Luminescent Ruthenium (II) Polypyridine Complexes for a Wide

Viewpoint Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Luminescent Ruthenium(II) Polypyridine Complexes for a Wide Variety of Biomolecular and Cellular Applications Justin Shum,† Peter Kam-Keung Leung,† and Kenneth Kam-Wing Lo*,†,‡,§ Department of Chemistry, ‡State Key Laboratory of Terahertz and Millimeter Waves, and §Center of Functional Photonics, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China

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ABSTRACT: Ruthenium(II) polypyridine complexes are one of the most extensively studied and developed systems in the family of luminescent transition-metal complexes. Notably, there has been a large amount of interest in the biological applications of these luminescent ruthenium(II) complexes because of their rich photophysical and photochemical properties. In this Viewpoint, we explore past and recent works on the possible biological and cellular applications of these promising complexes, with a focus on their use as bioimaging reagents, biomolecular probes, and phototherapeutic agents.

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INTRODUCTION The luminescence properties of d6 transition-metal complexes have gained much attention because of the diverse palate of available colors that these complexes exhibit.3,2 With a rich history of synthetic chemistry and tunable photophysical and photochemical properties based on their associated ligands, ruthenium(II) polypyridine complexes were utilized for many therapeutic and diagnostic applications.1,4 Compared to other transition-metal complexes, ruthenium(II) offers advantages such as the mimicking of iron to enhance uptake in cancer cells by binding to transferrin protein receptors located on the cell membrane, capability of undergoing ligand exchange because of their different octahedral geometry, and stable oxidation states instigating biological redox pathways.5,6 Notably, the interactions of ruthenium(II) polypyridine complexes with mismatched sites of DNA have been thoroughly investigated for their intercalative mode of action upon the minor groove.7 Photoactivated chemotherapy (PACT) emerged as a method to provide spatial and temporal control over the activation of a drug. PACT encompasses photodynamic therapy (PDT), a form of therapy reliant on the ability of the photosensitizer (PS) to generate reactive singlet oxygen (1O2; type II) or free radicals (type I).8 Unlike traditional PSs, which are based on tetrapyrrolic compounds, ruthenium(II)-based PDT agents have favorable photophysical properties (absorption in the visible spectra, one- and two-photon excitation in the biological therapeutic window, and some ruthenium PSs are able to retain a good PDT effect under hypoxia).9,10 In this Viewpoint, we hope to provide a concise and brief exploration through the numerous possibilities of luminescent ruthenium(II) polypyridine complexes for biological and cellular applications. We begin with the most basic application: imaging, which involves the conjugation of peptides or © XXXX American Chemical Society

biomolecules. After, ruthenium(II) complexes for the detection of biomolecules with implications as biomarkers will be discussed. The next topic, photofunctional complexes, focuses on the different mechanisms of action possible, such as binding toward guanine bases, intercalation to DNA strands, photorelease, photoactivation, and photosubstitution. The last section will cover the recent development of ruthenium(II) complexes as PDT agents.

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CELLULAR IMAGING AGENTS Complexes Conjugated with Biomolecules and Peptides for Targeted Delivery. Bioactive molecules such as proteins, peptides, hormones, and carbohydrates have been investigated for their ability to direct transition-metal complexes to various organelles. Our group has been interested in ruthenium(II) complexes with appended factors such as biotin for the assay of avidin.11,12 The modification of biotin on biomolecules has been shown to rarely affect the biological activity and functionality; hence, this system can be considered to be a nondisruptive probe for imaging. Indole derivatives appended to complexes have also been developed as probes for proteins.13 Intracellular imaging requires good cell permeability properties; most conventional dicationic ruthenium(II) complexes do not tend to passively diffuse across the cell membrane unless a lipophilic modification is induced. In light of this property, estradiol-appended ruthenium(II) polypyridine complexes 1 and 2 (Chart 1) were designed for cellular penetration and labeling.14 Complex 2 is a promising candidate for imaging with cellular localization distributed in the cytoplasm and to a smaller extent in the nucleus. The Ph2Received: October 20, 2018

