We have established a multiple higher accumulation of {99}mTc-Al[2]O[3] in SLM in comparison with import analogue. Considering this fact the clinical use of new domestic radiopharmaceutical will facilitate intraoperative identification of such nodes

Bragina, Olga Dmitrievna

Chernov, Vladimir Ivanovich

Dergilev, A. P.

Lyapunov, A. Yu.

Medvedeva, Anna Aleksndrovna

Sinilkin, Ivan Gennadjevich

Skuridin, Viktor Sergeyevich

Varlamova, Natalya Valeryevna

Zelchan, Roman Vladimirovich

IOP Conference Series : Materials Science and Engineering

Electronic archive of Tomsk Polytechnic University

  The Study of 99mTc-Aluminum Oxide Using for Sentinel Lymph Nodes Detection in Experiment A.A. Medvedeva 1, 2, I.G. Sinilkin 1, 2, R.V. Zelchan 1, 2, V.I. Chernov 1, 2, A.Yu. Lyapunov1, O.D. Bragina2, N.V. Varlamova2, V.S. Skuridin2, A.P. Dergilev3  1 Tomsk Cancer Research Institute, Kooperativny Street 5, Tomsk, Russia 2 Tomsk Polytechnic University, Lenin Avenue 30, Tomsk, Russia 3 Novosibirsk State Medical University, Krasny Prospect 52, Novosibirsk, Russia  E-mail: Сhernov@oncology.tomsk.ru  Abstarct: The purpose of the study was a comparative research of the possibility of using the radiopharmaceuticals 99mTc-Al2O3 and 99mTc-Nanocis for visualizing sentinel lymph nodes in the experiment. Measurement of the sizes of 99mТс-Al2O3 and 99mТс-Nanocis colloidal particles was performed in seven series of radiopharmaceuticals. Pharmacokinetics of 99mТс-Al2O3 and 99mТс-Nanocis was researched on 50 white male rats. The possibility of the use of 99mТс-Al2O3 and 99mТс-Nanocis for lymphoscintigraphy was studied in the experiments on 12 white male rats. Average dynamic diameter of the sol particle was 52-77 nm for 99mТс-Al2O3 and 16.7-24.5 nm for 99mТс-Nanocis. Radiopharmaceuticals accumulated in the inguinal lymph node – at 1 hour after administration the average uptake of 99mTc-Al2O3 was 8.6% in it and the accumula-tion of 99mTc-Nanocis was significantly lower - 1,8% (p <0,05). In all study point average up-take of 99mTc-Al2O3 in the lymph node was significantly higher 99mTc-Nanocis accumulation. The results dynamic scintigraphic studies in rats showed that 99mTc-Al2O3 and 99mTc-Nanocis actively accumulated into the lymphatic system. By using 99mTc-Al2O3 inguinal lymph node was determined in 5 minutes after injection and clearly visualize in all the animals in the 15th minute, when the accumulation became more than 1% of the administered dose. Further obser-vation indicated that the 99mTc-Al2O3 accumulation reaches a plateau in a lymph node (average 10.5%) for 2 hour study and then its accumulation remains practically at the same level, slight-ly increasing to 12% at 24 hours. In the case of 99mTc-Nanocis inguinal lymph node visualized in all animals for 15 minutes when it was accumulated on the average 1.03% of the adminis-tered dose. Plateau of 99mTc-Nanocis accumulation in the lymph node (average 2.05%) oc-curred at 2 hour of the study and remained almost on the same level (in average 2.3%) to 24 hours. Thus, the experimental study of a new domestic radiopharmaceutical showed that the 99mTc-Al2O3 several times actively accumulates in the lymph nodes as compared to imported analogue and its practical application will facilitate intraoperative identification of sentinel  lymph nodes. 