On the stability of characteristics of cellulose diacetate solutions with an iodine-containing radiopaque substance and solid emboli on their basis

Objectives. Among the materials used for embolization, liquid embolizing agents based on solutions of biocompatible polymers attract particular interest. Such compositions are capable of targeting and reliably occluding a branched vascular network by forming solid emboli directly in the patient’s body. The safety and effectiveness of such materials are determined by the stability of the initial composition and the resulting emboli. This article presents a long-term study of the stability of embolizing solutions of a polymer (cellulose diacetate) and a radiopaque additive iohexol in dimethyl sulfoxide, as well as emboli based thereon, in aqueous media.

Methods. The stability of the initial solutions exposed to 60°C for 45 days (“accelerated aging” corresponding to three years of storage at 23 ± 2°C) was studied by rotational viscometry using a Brookfield DV2T RV rotary viscometer equipped with a working unit in the form of two coaxial cylinders and by ultraviolet-visible spectrophotometry using a Cary 60 UV-Vis spectrophotometer. The long-term stability of emboli in aqueous media was studied by gel permeation chromatography using a Gilson chromatograph (Japan) with refractometric detection and by gas chromatography using an Agilent 6890N chromatograph with a DB-5MS column (30 × 0.25 × 0.5 μm), equipped with an Agilent 5973 N mass spectrometric detector.

Results. During “accelerated” storage of cellulose diacetate and iohexol solutions in the dark, no changes in the viscosity coefficient (0.268 ± 0.0049 Pa∙s at 25°C) and the quantitative content of bound iodine (50.1 ± 1.0 mg/mL) were observed. However, when iohexol solutions in dimethyl sulfoxide were stored under daylight, free iodine was separated in minor quantities. When emboli consisting of cellulose diacetate were stored in an aqueous medium for eight years, the molecular weight of the polymer (60 kDa) remained unchanged. The degradation products of cellulose diacetate, expected in the aqueous extract, were also absent.

Conclusions. The model embolic composition consisting of cellulose diacetate and iohexol in dimethyl sulfoxide is stable when stored in the absence of light. The as-formed solid emboli remain stable for at least eight years when stored in an aqueous environment.

1. Dan V.N. Angiodisplazii (vrozhdennye poroki razvitiya sosudov) (Angiodysplasia (Congenital Vascular Malformations)). Moscow: Verdana; 2008, 200 p. (In Russ.). ISBN 978-5- 901439-30-2

2. Chabrot P., Boyer L. Embolization. Springer; 2014, 453 p. https://doi.org/10.1007/978-1-4471-5182-1

3. Varghese K., Adhyapak S. Therapeutic Embolization. Springer; 2017, 133 p. https://doi.org/10.1007/978-3-319-42494-1

4. Goode J.A., Matson M.B. Embolisation of cancer: what is the evidence? Cancer Imaging. 2004;4(2):133–141. https://doi.org/10.1102/1470-7330.2004.0021

5. Alluhaybi A.A., Abdulqader S.B., Altuhayni K., AlTurkstani A., Kabbani A., Ahmad M. Preoperative trans-arterial embolization of a giant scalp congenial hemangioma associated with cardiac failure in a premature newborn. J. Int. Med. Res. 2020;48(12):1–7. https://doi.org/10.1177/0300060520977589

6. Potts M.B., Zumofen D.W., Raz E., Nelson P.K., Riina H.A. Curing arteriovenous malformations using embolization. Neurosurg. Focus. 2014;37(3);E19. https://doi.org/10.3171/2014.6.FOCUS14228

7. Orron D.E., Bloom A.I., Neeman Z. The role of transcatheter arterial embolization in the management of nonvariceal upper gastrointestinal bleeding. Gastrointest. Endosc. Clin. North Am. 2018;28(3):331–349. https://doi.org/10.1016/j.giec.2018.02.006

8. Dan V.N., Sapelkin S.V., Legon’kova O.A., Tsygankov V.N., Varava A.B., Kedik S.A., Zhavoronok E.S., Panov A.V. Materials and methods of arteriovenous malformations endovascular treatment: opportunities and problems. Voprosy biologicheskoi, meditsinskoi i farmatsevticheskoi khimii = Problems of Biological, Medical and Pharmaceutical Chemistry. 2016;19(7):3–11 (in Russ.). https://www.elibrary.ru/whpuev

9. Guimaraes M., Lencioni R., Gary P. Embolization Therapy: Principles and Clinical Applications. Wolters Kluwer Health; 2014. 816 p.