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DOI: 10.1021/acs.inorgchem.8b02979 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry Chart 1. Estradiol- and D-Fructose-Appended Ruthenium(II) Polypyridine Complexes

complex 8, appended with an octaarginine peptide, is able to direct the penetration of the cell membrane via endocytosis processes; however, it is unable to enter the nucleus because of entrapment in the endosomes. Complex 9 has relatively high cellular uptake in the nucleus; thus, highlighting slight modifications can affect the cellular localization and uptake. As expected under the same conditions, the ruthenium− fluorescein conjugate 10, lacking the octaarginine linker, is unable to enter the cell. Appending a fluorescein is quite promising for increasing penetrative properties; however, later work shows that this is not an effective general strategy.20 Appendage of a nuclear localization signal (NLS) peptide allows for the targeted delivery of two ruthenium(II) polypyridine complexes to the nucleus. The transcription factor nuclear factor kappa B (NF-κB) has been used to derive the NLS peptide sequence, which is appended to give complexes 11 and 12 (Chart 3).21 Interestingly, cellular studies in live CHO cells indicated that the more hydrophilic bpy complex 11 is directed to the nucleus by the NLS peptide, whereas the more lipophilic Ph2-phen conjugate 12 is concentrated inside the nucleolus. As shown in Figure 1, the complexes are able to penetrate the nucleus and exhibit strong colocalization with the 4′,6-diamidino-2-phenylindole (DAPI) dye. Later work implemented ruthenium(II) polypyridine complexes for specific organelle targeting and probes for stimulated emission depletion (STED) microscopy.22 Endoplasmic reticulum (ER) and nuclear targeting peptides have been conjugated with ruthenium(II) to give the complexes RuER (13) and Ru-NLS (14), respectively. Confocal microscopy revealed that complex 13 is selectively localized in the ER, and STED imaging provided clear images of the tubular structures

phen estradiol complexes bind toward estrogen receptor-α (ERα) and exhibit enhanced emission intensities and lifetimes once bound. Recently, our group has demonstrated mitochondria staining in HeLa cells utilizing an appended D-fructose pendant.15 In breast cancer tissues, the expression levels of glucose transporters (GLUTs) are much greater than those of normal cells because of the higher consumption of metabolites such as saccharides.16 One of the protein transporter members, GLUT5 has been identified as a selective transporter for fructose uptake; hence, complexes 3 and 4 were designed and synthesized. Four different cancer lines were investigated; MCF-7 cells were of interest because of their higher expression levels of GLUT5. The lipophilic ancillary Ph2-phen ligand renders complex 3 to be selectively localized in the mitochondria in HeLa cells. Complex 4 retains the membrane-staining potential in HeLa cells; however, it is able to be transported into MCF-7 cells because of a GLUTmediated pathway. To our knowledge, the first cell-permeable ruthenium−peptide conjugates, complexes 5 and 6 (Chart 2), were reported by Neugebauer et al.17 These complexes, appended with the arginine residues, are able to penetrate the cell membrane compared to their arginine-free counterparts. Furthermore, complex 6 with the longer polyarginine chain is more likely to undergo endocytosis processes. Complex 7 was later developed and found to also be able to cross the membrane to be distributed throughout the cell.18 Puckett and Barton explored the effects of appending a fluorescent tag on the octaarginine peptide-conjugated ruthenium(II) polypyridine complex.19 Complexes 8−10 were incubated in HeLa cells and exhibited vast differences in cellular uptake even in the premise of similar conditions. As previously demonstrated, B


