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Viewing Was Performed Using Planar Gamma Peritoneum of the Mice in the Ascites Form by Serial Camera (Hawkeye)32 JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES Karamalakova Y,Chuttani K,Sharma R,Gadjeva V,Gadjeva A,Mishra A. Nitroxyl- Labeled Glycine Containing 2-Chlorethylnitrosourea: A Study Of 99mTc-Radiolabeling, EPR Spectroscopy And Biological Evaluation Of New Potential Anticancer Agent For Tumor Imaging And Radiotherapy. J Pharm Biomed Sci 2015; 05(04):317-327. The online version of this article, along with updated information and services, is located on the World Wide Web at: www.jpbms.info Journal of Pharmaceutical and Biomedical Sciences (J Pharm Biomed Sci.), Member journal. Committee on Publication ethics (COPE) and Journal donation project (JDP). ISSN NO- 2230 – 7885 CODEN JPBSCT NLM Title: J Pharm Biomed Sci. Original article Nitroxyl-Labeled Glycine Containing 2- Chlorethylnitrosourea: A Study Of 99mTc- Radiolabeling, EPR Spectroscopy And Biological Evaluation Of New Potential Anticancer Agent For Tumor Imaging And Radiotherapy Yanka Karamalakova1,*, Krishna Chuttani2, Rakesh K. Sharma3, Veselina Gadjeva4, Antoaneta Zheleva5 and Anil K. Mishra6 Affiliation: Chemistry and Biochemistry, Str Armaiska 11, Medical 1. Assistant professor*; Department of Chemistry and Faculty, Trakia University, Stara Zagora- 6000, Biochemistry, Medical Faculty, Trakia University, 11 BULGARIA or at [email protected] Armeiska Str., 6000 Stara Zagora, Bulgaria Tel: +359 896964908 2. Assistant professor; Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Article citation: Medicine and Allied Sciences,Brig. S.K Mazumdar Karamalakova Y, Chuttani K, Sharma R, Gadjeva V, Gadjeva A, Mishra A. Nitroxyl-Labeled Glycine Marg, Delhi-110054, India 99m 3. Professor; Institute of Nuclear Medicine and Allied Containing 2-Chlorethylnitrosourea: A study of Tc- Sciences, Brig S. K. Mazumdar Marg, Delhi-110054, Radiolabeling, EPR spectroscopy and biological India evaluation of new potential anticancer agent for tumor 4.Professor; Department of Chemistry and imaging and radiotherapy. J Pharm Biomed Sci. Biochemistry, Medical Faculty, Trakia University, 11 2015; 05(04):317-327. Available at www.jpbms.info Armeiska Str., 6000 Stara Zagora, Bulgaria 5. Professor; Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, 11 ABSTRACT: Armeiska Str., 6000 Stara Zagora, Bulgaria Recently, a new class of in vitro and ex vivo 6.Professor; Division of Cyclotron and radiotracers/radioprotectors, the nitroxyl–labeled Radiopharmaceutical Sciences, Institute of Nuclear agent N-[N'-(2-chloroethyl)-N’-nitrosocarbamoyl- Medicine and Allied Sciences,Brig. S.K Mazumdar glycine amide of 2,2,6,6-tetramethyl-4- Marg, Delhi-110054, India aminopiperidine-1-oxyl (SLCNUgly), has been discovered. Our previous investigations demonstrated that SLCNUgly is a low-molecular-weight stable free The name of the department(s) and institution(s) to radical which is freely membrane permeable, easily which the work should be attributed: crosses the blood brain barrier and exhibited in/ex vivo 1.Department of Chemistry and Biochemistry, Medical the lowest general toxicity and higher anticancer Faculty, Trakia University, 11 Armeiska Str., 6000 Stara activity against some experimental tumor models. Zagora, Bulgaria 99m 2. Division of Cyclotron and Radiopharmaceutical Further investigation was aimed to develop a Tc- Sciences, Institute of Nuclear Medicine and Allied labeled SLCNUgly (96.5%) as a chelator and evaluate Sciences, Brig. S.K Mazumdar Marg,Delhi-110054, India its labeling efficiency and potential use as a tumor seeking agent and for early diagnosis. Tissue 99m Address reprint requests to biodistribution of Tc- SLCNUgly was determined in Yanka Karamalakova normal mice at 1, 2, and 24 h (n=4/ time interval, route Scientist and Assistant Professor, Electron of administration i.v.). The distribution data was Paramagnetic Resonance Laboratory, Department of compared to that using male albino non-inbred mice 317 ISSN NO- 2230 – 7885 CODEN JPBSCT NLM Title: J Pharm Biomed Sci. and EPR investigation. The imaging characteristics of pattern, as well as quick reduced duration from the 99mTc– SLCNUgly conjugate examined in Balb/c mice blood circulation. This study establishes Glycine grafted with Ehrlich Ascitis tumor in the thigh of hind Containing nitroxyl (SLCNUgly) as a new spin-labeled leg demonstrated major accumulation of the diagnostic marker which reduce the negative lateral radiotracer in organs and tumor. Planar images and effects of radiotherapy and for tumor- localization. auto-radiograms confirmed that the tumors could be 99m visualized clearly with 99mTc- SLCNUgly. Blood kinetic KEYWORDS: SLCNUgly, Ex Vivo EPR, Tc- study of radio-conjugate showed a biexponential conjugate, Biodistribution, EAT Tumor