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Increases Carmofur Stability and in Vitro Antiproliferative Effect

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Increases Carmofur Stability and in Vitro Antiproliferative Effect Toxicology Reports 2 (2015) 377–383 Contents lists available at ScienceDirect Toxicology Reports journa l homepage: www.elsevier.com/locate/toxrep Short communication 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) increases Carmofur stability and in vitro antiproliferative effect Ilona Domracheva, Ruslan Muhamadejev, Marina Petrova, Edvards Liepinsh, ∗ Anita Gulbe, Irina Shestakova, Gunars Duburs, Pavel Arsenyan Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia a r a t i b s c t l e i n f o r a c t Article history: Addition of DMPC considerably inhibits the degradation of Carmofur in neutral phosphate Received 21 October 2014 buffer solutions and this drug becomes less influenced by pH. Carmofur stabilization at Received in revised form 9 December 2014 neutral pH caused by DMPC addition for in vitro studies was characterized and monitored by Accepted 6 January 2015 1 H NMR. Antiproliferative activity studies on various tumor cell lines showed considerable Available online 28 January 2015 increase of Carmofur ability to prevent tumor cell growth, when it is added as a mixture with DMPC. This technique opens a way for Carmofur drug delivery in neutral and basic Chemical compounds studied in this article: media. 1,2-Dimyristoyl-sn-glycero-3- © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under phosphocholine (PubChem CID: 5459377) the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1-Hexylcarbamoyl-5-fluorouracil (PubChem CID: 2577) 5-Fluorouracil (PubChem CID: 3385) Keywords: Carmofur Cytotoxicity DMPC Drug delivery 5-Fluorouracil 1 H NMR 1. Introduction confirmed that the drug is effective on patients with this cancer type, extending their survival [1,2]. The Carmofur Carmofur (1-hexylcarbamoyl-5-fluorouracil, HCFU, molecule contains an active core of 5-fluorouracil and Mifurol) is one of the masked forms of 5-fluorouracil hexylcarbamoyl substituent as a transport form, and it widely used as an antineoplastic agent. This drug, in its helps 5-FU to penetrate into the cell. In the last years oral form, has been used as adjuvant chemotherapy for the interest in encapsulation of 5-fluorouracil derivatives curatively resected colorectal cancer patients. Trials have in liposomal formulations was increased [3]. Liposomal 5-FU microspheres are potent in the treatment of liver metastases increasing the intratumoral concentration of 5-FU up to 2203 times [4]. Recently, experimental research Abbreviations: DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; concerning antitumor activity of Carmofur water solu- Carmofur, 1-hexylcarbamoyl-5-fluorouracil; 5-Fu, 5-fluorouracil; NMR, bilized by lactic acid oligomer-grafted pullulan nanogels nuclear magnetic resonance. ∗ has been reported. Nanogel with Carmofur showed a Corresponding author. Tel.: +371 29849464; fax: +371 67550338. E-mail address: [email protected] (P. Arsenyan). strong suppressive effect of tumor cells grown, in contrast http://dx.doi.org/10.1016/j.toxrep.2015.01.009 2214-7500/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 378 I. Domracheva et al. / Toxicology Reports 2 (2015) 377–383 to the Carmofur solution [5]. Treatment of colorectal 30% of power for 5 min with on/off cycle of 10 s. Then to cancer using a combination of liposomal irinotecan and the 800 ␮l of the vesicle’s solution in the 5 mm NMR tube 5-fluorouracil leads to exposition time prolongation and 15 ␮l of 1 dissolved in CDCl3 with concentration 0.337 M improves antitumor activity [6]. The main disadvantages has been added. The resulting mixture was then immedi- of Carmofur is its low solubility; moreover, this drug ately inserted into spectrometer. relatively easily hydrolyzes under physiological conditions with pH > 7.0. Therefore the scope for use of this drug is 2.3. Computational details significantly narrowed. However, nanogels of HCFU have been formulated previously by cross-linked polymeric All HF calculations were performed in Jaguar 8.0 (release micelles of N-isopropylacrylamide and N-vinylpyrrolidone 515) from Schrödinger [15]. The basis set was 6-311G**++. and higher accumulation of HCFU in brain was reported Geometries were optimized in the gas phase, and energies [7,8]. As well as Carmofur loaded pluronic polymeric in solvent were calculated using the Poisson–Boltzmann micelles were produced and characterized [9]. finite-element (PBF) [16,17] implicit solvation model at the Our experience with the chemistry of nucleosides optimized