The novel highly effective ir-photosensitizer for photodynamic therapy of cancer

The present article is devoted to the synthesis and investigation of biological and physico-chemical properties of the bacteriopurpurinimide derivative that was used as a photosensitizer. These substances have an ability to accumulate selectively in the malignant tumours. Also this class of photosensitizers is of particular interest because of their strong light absorbtion spectrum in red and NIR-region in the “window of tissue transparency”. This property affords to treat deep-seated tumours at the depth of 2 cm. In this study it was implemented the method of photodynamic therapy of cancer. The photosensitizer for this study was prepared as the nanostructured water-soluble micellar dispersion of O-propyloxime-N-propoxybacteriopurpurinimide methyl ester. The photodynamic therapy using this substance provided the highly effective photoinduced antitumour in vitro and in vivo activity, 100% regression of the tumour and 90% cure of animals.

bacteriochlorophyll a, bacteriopurpurin, bacteriopurpurinimide, photosensitizer, photodynamic therapy, malignant tumours.

1. Dougherty T.J., Gomer C., Henderson B.W., Jori G., Kessel D., Korbelik M., Moan J., Peng Q. Photodynamic therapy // J. Natl. Cancer I. 1998. V. 90. № 12. P. 889-905.

2. Gross S., Gilead A., Scherz A., Neeman M., Salomon Y. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MR // Nature Medicine. 2003. V. 9. P. 1327-1331.

3. Oseroff A., Shieh S., Frawley N., Blumenson L., Parsons J.,Potter E., Graham A., Henderson B.W., Dougherty T.J. PDT for skin cancer: What do we know about how to go // Abstracts of 29th Annu, Meeting Am. Soc. Photobiol. USA, California, San Francisco, 2001. P. 146.

4. Keefe K.A., Tadir Y., Tromberg B., Berns M., Osann K., Hashad R., Monk B.J. Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid // Lasers Surg. Med. 2002. V. 31. P. 289-293.

5. Henderson B.W., Dougherty T.J. How does photodynamic therapy work? // Photochem. Photobiol. 1992. V. 55. P. 145-157.

6. Kessel D. Delivery of photosensitizing agents // Adv. Drug Deliv. Rev. 2004. V. 56. P. 7-8.

7. Oleinick N.L., Morris R.L., Belichenko T. The role of apoptosis in response to photodynamic therapy: What, where, why and how? // Photochem. Photobiol. Sci. 2002. V. 1. P. 1-21.

8. Dolmans D., Fukumura D., Jain R.K. Photodynamic therapy for cancer // Natl. Cancer Rev. 2003. V. 3. P. 380-387.

9. Sternberg E.D., Dolphin D., Brückner C. Porphyrin-based photosensitizers for use in photodynamic therapy // Tetrahedron. 1998. V. 54 (17). P. 4151-4202.

10. Pandey R.K., Smith K.M., Dougherty T.J. Porphyrin dimers as photosensitizers in photodynamic therapy // J. Med. Chem. 1990. V. 33. P. 2032-2038.

11. MacDonald I., Dougherty T.J. Basic principles of photodynamic therapy // J. Porphyrins Phthalocyanines. 2001. V. 5. P. 105-129.

12. Henderson B.W., Gollnick S.O. Mechanistic principles of photodynamic therapy // In: Biomedical Photonics Handbook / Ed. T. Vo-Dinh. Boca Raton: CRC Press, 2002.

13. Pandey R.K., Zheng G. Porphyrins as Photosensitizers in Photodynamic Therapy // In: The Porphyrin Handbook / Ed. by K.M. Kadish, K.M. Smith, R. Guilard. Academic Press, 2000. P. 157-230.

14. Grin M.A., Mironov A.F., Shtil A.A. Bacteriochlorophyll a and its derivatives: Сhemistry and perspectives for cancer therapy // Anti-Cancer Agents in Med. Chem. 2008. V. 8. № 6. P. 683-697.

15. Mironov A.F., Lebedeva V.S. Cyclic N-hydroxyimides in a series of chlorins and porphyrins // Tetrahedron Lett. 1998. V. 39. P. 905-908.