Imaging Statement of Originality of work: The manuscript has been read and approved by all the authors, the requirements for authorship have been met, and that each author believes that the manuscript represents honest and original work. Source of support: The research work was funded by the Institute of Nuclear Medicine and Allied Sciences, New Delhi, India (BIn–7/2008). INTRODUCTION trategies to attenuate drugs and radiation when cyclohexyl amino moiety in the structure of toxicity in modern chemotherapy along with antitumor drug CCNU was replaced by the nirtoxyl S radiation therapy were dosage optimization, free radical 4-Amino TEMPO17,18. Further a number synthesis and the use of analogues having lower of spin-labeled analogues of the anticancer drug toxicity or a combined therapy. Clinical and CCNU was synthesized and their biological activity experimental trials have been directed toward was studied. Some of these spin-labeled development of new drugs as anticancer agents to nitrosoureas showed advantages over CCNU, be applied individually or conjugated with toxins, having lower toxicity and higher anticancer activity drugs, natural extracts and antitumor radioisotops against experimental tumor models9,19-22. By EPR for chemotherapeutic and radiotherapeutic spectroscopy Gadjeva et al., 1994 shown that spin- treatments1-3. Isotope radiolabeling (99mTc-labeled) labeled nitrosoureas and their precursor 4-amino of active anticancer agents has been also TEMPO could scavenge .O2- and so exhibited high introduced for attaching the radio-isotope to the superoxide scavenging activity (SSA)23. antitumor drugs to increase the effectiveness of N-[N'-(2-chloroethyl)-N’-nitrosocarbamoyl-glycine interaction at cell levels4,5. Currently, the amide of 2,2,6,6-tetramethyl-4-aminopiperidine-1- radiopharmaceuticals combined with direct oxyl (SLCNUgly) (Fig. 1), has been synthesized as a radiography are the only options for investigation spin-labeled analog of CCNU(Zheleva et al., of location of tumor malformations and their 1995)19. Formerly reported results about its in visualization by gamma scintigraphic (real time) vitro determined physico-chemical properties imaging of the body6-8. showed higher alkylating activity, and almost twice The clinically used antitumor drug Lomustine 1-(2- lower carbamoylating activity compairing to those chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) of CCNU24,25. Half-life of SLCNUgly was also shorter indicates: 1) higher clinical activity against human comparing to that of CCNU (29 min for SLCNUgly malignancies, variety of human neoplasms, and 54 min for CCNU). In vivo SLCNUgly exhibited lymphomas, melanomas, Hodgkin’s disease and higher antileukaemic activity, higher brain tumors; 2) high toxicity against the normal antimelanomic effect and better cells, responsible for distortions to the integrity of immunomodulatory properties when was the subsequent DNA and induced chromosomal compared to its nonlabeled analogue antitumor aberration9,10. Different chemical structures have drug CCNU19,25. been used as selective carriers for the 2- As the nitroxyl radicals possess high T1 contrast chloroethyl- N-nitrosocarbamoyl cytotoxic group properties they could be used in MRI and EPR to optimize the antitumor action and/or decrease imaging investigations26. Because the chemical and the toxicity of 2-chloroethylnitrosourea drugs11-14. biological properties of SLCNUgly this nitroxyl It was found that presence of nitroxyl free radical containing drug is attractive for further studies moiety caused beneficial modifying effects on the that include in vivo and/or ex vivo techniques like toxicity and activity of the antitumor TEPA and as MRI and EPR organ diagnostics studies. The Thio TEPA drugs15,16. Reduced toxicity and conventional method for investigation of increased antineoplastic properties were achieved paramagnetic (spin-labeled) agents, their organ 318 ISSN NO- 2230 – 7885 CODEN JPBSCT NLM Title: J Pharm Biomed Sci. distribution, including the ex vivo tissue adjusted to 7.0 using 1M sodium bicarbonate sol. homogenates and in vivo live animals is the Freshly eluted 2mci(74MBq) 99mTc-pertecnetate electron paramagnetic resonance (EPR) in 0.5ml saline was added, mixed thoroughly and spectroscopy27. This unique technique allows the reaction mixture was incubated for 10-20 min measuring and representing processes of the at room temperature (22°C). After incubation of metabolism of free radicals, the reactive oxygen the radio-conjugate, the radiochemical purity and species (ROS), organ/tissue oxygenation and in vitro studies up to 24 hr were carried out by nitrous oxide production (RNS) in the normal paper chromatography using ITLC-SG (instant thin physiology and cancer processes. Unfortunately layer chromatography-silica gel) paper
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