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Inorganic Chemistry Chart 2. Ruthenium(II) Octaarginine Peptide Conjugates and a Control Complex

appended with two β-cyclodextrin units and can undergo selfassembly with a tumor-targeting adamantane cyclic RGD peptide. The nanostructure is able to specifically target αvβ3rich U87MG cancer cells and induce cell death through lysosomal damage, caspase activation, and elevation of reactive oxygen species (ROS). As shown in Figure 3, cellular colocalization studies indicated specific lysosomal staining. Bioorthogonal Probes. Bioorthogonal chemistry has been one of the forefront strategies for imaging of living systems. Bioorthogonal reactions tend to be highly specific, biologically and chemically inert, and occur quickly.26,27 Usually, bioorthogonal chemistry involves the modification of a cellular substrate with a bioorthogonal functional group and is introduced to the cell. The bioorthogonal functional group is nondisruptive and able to react with the probe containing the complementary functional group to label the substrate. Our group has developed complexes 19 and 20 (Chart 5), luminescent ruthenium(II) polypyridine complexes functionalized with a dibenzocyclooctyne unit capable of strainpromoted alkyne−azide cycloaddition.28 (CHO)-K1 and human lung adenocarcinoma (A549) cells were grown with or without pretreatment of 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-D-mannosamine. The complexes are able to selectively label the N-azidoglycans located on the cell surface of pretreated CHO-K1 and A549 cells. Furthermore, the N-azidoglycans can

of this organelle. In contrast, the NLS-appended metal complex 14 is specifically localized in the nucleus; through a series of STED images, the different stages of mitosis are clearly imaged, as shown in Figure 2. Mitochondria-targeting peptide-conjugated dinuclear ruthenium(II) polypyridine complexes have been explored. The two ruthenium(II) polypyridine units in conjugate 15 are bridged by a single penetrating peptide, FrFKFrFK, and cellular studies indicated mitochondrial localization.23 Various ruthenium(II) polypyridine peptide conjugates have been utilized in integrin imaging. Integrin αIIbβ3 is a heterodimeric glycoprotein cell adhesion receptor with two different conformation forms. In the activated conformation form, integrin αIIbβ3 exhibits a high affinity for probes appended with the Arg-Gly-Asp (RGD) peptide. Adamson et al. designed conjugates 16 and 17 (Chart 4) to detect the presence and conformation of integrin αIIbβ3.24 Eptifibatide, a potent inhibitor of the RGD binding site was utilized to demonstrate effective blocking of binding sites for both conjugates 16 and 17. Importantly, the RGD probes exhibit an 8-fold increase of the emission intensity upon binding and play a role in modulating the structure or oligomerization of the integrin. A ruthenium-containing nanostructure has been designed by Xue et al. to induce cell death in integrin αvβ3-rich tumor cells.25 The anticancer ruthenium(II) complex 18 is C


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Inorganic Chemistry Chart 3. Ruthenium(II) NLS, ER, and Mitochondria Peptide Conjugates

Figure 1. Confocal luminescence images of live CHO cells incubated with complexes 11 (A) and 12 (B). The ruthenium complexes (red, 40 μM, 16 h) were incubated and costained with DAPI (blue, 300 nM, 30 min) at 37 °C. The merged images of the ruthenium complex, DAPI dye, and the backscatter reflection are shown on the bottom right. The fluorescence intensity is shown on the bottom left. Reproduced from ref 21. Copyright 2013 Royal Society of Chemistry.

functionalized with a nitrone group.29 The nitrone moiety acts as an emission quencher by rapid CN isomerization and also as a bioorthogonal functional group. These complexes are very weakly emissive or nonemissive because of the quenching properties of the nitrone; however, they exhibit emission turnon properties upon strain-promoted alkyne-nitrone cyclo-

be visualized and monitored by confocal microscopy. The Nazidoglycan substrate is internalized by endocytosis processes and subsequently translocated to the Golgi apparatus and lysosomes for enzymatic processing. Recently, we reported a new class of phosphorogenic ruthenium(II) bioorthogonal probes, complexes 21−25 D


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Inorganic Chemistry

Figure 2. STED images of complex 14 bound to the DNA of the nucleus in fixed HeLa cells, depicting the various stages of cell division. HeLa cells were incubated with complex 14 (40 μM, 24 h). Reproduced from ref 22. Copyright 2016 Royal Society of Chemistry.

Chart 4. Ruthenium(II)-Based Probes for the Imaging of Integrins

Figure 3. Confocal microscopy images of U87MG cells incubated with nanostructures containing complex 18 and 2 equiv of a tumortargeting adamantane-appended cyclic RGD peptide ([Ru] = 10 μM, 24 h) and then stained with LysoTracker Deep Red (50 nM, 30 min) at 37 °C. Reproduced from ref 25. Copyright 2017 Royal Society of Chemistry.

