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Radiolabeling, Biodistribution and Gamma Scintigraphy of Noscapine

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Radiolabeling, Biodistribution and Gamma Scintigraphy of Noscapine Priyadarshani et al. Journal of Ovarian Research 2010, 3:10 http://www.ovarianresearch.com/content/3/1/10 RESEARCH Open Access Radiolabeling,Research biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats Anjali Priyadarshani1, Krishna Chuttani2, Gaurav Mittal2 and Aseem Bhatnagar*2 Abstract Background: Noscapine, an alkaloid from Papaver somniferum, widely used as an antitussive, is being clinically studied in the treatment of polycystic ovary syndrome (PCOS) and a few other cancers primarily because of its anti- angiogenesis properties. With the advent of diverse application of noscapine, we sought to determine whether the radiolabeling method can be useful in studying uptake and kinetics of the molecule in-vivo. Specific objectives of this study were to radiolabel noscapine with Technetium-99m (Tc-99m), to determine its organ biodistribution in rat model and study its uptake kinetics in PCOS model. Methods: A method for radiolabeling noscapine with Tc-99m was standardized using stannous reduction method and its in vitro and in vivo stability parameters were studied. The radiopharmaceutical was also evaluated for blood kinetics and biodistribution profile. An animal model of PCOS was created by using antiprogesterone RU486 and uptake of 99mTc-noscapine in normal and PCOS ovaries was compared using gamma scintigraphy. Results: Noscapine hydrochloride was successfully radiolabeled with Tc-99m with high labeling efficiency and in vitro stability. Most of the blood clearance of the drug (80%) took place in first hour after intravascular injection with maximum accumulation being observed in liver, spleen, kidney followed by the ovary. At 4 hours post injection, radiolabeled complex accumulation doubled in PCOS ovaries in rats (0.9 ± 0.03% ID/whole organ) compared to normal cyclic rats (0.53 ± 0.01% ID/whole organ). This observation was further strengthened by scintigraphic images of rats taken at different time intervals (1 h, 2 h, 4 h, and 24 h) where SPECT images suggested discrete accumulation in the PCOS ovaries. Conclusion: Through our study we report direct radiolabeling of noscapine and its biodistribution in various organs and specific uptake in PCOS that may show its utility for imaging ovarian pathology. The increased ovarian uptake in PCOS may be related to its receptor binding suggesting possible role of 99mTc-noscapine in PCOS diagnostics and therapeutics. Background tubulin resulting in apoptosis in cancerous cells both in Noscapine, a phthalideisoquinoline alkaloid has long vitro and in vivo [5-8]. Moreover, noscapine is also shown been used as a cough suppressant in humans and in to reduce neoangiogenesis resulting in reduced cell turn- experimental animals[1,2]. Unlike other opioids, noscap- over. Its role in tumor and tumor-like conditions is there- ine lacks sedative, euphoric, and respiratory depressant fore being investigated with great interest [9,10]. properties [3] and is free from serious toxic effects in Although animal studies have shown the therapeutic doses up to 100 times the antitussive dose [4]. Recently, potential of noscapine in inhibiting cancer progression in anticancer properties of noscapine have been reported animal models [10,11], there has been no study to ascer- and it has been shown that noscapine interacts with α tain whether noscapine can be used in the diagnosis of developing tumors, including those inflicting the ovaries. * Correspondence: [email protected] 2 Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, We were therefore interested in exploring the possibility Delhi-110 054, India of using nuclear medicine techniques, including gamma Full list of author information is available at the end of the article © 2010 Priyadarshani et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com- BioMed Central mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is properly cited. Priyadarshani et al. Journal of Ovarian Research 2010, 3:10 Page 2 of 8 http://www.ovarianresearch.com/content/3/1/10 scintigraphy for detecting ovarian dysfunctions using Animals noscapine. Polycystic ovarian syndrome (PCOS) was cho- Female New Zealand rabbits weighing approximately sen as the model system to study noscapine uptake 2.25 ± 2 kg and adult female Wister rats (aged 12-14 because of its easy inducibility [12]. Though pharmaco- weeks, body weight 200 ± 4.5 g) were housed in animal therapies like metformin, clomiphene citrate and flut- house facility at Institute of nuclear medicine and allied amide have been used for the treatment of PCOS, serious sciences, under