1. Introduction In recent years radionuclide techniques have proven themselves to identify the  sentinel  lymph nodes (SLN) - first lymph nodes on the path of lymph drainage from a malignant tumor. These nodes, filter-PowerPlants2016 IOP PublishingIOP Conf. Series: Materials Science and Engineering 135 (2016) 012027 doi:10.1088/1757-899X/135/1/012027Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distributionof this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.Published under licence by IOP Publishing Ltd 1  ing afferent lymph, become a “trap” for cancer cells, and that is why SLN biopsy with followed by histological examination is an objective diagnostic criterion for the lymphatic metastasis detection. It is believed that if the SLN are not affected by metastatic disease, all other regional lymph nodes re-main intact [1-3, 5-7].  The world practice has considerable experience in relation to radionuclide visualization of SLN at melanoma and breast cancer. At tumors in other locations (lungs, head, neck, gastrointestinal tract, uterus) the effectiveness of this method is studied in scientific research [1-3, 6].   Optimal radiopharmaceuticals to identify SLN is colloid labeled with technetium-99m [1,6]. In Russian Federation, to identify the SLN has been applied colloidal rhenium sulphide (99mTc-Nanocis, CIS bio International). The main disadvantage of this radiopharmaceutical is the low level of accumu-lation in the SLN (1.5-2% of the administered dose) and redistribution to lymph nodes 2 and 3 orders, which reduces the specificity of SLN visualization [1, 3, 6, 7]. Currently, in the Russian Federation there are no registered radiopharmaceuticals for SLN imaging. In this regard, the Tomsk Cancer Research Institute and Tomsk Polytechnic University developed by the original radiopharmaceutical based on labeled with technetium-99m aluminum oxide (99mTc-Al2O3) (the project № 16.N08.12.1011 «Preclinical studies of new lymphotropic radiopharmaceutical labeled by technetium-99m aluminum oxide" Federal Program "Development of the Russian Federa-tion, the pharmaceutical and medical industry period up to 2020 and beyond "). The aim of present investigation was a comparative study of the possibility of using the radiophar-maceuticals 99mTc-Al2O3 and 99mTc-Nanocis for visualizing sentinel lymph nodes in the experiment. 2. Material and Methods  Measurement of the sizes of 99mTc-Al2O3 and 99mТс-Nanocis colloidal particles was performed in sev-en series of radiopharmaceuticals on apparatus NICOMP 380 ZLS (company PSS NICOMP, USA).  Pharmacokinetics of 99mTc-Al2O3 and 99mТс-Nanocis was researched on white male rats “Wistar” weighing 200-250 g; radiopharmaceuticals was injected between the first and second fingers of the hind paw subcutaneously in a dose of 30 MBq. Before the injection of radiotracer animals were anes-thetized with ethyl ether. The volume of the injected dose was 0.1 ml (volume activity is 300 MBq/ml). The animals were decapitated in groups of 10 individuals (5 rats for each radiopharmaceuti-cal) in 1, 2, 3, 5 and 24 h after injection of radiopharmaceuticals. The recovered organs and tissues were packed into vials for weighing and direct radioactivity measurement. Standard radiopharmaceutical and bioassays have the same volume (after weighing vi-als filled with distilled water up to the same level) and the geometric form. Radioassay of blood and internal organs (the contents of the radiopharmaceutical as a percentage of the entered radioactivity per 1 ml of blood or 1 g of tissue or organ) performed on the