed dose of [67 Ga]-ethylenecysteamine cysteine [(67 Ga)ECC] to human organs was determined by using distribution data for rats. METHODS: For biodistribution data, the animals were sacrificed by CO2 asphyxiation at selected times after injection (0.5, 2 and 48 h, n = 3 for each time interval), then the tissue (blood, heart, lung, brain, intestine, feces, skin, stomach, kidneys, liver, muscle and bone) were removed. The absorbed dose was determined by Medical Internal Radiation Dose (MIRD) method after calculating cumulated activities in each organ. RESULTS: Our prediction shows that a 185-MBq injection of (67)Ga-ECC into the humans might result in an estimated absorbed dose of 0.029 mGy in the whole body. The highest absorbed doses are observed in the spleen and liver with 33.766 and 16.847 mGy, respectively. CONCLUSION: The results show that this radiopharmaceutical can be a good SPECT tracer since it can be produced easily and also the absorbed dose in each organ is less than permitted absorbed dose.