The synthetic fluorinated tetracarboranylchlorin as a versatile antitumor photoradiosensitizer

• Published in: Dyes and pigments Vol. 186; p. 108993
• Main Authors: Ol'shevskaya, Valentina A., Zaitsev, Andrei V., Petrova, Albina S., Arkhipova, Anastasia Yu, Moisenovich, Mikhail M., Kostyukov, Alexey A., Egorov, Anton E., Koroleva, Olga A., Golovina, Galina V., Volodina, Yulia L., Kalinina, Elena V., Kuzmin, Vladimir A., Sakurai, Yoshinori, Tanaka, Hiroki, Miyoshi, Norio, Shtil, Alexander A.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-02-2021
• Subjects: Boron neutron capture therapy; Carborane; Cell death; Chlorin; Fluorine; Photodynamic therapy; Chlorin; Carborane; Photodynamic therapy; Fluorine; Cell death; Boron neutron capture therapy
• ISSN: 0143-7208; 1873-3743
• DOI: 10.1016/j.dyepig.2020.108993

Tetrapyrrolic macrocycles are suitable for a variety of chemical modifications aimed at new agents for binary antitumor treatment and diagnosis. Previously we have reported that the conjugation of one single carborane cage to the chlorin e6 macrocycle, a modification designed for tumor sensitization in photodynamic (PDT) and boron neutron capture (BNCT) therapies, yielded the derivative with a higher photosensitizing potency in the models of transplanted rodent tumors. This effect was mechanistically linked to the localization of the carboranylchlorin in membrane organelles due to the carborane moiety. Further exploring the potential of modified tetrapyrrolic compounds as photoradiosensitizers we synthesized the chlorin derivative carrying four closo-carborane cages (44 boron atoms) and 16 fluorine atoms at the periphery of the macrocycle (fluorinated tetracarboranylchlorin, compound 1). For comparison of the properties of 1, its fluorine free congener (tetracarboranylchlorin 6) was obtained. The water soluble 1 and 6 accumulated preferentially in cells selected for resistance to chemotherapeutic drugs (multidrug resistance and cisplatin resistance) than in the parental non-selected counterparts. Compounds 1 and 6 showed a negligible dark cytotoxicity. In contrast, a monochromatic light illumination of cells loaded with low micromolar concentrations of 1 or 6 triggered rapid (within minutes) photonecrosis as determined by the entry of propidium iodide or SYTOX dyes into the parental as well as into resistant cells. In vivo 1 or 6 (up to 80 mg/kg i.p.) caused no general toxicity in Balb/c or C57BL6 mice. Illumination with a monochromatic light of B16 melanoma transplants in mice injected with 5 mg/kg 1 or 6 caused a significant shrinkage of tumor foci, with no re-growth in 77.8% animals by day 21 post PDT. BNCT on C6 rat glioma xenografts in Balb/c nu/nu mice injected i.p. with 5 mg/kg 1 led to a decrease of tumor foci and cure of animals by day 29 whereas the radiosensitizing potency of 6 was less pronounced. This difference was attributable to a limited intratumoral accumulation of 6. Altogether, an extensive modification of the chlorin macrocycle periphery with polyfluorines and polycarboranes yielded potent and well tolerable compounds for PDT and BNCT.
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•New water soluble tetracarboranyl-substituted polyfluorinated chlorins and their non-fluorinated analogues were synthesized.•The modified chlorins retained the ability to generate ROS. .•New compounds readily accumulated in tumor cells selected for drug resistance.•Rapid necrosis is the mechanism of photodamage of wild type and drug selected cells.•The lead compound 1 demonstrated good photoradiosensitizing properties in animal models.