radiometer RIS A1 (Russian Federation). For radiometric studies differential discriminator was set up on the photon peak of 140 keV, with a window width of 20%. According to the results of radioassay also determined the level of the radio-pharmaceutical level in inguinal lymph node and injection site. The possibility of the use of 99mТс-Al2O3 and 99mТс-Nanocis for lymphoscintigraphy was studied in the experiments on 12 white male rats “Wistar” (6 rats for each radiopharmaceutical) weighing 300-350 g. Before a single subcutaneous injection of radiopharmaceuticals between the first and second fingers of the hind paw at a dose of 18-20 MBq and during scintigraphic studies animals were anesthe-tized using ethyl ether. All scintigraphic studies were performed on the gamma-camera E-CAM-180 (Siemens, USA) with a setting up of a differential discriminator on a photon peak of 140 keV, with a window width of 20%, using a parallel low-energy high-resolution collimator. During the study ani-mals were put with their ventral surface to the detector of the gamma camera so that the whole body of the animal appeared in picture. Since the introduction, kinetics of the distribution of radiopharmaceu-ticals through the organs and tissues was fixed by step-frame recording within 15 min (1 frame per minute), in the matrix of 64 * 64 pixels. Static scintigraphy was performed in 1, 2, 3 and 24 hours in the front and rear projections in the matrix of 256 x 256 with a set of 500 pulses per position. Accord-PowerPlants2016 IOP PublishingIOP Conf. Series: Materials Science and Engineering 135 (2016) 012027 doi:10.1088/1757-899X/135/1/0120272  ing to the results of scintigraphic studies the percent of radiopharmaceuticals accumulation in the in-guinal lymph node and the injection site from administered dose were determined. Keeping and participation of the animals in the experiment were performed in accordance with the rules adopted by the "European Convention for the Protection of Vertebrate Animals used for Experi-mental and other Scientific Purposes" (Strasbourg, 1986). The data received were processed by the method of variation statistics using “STATGRAF" numer-ic package. Between-group comparisons were done by using the Wilcoxon rank-sum test. 3. Results and Discussion Measurement of the sizes of radioactive particles of 99mТс-Al2O3 and 99mТс-Nanocis in 7 batches showed that the average dynamic diameter of the sol particle was 52-77 nm for 99mТс-Al2O3 and 16.7-24.5 nm for 99mТс-Nanocis, which, according to the literature, is quite acceptable for scintigraphic vis-ualization of lymph nodes [1, 3, 6]. Radiometry of rats organs showed that 99mTc-Al2O3 and 99mTc-Nanocis actively withdrew subcuta-neous injection spot - after 1 hour in the spot was about 2/3 of the administered dose (Table 1). After 24 hours at the injection site remained about half of the dose. Leaving the injection site, the radiopharmaceuticals accumulated in the inguinal lymph node – in 1 hour after administration the average accumulation of 99mTc-Al2O3 was 8.6% in it and the accumulation of 99mTc-Nanocis was significantly lower - 1,8% (p <0,05). In the second hour of study average accumulation of  99mTc-Al2O3 in inguinal lymph node has exceeded 10% and in a day gradually increased to 12.8%. Accumu-lation of 99mTc-Nanocis after 2 hours reached 3.6% and slightly fluctuated at this level up to 24 hours of observation (Table 1). In all study point average