Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.

A Luminescent NOTA-Based Terbium(III) "Turn-Off" Sensor for Copper.

A bimacrocyclic luminescent terbium(III) sensor is reported for the selective "turn-off" detection of Cu2+ ions in aqueous solutions. The current sensor differentiates from previous sensors in that it offers the use of (1) time-gated luminescence detection to remove the background signal, (2) a longer excitation wavelength of up to 350 nm for increased biocompatibility, and (3) a practically irreversible detection as a form of probing Cu2+ ions with an extremely low limit of detection of about 1.7 nM.

A Ru(II) polypyridyl complex bearing aldehyde functions as a versatile synthetic precursor for long-wavelength absorbing photodynamic therapy photosensitizers.

The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, the currently clinically approved photosensitizers (PSs) have several drawbacks, including photobleaching, slow clearance from the organism and poor water solubility. To overcome these shortcomings, many efforts have been made in the development of new types of PSs, such as Ru(II) polypyridyl complexes. Nevertheless, most studied Ru(II) polypyridyl complexes have a low absorbance in the spectral therapeutic window. In this work, we show that, by carefully selecting substituents on the polypyridyl complex, it is possible to prepare a complex absorbing at a much higher wavelength. Specifically, we report on the synthesis as well as in-depth experimental and theoretical characterisation of a Ru(II) polypyridyl complex (complex 3) combining a shift in absorbance towards the spectral therapeutic window with a high 1O2 production. To overcome the absence or poor selectivity of most approved PSs into targeted cells/bacteria, they can be linked to targeting moieties. In this line, compound 3 was designed with reactive aldehyde groups, which can be used as a highly versatile synthetic precursor for further conjugation. As a proof of concept, 3 was reacted with benzylamine and the stability of the resulting conjugate 4 was investigated in DMSO, PBS and cell media. 4 showed an impressive ability to act as a PDT PS with no measurable dark cytotoxicity and photocytotoxicity in the low micromolar range against cancerous HeLa cells from 450 nm up to 540 nm.

Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells.

Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4-6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32-2.5 µM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 hour with 10 µM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm-1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus.

Critical Overview of the Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-Photon and Two-Photon Photodynamic Therapy.

Photodynamic Therapy (PDT) is an emerging technique to treat certain types of cancer, bacterial, fungal, and viral infections, and skin diseases. In past years, different research groups developed new ruthenium-containing photosensitizers (PSs) with tuned photophysical and biological properties to better fit the requirements of PDT. In this Account, we report and discuss the latest results in this research area, emphasizing particularly our own research. For example, inspired by the DNA intercalating complex [Ru(bpy)2(dppz)]2+ (bpy = 2,2'-bipyridine; dppz = (dipyrido[3,2-a:2',3'-c]phenazine), a series of ruthenium complexes bearing differently functionalized dppz ligands were synthesized to target DNA. The introduction of the substituents on the dppz ligand did not reduce much the affinity of the complexes to DNA but highly affected their cellular uptake. The most effective complex in this series, [Ru(bpy)2(dppz-7-OMe)]2+, showed IC50 values in the low micromolar range against several types of cancer cells upon light irradiation and, importantly, a high phototoxic index (PI) of >150. This value is comparable to or even better than several PSs used in clinics under comparable experimental conditions. This compound was found to localize in the nucleus and to induce DNA damage in HeLa cells upon light irradiation. Interestingly, cells in the mitotic phase were found to be more affected and to have a different mechanism of cell death (apoptosis) upon light irradiation than those in the interphase (paraptosis). To take advantage of that, the PS was combined with a cell cycle inhibitor to synchronize cells in the mitotic phase, further improving the phototoxicity by a factor of 3.6. In addition, our group recently demonstrated that [Ru(bphen)2(benzene-1,2-dislufinate)] (bphen = 4,7-diphenyl-1,10-phenanthroline) localizes in mitochondria and has an IC50 value of 0.62 µM with a PI of over 80 in HeLa cells upon light irradiation at 420 nm. Interestingly, this complex was also found to efficiently kill Gram-positive Staphylococcus aureus under light irradiation. Antimicrobial PDT (aPDT) is another field of research where Ru(II) polypyridyl complexes can play an interesting role to fight antibiotics resistance. [Ru(dqpCO2Me)(ptpy)]2+ (dqpCO2Me = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4'-phenyl-2,2':6',2″-terpyridine) is additionally efficient against Gram-negative Escherichia coli. The efficacy of positively charged Ru(II) PSs is related to their affinity to the negatively charged membrane of Gram-negative bacteria. A drawback of many Ru(II) polypyridyl PSs is their low absorption in the biological optical window (600-900 nm) where light penetration depth into tissue is the highest. The lowest energy transition in the UV/Vis spectra of Ru(II) polypyridyl complexes is usually a metal-to-ligand charge-transfer band. To shift the absorption into this range, tuning of the ligand system, for example, by extending π-systems, has been described in the literature. Another approach to make excitation in the optical biological window possible is Two-Photon Absorption (2PA). High photon density is needed and usually confocal laser beams are used for excitation. In collaboration with the Chao group, a series of homoleptic Ru(II) complexes bearing tertiary alkyl ammonium substituted bipyridine ligands with two photon cross sections between 185 and 250 GM at around 800 nm was tested in vitro. They showed IC50 values in the micromolar range and PIs between 103 and 313. The highly positive-charged complexes were found to enter the cell via endocytosis and to target lysosomes. Studies on 3D tumor cell spheroids, a model closer to real tumors than commonly used 2D cell monolayers, were also performed. It could be demonstrated that 2P-PDT treatment with 800 nm laser irradiation was significantly more effective than that with 450 nm laser irradiation.