Figure 4. Laser scanning confocal microscopy images of untreated (upper row) and BCN-C10-pretreated (bottom row) HeLa cells incubated with complexes 21−25 (40 μM, 12 h) at 37 °C. Reproduced from ref 29. Copyright 2016 Wiley-VCH on behalf of ChemPubSoc Europe.

addition reaction with bicyclo[6.1.0]nonyne (BCN)-modified substrates. As shown in Figure 4, the incubation of BCN-C10pretreated HeLa cells with the complexes results in different

cellular staining: complexes 21 and 23 exhibit punctated cell surface staining, complexes 22 and 25 display staining of the cell membrane, and complex 24 shows cytosolic staining.

Chart 5. Ruthenium(II)-Based Bioorthogonal Probes

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Inorganic Chemistry Chart 6. Ruthenium(II) Polypyridine Complexes for the Detection of HOCl

Biomolecule Targeting Sensors. The ability to monitor biomolecules allows for a wide range of possibilities, considering their key roles in the maintenance and metabolic processes of living organisms. Sensing is an extensive field that encompasses many biomolecules; hence, we will mainly focus on probes for the sensing of hypochlorous acid (HOCl), nitric oxide (NO), thiols, esterase, and oxygen to provide insight into the various biomolecules available. HOCl is produced naturally as an immune-responsive mechanism against microorganisms and inflammation.30 Zhang et al. have designed highly sensitive and selective probes, complex 26 (Chart 6).31 This complex is functionalized with 4-(2,4-dinitrophenylthiomethylene-4′methyl-2,2′-bipyridine) (DNPS-bpy), which can quench the red emission of ruthenium(II) bipyridine complexes. The ruthenium(II) polypyridine unit undergoes effective photoinduced electron transfer (PET) to the electron acceptor 2,4dinitrophenyl (DNP). The DNP moiety can be cleaved by HOCl by oxidation, resulting in the formation of a highly luminescent ruthenium(II) carboxybipyridine complex, 27, and is marked by 190-fold luminescence enhancement. Cell imaging in HeLa and RAW 264.7 cells demonstrated exogenous HOCl detection and endogenous HOCl detection in macrophages, respectively. Cao et al. demonstrated the sensing of HOCl in lysosomes.32 Complex 28 is functionalized with a ferrocene (Fc) moiety capable of an effective PET process from the Fc molecule to the excited ruthenium(II) polypyridine. In the presence of HOCl, the Fc moiety is released, which, in turn, leads to the formation of complex 27. The cleavage results in both photoluminescence (PL) and electrochemiluminescence (ECL) enhancement. Ruthenium(II) polypyridine probes for selective NO sensing have been developed. NO, a well-known signaling molecule, plays an important role in multiple key physiological processes.33,34 In animals, NO regulates the immune response against infectious diseases and pathogens. Zhang et al. have designed complex 29 (Chart 7) for the detection of NO in biological systems.35 The complex is functionalized with a 5,6diamino-1,10-phenathroline moiety capable of PET processes from the electron-donating diamino group to the excited ruthenium(II) polypyridine unit. In the presence of NO, the complex is converted to its triazole counterpart, complex 30. Because this triazole complex is not restricted by PET processes, its PL and ECL efficiencies are greatly increased compared to those of complex 29. Similarly, the diaminophe-