controlled light (12 h light: 12 h dark) and side effects with long treatment schedule makes them temperature (22-24°C) conditions. The animals were pro- unapproachable [13-16]. Consequently, there is an urgent vided water and their respective chow. Animal handling need for better drugs that can target the core of PCOS, and experimentation was carried out as per the guide- hypothalamus-pituitary-ovarian (HPO) axis and normal- lines of the institutional animal ethics committee. ize the broad spectrum of PCOS anomalies with minimal Radiolabeling and its subsequent quality control side effects [17]. Keeping the drawbacks of existing thera- parameters, including radiochemical purity, in vitro and peutic modalities for the syndrome in mind, the present in vivo stability, blood kinetics and biodistribution stud- investigation also aimed to give important leads to inves- ies were broadly determined as per established nuclear tigators for developing noscapine as a novel alternative medicine procedures [22-27]. However, procedural for treatment of various ovarian dysfunctions, including details with respect to noscapine have been given in the PCOS. subsequent sections. Since the plasma half-life of noscapine is 2.5 h to 4.5 h[18,19] it is theoretically quite compatible with the phys- Radiolabeling of Noscapine with Tc-99m ical half-life of 6 hrs of Technetium-99m (Tc-99m). More- 99mTc-noscapine was prepared by dissolving 500 μg of over, noscapine is grouped as part of the noscapine hydrochloride in 1 ml of distilled water fol- benzylisoquinolines, and possesses certain electron rich lowed by the addition of 50 μg of SnCl2.2H2O, the pH sites such as methoxy side chain, N-methyl group, carbo- being adjusted to 6.5. The contents were filtered through nyl, lactonyl, dioxide site that makes it available for bind- 0.22 μm membrane filter (Millipore Corporation, Bed- ing to radioisotopes such as Tc-99m [20]. Keeping in view ford, MA USA) into a sterile vial. Approximately 55-60 the inherent properties of Tc-99m, attempts were made MBq Tc-99m was added to the contents, mixed and incu- to radiolabel noscapine with Tc-99m. We then sought to bated for 5-10 min. The percent radiolabel was deter- determine various factors influencing the radiolabeling mined by using instant thin layer chromatography (ITLC) process and in vitro stability of the labeled complex. Sub- by the method previously reported from our lab [27]. sequently blood kinetics in rabbits; and tissue distribu- Effect of concentration of stannous chloride and pH on the tion and gamma scintigraphy studies of 99mTc-noscapine labeling efficiency were performed in female rats. Furthermore, levels of labeled noscapine in ovary of healthy rats were compared To examine the effect of varying concentration of with the rats induced with precancerous conditions of SnCl2.2H2O on labeling efficiency, amount of polycystic ovary syndrome (PCOS) wherein the theca cell SnCl2.2H2O was varied from 10 to 400 μg keeping the pH turnover is significantly more than the healthy controls constant at 6.5. In another experiment, the amount of [21]. The objective was to generate organ distribution stannous chloride dihydrate was kept constant (50 μg) data with respect to noscapine using nuclear medicine while the pH was varied from 4 to 7 by adding 0.5 M techniques and to ascertain whether radiolabeled noscap- NaHCO3. The experiment was performed in triplicate ine can have a diagnostic application in ovarian dysfunc- and labeling yield was measured using 100% acetone as tion, with particular reference to PCOS. the mobile phase. Percentage of colloids was detected by pyridine: acetic acid: water (3:5:1.5 v/v) as the mobile Methods phase. Drugs/Chemicals Noscapine hydrochloride and Antiprogesterone RU486, Radiochemical purity 11β-(4-dimethyl amino phenyl)-1 β-hydroxy-17α-(1-pro- The radiochemical purity of Tc-99m with noscapine was penyl)-oestra-4, 9-diene-3-one were procured from estimated by instant thin layer chromatography (ITLC) Sigma Chemical Co., St. Louis, MO, while Tc-99m was using silica gel coated fibre sheets (Gelman Sciences. Inc., eluted from 99Mo by methyl ethyl ketone extraction and Ann Arbor, MI USA). ITLC was performed using 100% provided by BRIT, BARC, India. All the chemicals used in acetone and 0.9% saline as the mobile phase. A measured this study were of analytical grade. amount of 2-3 μl of the radiolabeled complex was applied at a point 1 cm from one end of an ITLC-SG strip and Priyadarshani et al. Journal of Ovarian Research 2010, 3:10 Page 3 of 8 http://www.ovarianresearch.com/content/3/1/10 allowed to run for approximately 10 cm. Amount of polycystic ovaries associated with persistent vaginal reduced/hydrolyzed Tc-99m was determined
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