A major challenge for cancer treatment is the preferential and irreversible killing of tumor cells and minimal damage of normal tissues, both in the site of the malignancy and in the body. The agents used in boron neutron capture therapy (BNCT) are supposed to have the following advantages over many conventional chemotherapeutics: 1) when irradiated with thermal neutrons, an unstable isotope 11B is formed whose rapid decay yields local radioactivity and a thermal effect; 2) because the free path of the released particles is close to the cell diameter, the tissues outside the tumor should gain less damage; 3) local radioactivity and heat should be harmful for cells that, in the course of their natural history, acquired the determinants of altered response to many toxic stimuli. However, a higher specificity of damage would be achieved if the drugs accumulate mostly in cancer cells rather than in non-malignant counterparts. Therefore, optimization of agents for BNCT presumes the design of chemicals with improved accumulation / retention in cancer cells. In particular, carboranyl-substituted porphyrins, the stable conjugates of macrocyclic porphyrins with complex boron-containing polyhedra, are considered good candidates for BNCT due to their uptake by cancer cells and high boron content. Importantly, the proposed mechanisms of pharmacological effects of carboranylporphyrins make these compounds potentially appropriate for elimination of pleiotropically resistant tumor cells.

Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu²⁺ in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2–3 orders of magnitude determined by IC₅₀ values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1–1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2–6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu–organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu–organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu⁺¹ complexes can generate a superoxide anion in a Fenton-like reaction Cu⁺¹L + O₂ → O₂^−. + Cu⁺²L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.

The conjugates of porphyrin macrocycles with boron-containing polyhedra are under investigation as agents for binary treatment strategies of cancer. Aiming at the design of photoactive compounds with low-to-zero dark toxicity, we synthesized a series of carboranyl and monocarbon-carboranyl derivatives of protohaemin IX using the activation of porphyrin carboxylic groups with di-tert-butyl pyrocarbonate or pivaloyl chloride. The water-soluble 1,3,5,8-tetramethyl-2,4-divinyl-6(7)–[2′-(closo-monocarbon-carborane-1″-yl)methoxycarbonylethyl]-7(6)-(2′-carboxyethyl)porphyrin Fe(III) (compound 9) exerted no discernible cytotoxicity for cultured mammalian cells, nor did it cause general toxicity in rats. Importantly, 9 demonstrated dose-dependent activity as a phototoxin in photodynamic therapy of M-1 sarcoma-bearing rats. In animals injected with 20 mg kg⁻¹ of 9, the tumours shrank by day 3 after one single irradiation of the tumour with red laser light. Between 7 and 14 days post-irradiation, 88.9% of rats were tumour-free; no recurrence of the disease was detectable within at least 90 days. Protohaemin IX alone was without effect, indicating that boronation is important for the phototoxic activity of 9. This is the first study that presents the synthesis and preclinical in vivo efficacy of boronated derivatives of protohaemin as phototoxins. The applicability in photodynamic treatment broadens the therapeutic potential of boronated porphyrins beyond their conventional role as radiosensitizers in boron neutron capture therapy.