Search

The tetrapyrrolic macrocycle as a scaffold for various chemical modifications provides broad opportunities for the preparation of complex multifunctional conjugates suitable for binary antitumor therapies. Typically, illumination with monochromatic light triggers the photochemical generation of reactive oxygen species (ROS) (photodynamic effect). However, more therapeutically valuable effects can be achieved upon photoactivation of tetrapyrrole derivatives. Herein we report the novel porphyrin-based complexes of transition metals with isocyanide and carbonyl ligands. Synthesis of complexes presumed the use of 5-( p -isocyanophenyl)-10,15,20-triphenylporphyrin as a ligand in reactions with metal carbonyl complexes, M(CO) 6 (M = Cr, Mo, W), Re 2 (CO) 10 and Re(CO) 5 Cl. Based on these complexes and isocyanocarborane, the heteroleptic carbonyl complexes with porphyrin and carborane isocyanide ligands were prepared. In cell-free systems, the new compounds retained photochemical characteristics of the parental porphyrin derivative, such as triplet state formation and ROS generation, upon light-induced activation. In the cell culture, the carborane-containing derivatives demonstrated a more pronounced intracellular accumulation than their nonboronated counterparts. As expected, illumination at the Soret band (405 nm) of cells loaded with the new complexes caused photodynamic cell damage. In contrast, illumination at 530 nm instead initiated the release of carbon oxide (CO) followed by cell death independently of the photodynamic effect. Light-induced CO release was analyzed using second derivatives of UV-Vis spectra and our originally developed S pectrophotometric elimi NA tion of P hotoinduced S ide reactions (SNAPS) method. The yield of CO release decreased in the raw depending on metals in the carbonyl moiety: Mo ≥ Cr > W > Re ≥ Re 2 . Overall, our novel metal carbonyl complexes with porphyrin and carborane isocyanide ligands emerge as potent bi-functional conjugates for combined photodynamic and photoinducible CO-releasing antitumor agents.

The efficacy of photodynamic therapy (PDT) strictly depends on the availability of molecular oxygen to trigger the light-induced generation of reactive species. Fluorocarbons have an increased ability to dissolve oxygen and are attractive tools for gas delivery. We synthesized three fluorous derivatives of chlorin with peripheral polyfluoroalkyl substituents. These compounds were used as precursors for preparing nanoemulsions with perfluorodecalin as an oxygen depot. Therefore, our formulations contained hydrophobic photosensitizers capable of absorbing monochromatic light in the long wavelength region and the oxygen carrier. These modifications did not alter the photosensitizing characteristics of chlorin such as the generation of singlet oxygen, the major cytocidal species in PDT. Emulsions readily entered HCT116 colon carcinoma cells and accumulated largely in mitochondria. Illumination of cells loaded with emulsions rapidly caused peroxidation of lipids and the loss of the plasma membrane integrity (photonecrosis). Most importantly, in PDT settings, emulsions potently sensitized cells cultured under prolonged (8 weeks) hypoxia as well as cells after oxygen depletion with sodium sulfite (acute hypoxia). The photodamaging potency of emulsions in hypoxia was significantly more pronounced compared to emulsion-free counterparts. Considering a negligible dark cytotoxicity, our materials emerge as efficient and biocompatible instruments for PDT-assisted eradication of hypoxic cells.

A novel amphiphilic cationic chlorin e 6 derivative was investigated as a promising photosensitizer for photodynamic therapy. Two cationic -N(CH 3 ) 3 + groups on the periphery of the macrocycle provide additional hydrophilization of the molecule and ensure its electrostatic binding to the mitochondrial membranes and bacterial cell walls. The presence of a hydrophobic phytol residue in the same molecule results in its increased affinity towards the phospholipid membranes while decreasing its stability towards aggregation in aqueous media. In organic media, this chlorin e 6 derivative is characterized by a singlet oxygen quantum yield of 55%. Solubilization studies in different polymer- and surfactant-based supramolecular systems revealed the effective stabilization of this compound in a photoactive monomolecular form in micellar nonionic surfactant solutions, including Tween-80 and Cremophor EL. A novel cationic chlorin e 6 derivative also demonstrates effective binding towards serum albumin, which enhances its bioavailability and promotes effective accumulation within the target tissues. Laser confocal scanning microscopy demonstrates the rapid intracellular accumulation and distribution of this compound throughout the cells. Together with low dark toxicity and a rather good photostability, this compound demonstrates significant phototoxicity against HeLa cells causing cellular damage most likely through reactive oxygen species generation. These results demonstrate a high potential of this derivative for application in photodynamic therapy.