ИСТИНА

The subject of this lecture is our recent results on the synthesis of cobalt bis(dicarbollide) anion [3,3’-Co(1,2-C2B9H11)2]- conjugates with porphyrins and phthalocyanines and investigation of their interaction with cancer cells in order to find compounds for potential BNCT application. 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). The 1,4-dioxane derivative of cobalt bis(dicarbollide) reacts with amino derivatives of chlorin e6 prepared by the E ring cleavage in pheophorbide a methyl ester with α,ω-diaminoalkanes to give the conjugates of chlorin e6 and cobalt bis(dicarbollide) with NH(CH2CH2)nNH2(CH2CH2O)2 (n = 1, 2, 3) spacers between them. An interaction of these conjugates with human lung adenocarcinoma A549 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) (n = 3, 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.