accumulation of 99mTc-Al2O3 in the lymph node was significantly higher 99mTc-Nanocis accumulation. Received through the thoracic duct into the blood radiopharmaceuticals, very actively uptake in liver and spleen. The hepatic level of accumulation of 99mTc-Al2O3 rise from 3.8% in 1 h after injection to 21.1% in 24 hours of the study, for 99mTc-Nanocis these values were 6.6% and 18.3%, respectively. In the spleen, the magnitude accumulation of 99mTc-Al2O3 ranges from 1.5% (in 1 hour) to 4.5% (in 24 hours), the level of accumulation of 99mTc-Nanocis grew from 1.3% (in 1 hour) to 3.6% (in 24 hours ). It was noted a slight content of radiopharmaceuticals in the heart, lungs and blood, which recorded less than 1% of the injected dose. The results dynamic scintigraphic studies in rats showed that 99mTc-Al2O3 and 99mTc-Nanocis ac-tively accumulated into the lymphatic system from the injection site (Table. 2). After 2 hours at the in-jection site was 57% of the administered dose of 99mTc-Al2O3 and 50.5% of 99mTc-Nanocis. After 24 hours the injection spot was kept less than half the dose of the radiopharmaceuticals.   Table 1. The content of 99mTc in the organs and tissues of rats at different times after subcutaneous in-jection of radiotracer 99mTc-Al2O3 and 99mTc-Nanocis according to direct radiometry. Time 1h 2h 3h 5h 24h 99mTc-Al2O3 Injection site (%) 68.3±5.3 57.0±8.7 53.6±5.0 51.1±5.2 46.7±6.7 Lymph node % 8.6± 1.1* 10.5± 1.6* 11.2± 1.6* 11.8± 1.9* 12.8± 1.4* Blood %/ml 0.91±0.01 0.26± 0.08 0.28± 0.08 0.30± 0.07 0.31±0.08+ Liver % 0.33± 0.15 0.38± 0.11 0.45± 0.14 0.43± 0.12 0.35± 0.11 %/g 0.13± 0.06 0.15± 0.05 0.18± 0.06 0.18± 0.05 0.14± 0.07 Stomach % 3.8±1.2 9.6±1.1 12.1±2.4 16.8±1.8 21.1±1.6 %/g 0.32±0.1 0.8±0.09 1.0±0.14 1.4±0.15 1.8±0.14 Spleen % 1.5± 0.4 2.6± 0.6 4.1± 0.9 4.3± 0.8 4.5± 0.9 PowerPlants2016 IOP PublishingIOP Conf. Series: Materials Science and Engineering 135 (2016) 012027 doi:10.1088/1757-899X/135/1/0120273  %/g 0.74±0.2 1.4±0.29 2.1±0.43 2.2±0.4 2.2±0.42 Heart % 0.41±0.11 0.29±0.12 0.67±1.08 0.6±0.07 0.9±0.1 %/g 0.34±0.1 0.24±0.09 0.56±0.11 0.61±0.06 0.76±0.07 Lung % 0.34±0.12 0.26±0.09 0.15±0.06 0.13±0.02 0.1±0.08 %/g 0.12±0.05 0.09±0.04 0.06± 0.03 0.05± 0.04 0.04±0.3 99mTc-Nanocis Injection site (%) 66.3±3.15 59.0±4.1 55.5±5.7 53.2±4.9 51.2±4.3 Lymph node % 1.8± 1.2 3.6± 2.4 3.6± 1.8 3.6± 1.7 3.2± 1.0 Blood %/ml 0.2±0.1 0.24± 0.04 0.27± 0.03 0.27± 0.07 0.3±0.1 Liver % 1.2± 0.2 1.5± 0.2 1.5± 0.4 1.5± 0.7 2.2± 0.4 %/g 0.48± 0.1 0.60± 0.15 0.62± 0.22 0.63± 0.31 0.88± 0.38 Stomach % 6.6±0.3 10.5±0.9 13.9±2.07 16.3±1.9 18.3±1.4 %/g 0.55±0.2 0.87±0.21 1.15±0.24 1.35±0.31 1.52±0.29 Spleen % 1.3± 0.2 2.1± 0.3 2.8± 0.5 3.3± 0.7 3.6± 0.6 %/g 0.65±0.1 1.1±0.15 1.4±0.14 1.65±0.2 1.80±0.2 Heart % 0.3±0.1 0.3±0.06 0.31±0.09 0.3±0.11 0.4±0.15 %/g 0.25±0.09 0.24±0.08 0.25±0.08 0.24±0.06 0.23±0.07 Lung % 0.6±0.1 0.6±0.12 0.61±0.15 0.59±0.14 0.54±0.2 %/g 0.22±0.09 0.22±0.1 0.23± 0.08 0.21± 0.06 0.20±0.1            * - p <0.05% compared to 99mTc-Nanocis  Table 2. The content of 99mTc at the injection site and inguinal lymph node after subcutaneous injec-tion of radiotracer 99mTc-Al2O3 and 99mTc-Nanocis according to dynamic scintigraphy. Localization Time after the in-jection Average accumulation of 99mTc-Al2O3 (%) Average accumulation of 99mTc-Nanocis (%) Injection site 5 minutes 76.8+3.7 82.7+5.0 15 minutes 71.3+4.2 67.7+3.0 1 h 68.2+5.3 55. 