10. Hoshino J., Ubara Y., Suwabe T., Sumida K., Hayami N., Mise K., Hiramatsu R., Hasegawa E., Yamanouchi M., Sawa N., Takei R., Takaichi K. Intravascular embolization therapy in patients with enlarged polycystic liver. Am. J. Kidney Dis. 2014;63(6):937–944. https://doi.org/10.1053/j.ajkd.2014.01.422

11. Reshetnyak D.V., Zhavoronok E.S., Legon’kova O.A., et al. Modern Liquid Embolization Agents Based on Polymers: Composition, Characteristics, and Areas of Application. Review. Polym. Sci. Ser. D. 2022;15(1):64–70. https://doi.org/10.1134/S1995421222010154 [Original Russian Text: Reshetnyak D.V., Zhavoronok E.S., Legon’kova O.A., Ogannisyan A.S., Panov A.V., Kedik S.A. Modern liquid embolizing agents based on polymers: composition, properties and application (Review). Vse materialy. Ehntsiklopedicheskii spravochnik. 2021;6:3–13 (in Russ.). https://doi.org/10.31044/1994-6260-2021-0-6-3-13 ]

12. Legon’kova O.A., Dan V.N., Sapelkin S.V., et al. Regularities of formation of emboli of liquid polymer solutions in aqueous medium. Polym. Sci. Ser. D. 2017;10(1):68–73 (in Russ.). https://doi.org/10.1134/S1995421217010154 [Original Russian Text: Legon’kova O.A., Dan V.N., Sapelkin S.V., Kedik S.A., Zhavoronok E.S., Panov A.V., Asanova L.Yu., Ogarkova P.L., Shilov M.S. Regularities of formation of emboli of liquid polymer solutions in aqueous medium. Vse materialy. Ehntsiklopedicheskii spravochnik. 2016;6:9–15 (in Russ.). https://www.elibrary.ru/wfnipv ]

13. Legon’kova O.A., Stafford V.V., Ogannisyan A.S., Panov A.V., Zhavoronok E.S., Kedik S.A., Pozyabin S.V., Chupin A.V., Sapelkin S.V., Alekyan B.G. Safety and efficacy assessment of cellulose acetate in modeling of rabbit femoral artery embolization. Ehndovaskulyarnaya khirurgiya = Russ. J. Endovascular Surgery. 2021;8(4):398–411 (in Russ.). https://doi.org/10.24183/2409-4080-2021-8-4-398-411

14. Legon’kova O.A., Stafford V.V., Oganissyan A.S., Zhavoronok E.S., Panov A.V., Vinokurova T.I., Kedik S.A. Influence of the nature of radiopaque substances on the behavior of embolizing systems in vivo. Biotekhnologiya = Biotechnology. 2022;38(3):62–69 (in Russ.). https://doi.org/10.56304/S0234275822030048

15. Tokunaga K., Kinugasa K., Meguro T., Sugiu K., Nakashima H., Mandai Sh., Ohmoto T. Curative treatment of cerebral arteriovenous malformations by embolisation using cellulose acetate polymer followed by surgical resection. Journal of Clinical Neuroscience. 2000;7(Suppl. A):1–5. https://doi.org/10.1054/jocn.2000.0700

16. Wright K.C., Greff R.J., Price R.E. Experimental evaluation of cellulose acetate NF and ethylene-vinyl alcohol copolymer for selective arterial embolization. J. Vascul. Int. Radiol. 1999;10(9): 1207–1218. https://doi.org/10.1016/S1051-0443(99)70221-6