gas phase geometries. [10,11] and antitumor activity studies [12–14] inspired us to investigate the stability of Carmofur (1) in aqueous 2.4. Preparation of DMPC vesicles with 1 for in vitro phosphate buffer solutions at pH from 5.0 to 8.0 and 1,2- 3 studies ( ) dimyristoyl-sn-glycero-3-phosphocholine (DMPC) influ- 1 ence on Carmofur stability monitored by H NMR. Carmofur (26 mg, 0.1 mmol) and DMPC (0.334 g, 0.5 mmol) were dissolved in 25 ml of chloroform and evap- 2. Materials and methods orated on rotatory evaporator under reduced pressure with slow rotation without any heating. Then additional portion Carmofur was purchased from TCI, DMPC was pur- of chloroform was added and the procedure was repeated chased from NOF Corporation (Tokyo, Japan) and used 1 for 5 times. without further purification. H NMR spectra of 1 were run on a Varian-Mercury BB 400 MHz spectrometer at 298 K, with a standard pulse sequence WET for residual water 2.5. In vitro cytotoxicity assay signal suppression. The spectral parameters were: 4695 Hz spectral width, 16K complex data points, number of scans Monolayer tumor cell line: HT-1080 (human connec- 128, acquisition time 3.5 s, digital resolution 0.007 Hz and tive tissue fibrosarcoma), C6 (rat glial tumor), SH-SY-5Y relaxation delay 2 s. The acquired FIDs were processed with (human neuroblastoma), MH-22A (mouse hepatoma), zero-filling to 32 K. MDA-MB-435s (human melanoma), MCF-7 (human breast adenocarcinoma, estrogen-positive), and normal cell lines: 2.1. Stability studies by NMR H9C2 (rat myocardium) and NIH 3T3 (Mouse Swiss Albino embryo fibroblasts) were grown in standard medium For integration the C6H signals of 1 (1A + 1B) was used. Dulbecco’s modified Eagle’s medium (DMEM) supple- The samples were prepared in phosphate buffers in D2O at mented with 10% fetal bovine serum (FBS, “Sigma”). pH 5.0–8.0; the difference of pH values in D2O and H2O 4 About 1–2 × 10 cells/well (depending on line nature) were water buffers were less than 0.4. Each of the 8 experi- placed in 96-well plates immediately after compounds ments with a specific concentration of HCFU was single (250, 50, 10, 2, 0.4 and 0.08 ␮M) were added to the wells. point. 86.87 mg (0.338 M) of HCFU was dissolved in 1 ml of The control cells without test compounds were cultured chloroform-d1 (CDCl3). The sample was stored in the fridge ◦ on separate plate. The plates were incubated for 72 h, at at 4 C in the container with a cap-sung. For the sample ◦ 37 C, 5% CO2. The number of surviving cells was deter- preparation 15 ␮l of solution of CHFU in CDCl3 were taken mined using MTT (thiazolyl blue tetrazolium bromide), and by the gamiltanian syringe and added to the vial with buffer OD was read = 540 nm. The IC50 was calculated using liposomes. Then the sample was thoroughly shaken and ® program Graph Pad Prism 3.0, r < 0.05. The control cells put into the NMR spectrometer. The temperature inside the ◦ without test compounds were cultured on separate plate NMR spectrometer was 25 C and it was controled by the and an appropriate volume of control buffer was added to integrated thermometer. Each spectrum was acquired with control cells. Each assay was conducted in triplicate. t2max = 3.49 s, the relaxation delay was 2 s, and the num- ber of scans was 128. The chemical shifts of the hydrogen 2.6. Standard operating procedure (SOP) for the Balb/c atoms of 1 are presented in ppm and referred to the resid- 1 1 3T3 neutral red uptake cytotoxicity test – a test for basal ual signals of CDCl3 ı = 7.26 and D2O ı = 4.5 ( H) ppm. H cytotoxicity NMR (CDCl3, 400 MHz) ı (ppm): 0.87 (3H, t, J = 7.2, CH3), 1.73–1.28 (6H, m, 3CH2), 1.59 (2H, m, J = 7.2, CH2), 3.37 (2H, The SOP was submitted in 1992 to INVITTOX, where td, J = 7.2, J = 5.1, NCH2), 8.42 (1H, d, J = 6.9, CH), 8.91 (1H, it is still available as Protocol No. 46 (NRU Assay). The br s, NH), 8.96 (1H, t, J = 5.1, NH). NRU cytotoxicity assay procedure is a cell survival/viability chemosensitivity assay based on the ability of viable cells 2.2. DMPC vesicles preparation for NMR studies to incorporate and bind neutral red, a supra-vital dye. The DMPC has been dissolved in buffer/water and then soni- basal cytotoxicity is to be used to predict starting doses cated by Ultrasonic Processor Cole Parmer© CPX130 with for in vivo acute oral LD50 values in rodent. Using the 3T3 I. Domracheva et al. / Toxicology Reports 2 (2015) 377–383 379 O OH O O F F F HN increasing of pH N N hydrolys is F + HN O N O N HO N O N H O N O N O N H H H 1 1A 1B 5-Fluorouracil Scheme 1. Tautomeric forms of 1. cell line the borderline concentration, relevant to the high- molecule.
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