The Gasser Group, France's equivalent of the McFarland Group, is taking a different approach to cancer cell selectivity by combining Osmium and Ruthenium PSs with cancer cell selective biomolecules.
Ru(II)/Os(II)-based carbonic anhydrase inhibitors asphotodynamic therapy photosensitizers for the treatment of hypoxic tumours Youchao Wang, Pierre Mesdom, Kallol Purkait, Bruno Saubam, Pierre Burckel, Philippe Arnoux, Celine Frochot, Kevin Cariou, Thibaud Rossel and Gilles Gasser
Photodynamic therapy (PDT) is a medical technique for the treatment of cancer. It is based on the use of non-toxic molecules, called photosensitizers (PSs), that become toxic when irradiated with light and producereactive oxygen specious (ROS) such as singlet oxygen (1O2). This light-induced toxicity is rather selective since the physician only targets a specic area of the body, leading to minimal side eects. Yet, a strategy to improve further the selectivity of this medical technique is to conne the delivery of the PS to cancer cells only instead of spreading it randomly throughout the body prior to light irradiation. To address this problem, we present here novel sulfonamide-based monopodal and dipodal ruthenium and osmium polypyridyl complexes capable of targeting carbonic anhydrases (CAs) that are a major target in cancer therapy. CAs are overexpressed in the membrane or cytoplasm of various cancer cells. We therefore anticipated that the accumulation of our complexes in or outside the cell prior to irradiation would improve the selectivity of the PDT treatment. We show that our complexes have a high anity for CAs,accumulate in cancer cells overexpressing CA cells and importantly kill cancer cells under both normoxic and hypoxic conditions upon irradiation at 540 nm. More importantly, Os(II) compounds still exhibit some phototoxicity under 740 nm irradiation under normoxic conditions. To our knowledge, this is the rst description of ruthenium/osmium-based PDT PSs that are CA inhibitors for the selective treatment of cancers.
Introduction
Photodynamic therapy (PDT) has recently emerged as a promising medical technique to treat certain forms of cancer due to its high spatiotemporal precision, leading to minimal side eects. 1,2 A PDT treatment mainly relies on a photosensitizer (PS) to produce cytotoxic reactive oxygen species (ROS) upon light irradiation. The ROS produced usually include superoxide anion radicals (O2c−),hydroxyl radicals (OHc), or hydrogen peroxide (H2O2) intype IPDT and singlet oxygen (1O2) in typeII PDT.3–6 Apart from classical porphyrins or other organic-based PSs, transition metal-based PDT PSs, such as Ru(II) or Os(II) polypyridyl complexes, among others, have been extensively studied in the last few years due to their high stability, low photobleaching rate and high 1O2 production. 7–16 For example, the metal-based PSs Photosens (Al-phthalocyanines) and Tookad (padeliporfin) have successively been approved for clinical use and the Ru(II)-based PS TLD1433 has entered phase II clinical trials against bladder cancer (seeFig. 1).17 We note that, compared to Ru(II) polypyridyl complexes,Os(II) polypyridyl complexes typically exhibit absorption maxima in the near-infrared region, which is closer to the most favorable photodynamic therapeutic window if deep-seated or large tumors are targeted.7,18–21
cancer cell
However, the common Ru(II) or Os(II) polypyridine complexes reported so far in the literature are not inherently selective for cancer cells. 22 To overcome these limitations, metal complexes have been combined with some cancer cell-selective biomolecules (e.g., peptides, aptamers, and antibodies). 22–30 It is also noteworthy that the tumor microenvironment (TME) is underhypoxic conditions due to the uncontrolled growth of tumor cells that consume a massive quantity of O2, reducing the efficacy of PDT treatments. 31,32 Therefore, it is of great interest to discover PSs that can equally or more eectively work against the hypoxic TME to improve the therapeutic potency of PDT.
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Conclusions
In this work, we mainly designed and synthesized four complexes bearing sulfonamide moieties and explored their photophysical and photochemical properties. The sulfonamide containing Ru(II) complexes (5and 6) displayed a1O2 production quantum yield of 77%, while the absorption spectrum of the sulfonamide-containing Os(II) complexes (11 and 12) exhibited a notable red shift. Furthermore, these complexes have good binding ability to CAII. More importantly, A549 cells were considered as CAIX positive cells and MDA-MB-231 cells as negative cells through western blotting and immunofluorescence experiments. The biological evaluation was performed on these compounds, which exhibited micromolar phototoxicity against the A549 cells under both normoxic and hypoxic conditions, particularly at 540 nm. Notably, as the wavelength increased, the cellular phototoxicity decreased. However,compared with Ru(II) compounds, Os(II) compounds still showed significant phototoxicity upon irradiation at 740 nm under normoxic conditions. These findings demonstrate the potential of sulfonamide-containing Ru(II)/Os(II)-based PSs as an eective drug for PDT. Their ability to induce phototoxicity in the visible and near-infrared regions, as well as under hypoxic conditions, holds promise for targeted cancer therapy. Further refinement and exploration of these compounds may contribute to the development of new therapies that exploit unique features of the tumor microenvironment, such as hypoxia and enzyme overexpression, and red-shifted absorption, to enhance therapeutic ecacy.