ИСТИНА

The subject of this lecture is our recent results in the chemistry of cobalt bis(dicarbollide) anion [3,3’-Co(1,2-C2B9H11)2]- and its derivatives and their potential application in medicine. Conjugation of polyhedral boron hydrides with porphyrins is an attractive way to create dual agents for anticancer boron neutron capture therapy (BNCT) and photodynamic therapy (PDT). Reaction of 1,4-dioxane derivatives of cobalt bis(dicarbollide) with amino derivatives of chlorin e6 gives conjugates of cobalt bis(dicarbollide) anion [3,3’-Co(1,2-C2B9H11)2]- with chlorin e6. Interactions of these conjugates with cancer cells were studied, namely, ability of conjugates to penetrate in cells, intracellular distribution and localization, quantitative characteristics of intracellular accumulation. Based on these data the most promising conjugates for BNCT are described. We report on breakthroughs in the structural optimization of conjugates of chlorin e6 derivative with bis(dicarbollide)cobalt resulting in the creation of dimethyl ester 13-carbomoylchlorin e6 [N-hexylamine-N’-ethoxyethoxy]-cobalt-bis(dicarbollide) (conjugate 1). Conjugate 1 is able to accumulate quickly and efficiently (distribution factor of 80) in cancer cells, thus delivering more than 109 boron atoms per cell when its extracellular concentration is more than 1 μmol L−1. Also 1 is an active photosensitizer and phototoxic towards human lung adenocarcinoma A549 cells at 80 nmol L−1 (50% cell death). Photoinduced cytotoxicity of 1 is associated with lipid peroxidation, lysosome rupture and protease activity enhancement. Conjugate 1 fluoresces in the red region (670 nm), which is useful to monitor its accumulation and distribution in vivo. It is not toxic to cells without activation by neutrons or photons. Structural features that improve the functional properties of 1 are discussed. The properties of 1 warrant its preclinical evaluation as a multifunctional agent for BNCT, photodynamic therapy and fluorescent tumor diagnosis. A new highly boronated Zn(II)-phthalocyanine with eight cobalt bis(dicarbollide) units (144 boron atoms) was prepared and its intracellular accumulation and distribution in GL6 human glioblastoma cells were studied. It was found that the boronated phthalocyanine undergoes strong aggregation in intracellular environment. Acknowledgement. Authors thank Russian Foundation for Basic Research for financial support (grants 13-03-00581, 13-04-00670 and 13-03-00577).