Rationally designed ruthenium complexes for 1- and 2-photon photodynamic therapy

Abstract

The use of photodynamic therapy (PDT) against cancer has received increasing attention over recent years. However, the application of the currently approved photosensitizers (PSs) is limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E′)-4,4′-bisstyryl-2,2′-bipyridine ligands show impressive 1-and 2-Photon absorption up to a magnitude higher than the ones published so far. While nontoxic in the dark, these compounds are phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and are able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2-Photon excitation.

<p>Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives</p>

“…One of the excellent examples would be 41 which showed a promising phototoxic profile. 121 It displayed IC 50 > 100 μM in dark without irradiation while its IC 50 is less than 1 μM when irradiated against CT-26 colon carcinoma cells reaching safety index >100. As for the recent examples of PACT, Karaoun et al 122 constructed Ru(II) complexes with either one or two imidazole-based antifungal agent econazole ligands for dual applications in cell imaging and PACT agents.…”

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy

“…In acetonitrile, 1-5 showed high φ values ranging from 58 to 88 % upon irradiation at 420 nm, which are comparable to structurally similar ruthenium polypyridyl complexes reported previously. [10,12,14,15,66] However, we noted that φ values are much lower (2-6 %) when measured in PBS. This observation is consistent with our previous studies on polypyridyl complexes and attributed to the interaction of the dppz ligands with water molecules, which does not allow energy transfer to molecular oxygen.…”

“…[7] More recently, Ru II polypyridyl complexes have sparked great interest due to their exceptional properties, including generally good water solubility, high 1 O 2 production rates and high photochemical stability as well as original mode of actions related to their unique intracellular distribution (i. e., mitochondria, nucleus, lysosome, etc). [8][9][10][11][12][13][14][15][16][17][18] As a proof of the promising nature of these third-generation PSs, TLD-1433 ( Figure 2) has recently entered a phase II clinical trial for the treatment of non-muscle invasive bladder cancer. [7,19] Over the years, in order to increase chemotherapeutics efficacy, reduce side effects and overcome resistance mechanisms, the development of organelle-targeted drugs appeared highly beneficial.…”

One‐ and Two‐Photon Phototherapeutic Effects of RuII Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor‐Bearing Mice**

“…However, the Ru II polypyridine complexes reported so far were found to have relatively poor 2P photophysical properties [7, 9a, 12] compared to porphyrins, porphyrin oligomers or expanded porphyrinoids, [13] limiting the application of this technique with these complexes. In this context, we have recently reported the rational design of the complexes [Ru(bipy) n ( L ‐NMe 2 / L ‐OMe) 3− n ] 2+ (bipy=2,2'‐bipyridine, L ‐NMe 2 =( E , E ′)‐4,4'‐bis[ p ‐( N , N ‐dimethylamino)styryl]‐2,2'‐bipyridine, L ‐OMe=( E , E ′)‐4,4'‐bis[ p ‐methoxystyryl]‐2,2'‐bipyridine, n =0, 1, 2, Figure 1) as effective PSs for 1P (540 nm) and 2P (800 nm) PDT [14] . Worthy of note, the use of ( E , E ′)‐4,4'‐bisstyryl‐2,2'‐bipyridine type Ru II polypyridine complexes was previously reported as effective 2P absorbing chromophores [15] .…”