16. Миронов А.Ф. Разработка сенсибилизаторов второго поколения на основе природных хлорофиллов // Рос. хим. журнал. 1998. Т. 1, № 4, C. 23-26.

17. Mironov A.F., Grin M.A., Tsiprovskiy A.G. Synthesis of the first N-hydroxycycloimide in bacterio-chlorophyll a series // J. Porphyrins Phthalocyanines. 2002. V. 6. № 5. P. 358-361.

18. Feofanov A., Sharonov G., Grichine A., Karmakova T., Pljutinskaya A., Lebedeva V., Ruziyev R., Yakubovskaya R., Mironov A., Refregier M., Maurizot J.-C., Vigny P. Comparative study of photodynamic properties of 13,15-N-cycloimide derivatives of chlorin p6 // Photochem. Photobiol. 2004. V. 79. P. 172-188.

19. Karmakova T., Feofanov A., Pankratov A., Kazachkina N., Nazarova A., Yakubovskaya R., Lebedeva V., Ruziyev R., Mironov A., Maurizot J.-C., Vigny P. Tissue distribution and in vivo photo-sensitizing activity of 13,15-N-(3-hydroxypropyl)cycloimide chlorin p6 and 13,15-N-methoxycycloimide chlorin p6 methyl ester // Photochem. Photobiol. B: Biology. 2006. V. 82. P. 28-36.

20. Brandis A., Mazor O., Neumark E., Rozenbach-Belkin V., Salomon Y., Scherz A. Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins // Photochem. Photobiol. 2005. V. 81. P. 983-992.

21. Pandey R.K., Sumlin A.B., Constantine S., Aoudia M., Potter W.R., Bellnier D.A., Henderson B.W., Rodgers M.A., Smith K.M., Dougherty T.J. Synthesis, photophysical properties and photodynamic efficacy // Photochem. Photobiol. 1996. V. 64 (1). P. 194-204.

22. Boyle R., Dolphin D. Structure and biodistribution relationship of phothodynamic sensitizer // Photochem. Photobiol. 1996. V. 64. P. 469-485.

23. Миронов А.Ф., Ципровский А.Г., Грин М.А., Меерович И.Г., Меерович Г.А., Оборотова Н.А., Лощенов В.Б., Барышников А.Ю. Фотодинамически активная субстанция на основе производных бактериохлорина р, способ ее получения, фотосенсибилизатор на ее основе и способ фотодинамической терапии с его использованием : пат. 2411943 Рос. Федерация. № 2009113808/15; заявл. 14.04.2009; опубл. 20.02.2011, Бюл. № 5, 13 с.

24. Чиссов В.И., Якубовская Р.И., Миронов А.Ф., Грин М.А., Плотникова Е.А., Морозова Н.Б., Цыганков А.А. Препарат для фотодинамической терапии и способ фотодинамической терапии рака с его использованием : заявка № 2012153433/15 (085004), 2012 г. Положительное решение о выдаче патента на изобретение от 25.03.2014.

25. Sharonov G.V., Karmakova T.A., Kassies R., Pljutinskaya A.D., Refregiers M., Yakubovskaya R.I., Mironov A.F., Grin M.A., Maurizot J-C., Vigny P., Otto C., Feofanov A.V. Cycloimide bacteriochlorin p derivatives: Photodynamic properties, cellular- and tissue distribution // Free Radicals Biol. Med. 2006. V. 40. P. 407-419.

26. Mironov A.F., Kozyrev A.N., Brandis A.S. Sensitizers of second generation for photodynamic therapy of cancer based on chlorophyll and bacteriochlorophyll derivatives // Proc. SPIE. 1992. V. 1922. P. 204-208.

27. Carmichael J., DeGraff W.G., Gazdar A.F., Minna J.D., Mitchell J.B. Evaluation of a tetrazolium-based semiautomated colorimetric assay: Assessment of chemosensitivity testing // Canser Res. 1987. V. 47. P. 936-942.

28. Zharkova N.N., Kozlov D.N., Polivanov Yu.N. [et al.] Laser-excited fluorescence spectro-photometric system for tissue diagnostics // SPIE. 1994. V. 2328. P. 196-201.