7+4.8 2 h 57.0+8.6 50.5+5.1 3 h 53.5+4.9 47.7+4.6 24 h 46.7+6.8 35.33+3.3 Inguinal lymph node 5 minutes 0.9+0.2 0.98+0.22 15 minutes 1.19+0.13 1.03+0.22 1 h 8.6+1.1 1.4+0.86 2 h 10.5+1.6 2.05+1.67 3 h 11.1+1.2 2.18+1.57 24 h 12.0+1.4 2.31+1.45         * - p <0.05% compared to 99mTc-Nanocis By using 99mTc-Al2O3 inguinal lymph node was determined in 5 minutes after injection and clearly visualize in all the animals in the 15th minute, when the accumulation became more than 1% of the administered dose. Further observation indicated that the 99mTc-Al2O3 accumulation reaches a plateau in a lymph node (average 10.5%) for 2 hour study (Fig. 1) and then its accumulation remains practical-ly at the same level, slightly increasing to 12% in 24 hours. In the case of 99mTc-Nanocis inguinal lymph node visualized in all animals for 15 minutes when it was accumulated on the average 1.03% of the administered dose. Plateau of 99mTc-Nanocis accumulation in the lymph node (average 2.05%) occurred in 2 hour of the study (Fig. 1) and remained almost on the same level (in average 2.3%) to 24 hours. PowerPlants2016 IOP PublishingIOP Conf. Series: Materials Science and Engineering 135 (2016) 012027 doi:10.1088/1757-899X/135/1/0120274    (a) (b) Figure 1. Scintigrams rats performed through 2 hours after injection of 99mTc-Al2O3  (a) and 99mTc-Nanocis (b). A - The level of radioactivity in the injection point (IP) – 56.3% of the injected dose, in the inguinal lymph node (LN) – 11.2%. B - bladder. B - The level of radioactivity in the injection point (IP) – 61.3% of the injected dose, in the inguinal lymph node (LN) – 3.5%. In oncology practice spot of radiopharmaceutical injections are often located in close proximity to the sentinel lymph node, making it difficult to visualize [1, 6]. We have established a multiple higher accumulation of 99mTc-Al2O3 in SLM in comparison with import analogue. Considering this fact the clinical use of new domestic radiopharmaceutical will facil-itate intraoperative identification of such nodes.  4. Conclusions Thus, the experimental study of a new domestic radiopharmaceutical showed that the 99mTc-Al2O3 several times actively accumulates in the lymph nodes as compared to imported analogue and its prac-tical application will facilitate intraoperative identification of SLN. References [1] Chernov VI, Sinilkin IG, Choynzonov EC, Chijevskaya SY, Titskaya AA, Zelchan RV, Bragina OD, Lyapunov AY, Skuridin VS  2015 Eur J Nucl Med Mol Imaging 42 (Suppl 1) 704 [2] Chernov VI, Sinilkin IG, Shiryaev SV. 2010 National leadership on nuclear medicine Ed. Lishmanov YB, Chernov VI Tomsk STT B 2 336 [3] Afanasyev SG, Avgustinovich AV, Chernov VI, Sinilkin IG 2009 Siberian Journal of Oncology 34 27 [4] Jimenez IR, Roca M, Vega E, García ML, Benitez A, Bajén M et al. 2008 Nucl Med Commun 29 166 [5] Paredes P, Vidal-Sicart S, Zanón G et al. 2005 E.J.Nucl. Med. 32 1283 [6] Schauer AJ et al. 2005 The Sentinel Lymph Node Concept Springer Berlin Heidelberg New York P 565 [7] Sinilkin I, Chernov V, Zelchan R, Titskaya A, Skuridin V 2014 Eur J Nucl Med Mol Imaging 41 (Suppl 2) 518  B LN IP LN IP PowerPlants2016 IOP PublishingIOP Conf. Series: Materials Science and Engineering 135 (2016) 012027 doi:10.1088/1757-899X/135/1/0120275

The Study of {99}mTc-Aluminum Oxide Using for Sentinel Lymph Nodes Detection in Experiment

The Study of {99}mTc-Aluminum Oxide Using for Sentinel Lymph Nodes Detection in Experiment

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