Bruno Therrien

Ruthenium Porphyrin Compounds for Photodynamic Therapy of Cancer

Five 5,10,15,20-tetra(4-pyridyl)porphyrin (TPP) areneruthenium(II) derivatives and a p-cymeneosmium and two pentamethylcyclopentadienyliridium and -rhodium analogues were prepared and characterized as potential photosensitizing chemotherapeutic agents. The biological effects of all these derivatives were assessed on human melanoma tumor cells, and their cellular uptake and intracellular localization were determined. All molecules, except the rhodium complex which was not cytotoxic, demonstrated comparable cytotoxicity in the absence of laser irradiation. The ruthenium complexes exhibited excellent phototoxicities toward melanoma cells when exposed to laser light at 652 nm. Cellular uptake and localization microscopy studies of [Ru 4(eta (6)-C 6H 5CH 3) 4(TPP)Cl 8] and [Rh 4(eta (5)-C 5Me 5) 4(TPP)Cl 8] revealed that they accumulated in the melanoma cell cytoplasm in granular structures different from lysosomes. The fluorescent porphyrin moiety and the metal component were localized in similar structures within the cells. Thus, the porphyrin areneruthenium(II) derivatives represent a promising new class of organometallic photosensitizers able to combine chemotherapeutic activity with photodynamic therapeutic treatment of cancer.

Organometallic cages as vehicles for intracellular release of photosensitizers.

Water-soluble metalla-cages were used to deliver hydrophobic porphin molecules to cancer cells. After internalization, the photosensitizer was photoactivated, significantly increasing the cytotoxicity in cells. During the transport, the photosensitizer remains nonreactive to light, offering a new strategy to tackle overall photosensitization, a limitation often encountered in photodynamic therapy.

Evidence for Drug Release from a Metalla-Cage Delivery Vector Following Cellular Internalisation

The authors have encapsulated in the cavity of [Ru6(p-iPrC6H4Me)6(tpt)2-(C6H2O4)3]6+ (tpt = 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine), and intrinsically fluorescent pyrenyl compd. (pyrene-R = 1-(4,6-dichloro-1,3,5-trianzin-2-yl)pyrene), thus giving rise to the hexanuclear metalla-prism, in which the pyrenyl deriv. occupies the cavity of [Ru6(p-iPrC6H4Me)6(tpt)2-(C6H2O4)3]6+. Once inside a tumor cell the hexaruthenium chage releases the fluorescent guest. Microscopy and flow cytometry could be used to monitor the uptake of the fluorophores into human ovarian carcinoma cells. The uptake was probably by assisted diffusion.

Transporting and Shielding Photosensitisers by Using Water-Soluble Organometallic Cages: A New Strategy in Drug Delivery and Photodynamic Therapy

Skin photosensitivity remains one of the main limitations in photodynamic therapy. In this Concept article a strategy to overcome this limitation is described, in which the photosensitizer is hidden inside the hydrophobic cavity of a water-soluble organometallic cage. The metallacage not only protects the photosensitizer from light, it also facilitates its delivery to cancer cells.

Drug Delivery by Water-Soluble Organometallic Cages

Until recently, organometallic derivatives were generally viewed as moisture- and air-sensitive compounds, and consequently very challenging to synthesise and very demanding in terms of laboratory requirements (Schlenk techniques, dried solvent, glove box). However, an increasing number of stable, water-soluble organometallic compounds are now available, and organometallic chemistry in aqueous phase is a flourishing area of research. As such, coordination-driven self-assemblies using organometallic building blocks are compatible with water, thus opening new perspectives in bio-organometallic chemistry.This chapter gives a short history of coordination-driven self-assembly, with a special attention to organometallic metalla-cycles, especially those composed of half-sandwich complexes. These metalla-assemblies have been used as sensors, as anticancer agents, as well as drug carriers.