17. Tokunaga K., Kunigasa K., Kawada S., Nakashima H., Tamiya T., Hirotsune N., Mandai Sh., Ohmoto T. Embolization of cerebral arteriovenous malformations with cellulose acetate polymer: a clinical, radiological, and histological study. Neurosurgery. 1999;44(5):981–989. https://doi.org/10.1097/00006123-199905000-00026

18. Brayton C.F. Dimethyl sulfoxide (DMSO): a review. Cornell Veter. 1986;76(1):61–90.

19. Madsen B.K., Hilscher M., Zetner D., Rosenberg J. Adverse reactions of dimethyl sulfoxide in humans: a systematic review. F1000Res. 2019;7:1746. https://doi.org/10.12688/f1000research.16642.2

20. Lord J., Britton H., Spain S.G., Lewis A.L. Advancements in the development on new liquid embolic agents for use in therapeutic embolization. J. Mater. Chem. B. 2020;8(36): 8207–8218. https://doi.org/10.1039/d0tb01576h

21. Hu J., Albadawi H., Chong B.W., Deipolyi A.R., Sheth R.A., Khademhosseini A., Oklu R. Advances in biomaterials and technologies for vascular embolization. Adv. Mater. 2019;31(33):e1901071. https://doi.org/10.1002/adma.201901071

22. Tian L., Lu L., Feng J., Melancon M.P. Radiopaque nano and polymeric materials for atherosclerosis imaging, embolization and other catheterization procedures. Acta Pharm. Sinica B. 2018;8(3):360–370. https://doi.org/10.1016/j.apsb.2018.03.002

23. Reshetnyak D.V., Zhavoronok E.S., Legon’kova O.A., et al. A Spectrophotometric Study of the Interaction of Aromatic and Aliphatic Iodine-Containing Substances with Dimethyl Sulphoxide. Polym. Sci. Ser. D. 2022;15(4):543–548. https://doi.org/10.1134/s1995421222040232 [Original Russian Text: Reshetnyak D.V., Zhavoronok E.S., Legon’kova O.A., Ogannisyan A.S., Panov A.V., Kedik S.A. A Spectrophotometric Study of the Interaction of Aromatic and Aliphatic Iodine-Containing Substances with Dimethyl Sulphoxide. Klei. Germetiki. Tekhnologii = Adhesives. Sealants. Technologies. 2022;5:25–31(in Russ.). https://doi.org/10.31044/1813-7008-2022-0-5-25-31 ]

24. Klyubin V.V., Klyubina K.A., Makovetskaya K.N. A Spectroscopic Method for Determining Free Iodine in Iodinated Fatty-Acid Esters. Opt. Spectrosc. 2018;124(1): 53–56. https://doi.org/10.1134/S0030400X18010101 [Original Russian Text: Klyubin V.V., Klyubina K.A., Makovetskaya K.N. A Spectroscopic Method for Determining Free Iodine in Iodinated Fatty-Acid Esters. Optika i spektroskopiya. 2018;124(1):56–59 (in Russ.). http://doi.org/10.21883/OS.2018.01.45357.135-17 ]

25. Giordano M.C., Bazán J.C., Arvia A.J. The interaction of iodine with dimethylsulphoxide in carbon tetrachloride solutions. J. Inorg. Nuclear Chem. 1966;28(5):1209–1214. https://doi.org/10.1016/0022-1902(66)80447-5

26. Thomsen H.S., Bellin M.-F., Jakobsen Ja.A., Webb Ju.A.W. Contrast media classification and terminology. In: Thomsen H., Webb Ju. (Eds.). Contrast Media. Safety Issues and ESUR Guidelines. Berlin, Heidelberg: Springer-Verlag; 2014. P. 3–11. https://doi.org/10.1007/174_2013_864

27. Nikulin A.V., Martynov L.Yu., Gabaeva R.S., Lazov M.A. Development of a new inversion-voltammetric technique in determining inorganic iodine in Laminariae thalli L. for the quality control of raw materials in factory laboratories. Tonk. Khim. Tekhnol. = Fine Chem. Technol. 2024;19(4):372–383. https://doi.org/10.32362/2410-6593-2024-19-4-372-383