Double Targeting of Tumours with Pyrenyl‐Modified Dendrimers Encapsulated in an Arene–Ruthenium Metallaprism

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene-ruthenium building blocks and 5,8-dioxido-1,4-naphthoquinonato (donq) bridges, in the presence of pyrenyl-containing dendrimers of different generations (P(0), P(1) and P(2)), affords the triangular prismatic host-guest compounds [P(n)⊂Ru(6)(p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([P(n)⊂1](6+)). The host-guest nature of these systems, with the pyrenyl moiety being encapsulated in the hydrophobic cavity of the cage and the dendritic functional group pointing outwards, was confirmed by NMR spectroscopy ((1)H, 2D and DOSY). The host-guest properties of these systems were studied in solution by NMR and UV/Vis spectroscopic methods, allowing the determination of their affinity constants (K(a)). Moreover, the ability of these water-soluble host-guest systems to carry the pyrenyl-containing dendrimers into cancer cells was evaluated on human ovarian cancer cells. The host-guest systems are all more cytotoxic than the empty cage [1][CF(3)SO(3)](6) (IC(50)≈4 μM), with the most active compound, [P(0)⊂1][CF(3)SO(3)](6), being an order of magnitude more cytotoxic.

Self-assembled hexanuclear arene ruthenium metallo-prisms with unexpected double helical chirality

Self-assembly of 2,4,6-tripyridyl-1,3,5-triazine (tpt) subunits with arene ruthenium building blocks and oxalato bridges affords cationic triangular metallo-prisms of the type [Ru6(arene)6(tpt)2(C2O4)3]6+ (arene = C6Me6 and p-Pr(i)C6H4Me); the unexpected double helical chirality of the metallo-prisms observed in the solid state persists in solution giving rise to two different stereodynamic processes as demonstrated by NMR enantiodifferentiation experiments.

Anticancer activity of opened arene ruthenium metalla-assemblies

Cationic tetranuclear and hexanuclear opened metalla-assemblies incorporating 5,15-bis(4-pyridyl)-10,20-diphenylporphyrin (bpp) or 5,10,15-tris(4-pyridyl)-20-phenylporphyrin (tpp) panels and dinuclear arene ruthenium clips [(p-cymene)(2)Ru(2)(OO[intersection]OO)(2)](2+) (OO[intersection]OO = oxalato, 2,5-dioxydo-1,4-benzoquinonato (dobq)) have been assembled in the presence of silver triflate. All complexes were characterised by NMR, IR and UV-visible spectroscopy and electrospray ionisation mass spectrometry. The cytotoxicities of the tetranuclear and hexanuclear ruthenium complexes have been established on ovarian A2780 and A2780cisR cancer cell lines. The compounds are quite cytotoxic, the most active metalla-assembly being [Ru(6)(p-cymene)(6)(dobq)(3)(tpp)(2)](6+), with IC(50) values of 2.1 microM and 3.8 microM against A2780 and A2780cisR cells, respectively.

Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of highly cytotoxic anticancer agents

New cationic diruthenium complexes of the type [(arene)(2)Ru(2)(SPh)(3)](+), arene being C(6)H(6), p-(i)PrC(6)H(4)Me, C(6)Me(6), C(6)H(5)R, where R = (CH(2))(n)OC(O)C(6)H(4)-p-O(CH(2))(6)CH(3) or (CH(2))(n)OC(O)CH=CHC(6)H(4)-p-OCH(3) and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl(2)](2) and thiophenol and isolated as their chloride salts. The complexes have been fully characterised by spectroscopic methods and the solid state structure of [(C(6)H(6))(2)Ru(2)(SPh)(3)](+), crystallised as the hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC(50) values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato compounds [(arene)(2)Ru(2)(S-p-C(6)H(4)OH)(3)]Cl (IC(50) values around 100 μM) are much less cytotoxic. Thus, it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to the presence of the phenyl or toluyl substituents at the three thiolato bridges.

Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water soluble metalla-cage

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-Pr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the presence of a functionalised pyrenyl derivative (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R) [symbol: see text] Ru(6)(p-Pr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R) [symbol: see text] 1](6+)). The inclusion of eight mono-substituted pyrenyl derivatives including biologically relevant structures (a = 1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative (i = 1,8-bis(3-methyl-butyn-1-yl-3-ol)pyrene), has been accomplished. The carceplex nature of these systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with the functional groups pointing outwards was confirmed by NMR ((1)H, 2D, DOSY) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 cancer cells. All the host-guest systems are more cytotoxic than the empty cage itself [1][CF(3)SO(3)](6) (IC(50) = 23 microM), the most active carceplex [f [symbol: see text] 1][CF(3)SO(3)](6) is an order of magnitude more cytotoxic.