Chart 7. Ruthenium(II) Polypyridine Complexes for the Detection of NO

noxy complex 31 is shown to be able to image NO in living cells and exhibits turn-on properties similar to those of complex 29.36 In the presence of NO, complex 31 forms the ruthenium(II) triazole derivative complex 32, which is accompanied by an increase in the luminescence quantum yield. The detection and imaging of thiols have drawn considerable interest because of their prevalent nature in peptides, proteins, and cofactors.37 Thiols are considered to play a major role in antioxidant defense because of their sensitive interactions with ROS. Zhang et al. developed probes for the selective detection of thiophenols in aqueous solutions.38 Dinitrophenoxy complexes such as complex 33 (Chart 8) functionalized with either one or more 4-[4-(2,4dinitrophenoxy)phenyl]-2,2′-bipyridine moiety have been isolated. In the presence of thiophenols, the quenching unit is cleaved to form complex 34, which exhibits emission turn-on properties. Recently, a new ruthenium(II) complex, 35, was reported for the monitoring and quantitative detection of hydrogen sulfide (H2S).39 The complex is functionalized with a 2-((2,4-dinitrophenyl)thio)benzoate unit and shows turn-on properties upon cleavage by a H2S-triggered reaction to yield a highly luminescent ruthenium(II) derivative complex, 36. The probe 35 could monitor the exogenous/endogenous H2S in live Daphnia magna, zebrafish, and mice. The functionalization of ruthenium(II) polypyridine complexes with coumarin derivatives for biomolecule sensing has F


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Inorganic Chemistry Chart 8. Ruthenium(II) Polypyridine Complexes for the Detection of Thiols

Chart 9. Coumarin-Appended Ruthenium(II) Polypyridine Complexes for Sensing of Esterase and Oxygen

the probe is noticeably weaker under aerobic conditions because of quenching of the ruthenium chromophore by oxygen.

provided interesting properties and unique designs. Coumarin and its derivatives have been widely utilized because of their small size, excellent fluorescence quantum yields, and high photostability.40 Li et al. have designed two bichromophoric ruthenium(II) complexes, 37 and 38 (Chart 9), for the sensing of esterase.41 These bichromophoric complexes are developed as fluorescent resonance energy transfer (FRET) probes in which the excited coumarin derivative is efficiently quenched by the ruthenium(II) chromophore. Excitation of complexes 37 and 38 at 300 and 430 nm, respectively, leads to the characteristic emission of the ruthenium(II) chromophore at 620 nm. In the presence of esterase, complex 38 undergoes hydrolysis to yield complex 36 and a coumarin derivative. The separation of the two components means the FRET process is inhibited; thus, excitation at the isosbestic wavelength of 430 nm is accompanied by dramatic emission enhancement at 485 nm due to the CMC343 coumarin. Localization studies in HepG2 cells indicated that the complex is distributed in the cytoplasm and binds to hydrophobic organelles. The reaction of complex 38 with esterase in living cells would induce a change in the luminescence color from red to blue. Hara et al. have demonstrated sensing of the oxygen concentration in a living system by dual-emissive probes.42 Complex 39 is functionalized with an alkyl coumarin unit capable of emitting constant fluorescence regardless of the oxygen concentration. The ruthenium(II) chromophore attached to the coumarin displays oxygen-sensitive phosphorescence. The dual-emissive probe has been utilized for cellular imaging of A549 cells under hypoxic (0% O2) or aerobic (20% O2) conditions. Under hypoxic conditions, complex 39 exhibits strong phosphorescence in the cytoplasm of the cells. The phosphorescence of

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PHOTOFUNCTIONAL COMPLEXES Formation of DNA Adducts. The 1,4,5,8-tetraazaphenanthrene (tap) ligand has generated a large amount of interest because of their DNA interactions and photoinduced reactivity toward guanine bases of DNA.43 Jacquet et al. were one of the first groups to explore the mechanism of the formation of ruthenium(II)-based covalent adducts in the presence of duplex DNA.44 Under irradiation, the excited state of complex 40 (Chart 10) exhibits oxidizing properties to undergo electron transfer with guanine bases. The formation of the DNA adduct is due to the reaction between the reduced ruthenium(II) complex and the deprotonated radical cation of guanine. Complex 41 determined that the mechanism of linkage of a guanine to the polyazaaromatic ruthenium(II) complex involves the C-2 or C-7 of a tap ligand.45 After demonstrating guanine linkage to oxidizing polyazaaromatic ruthenium(II) complexes, Ghizdavu et al. designed a new strategy for the photo-cross-linking of two strands of an oligonucleotide (ODN) duplex.46 The strategy involves irradiation of complex 42 to facilitate adduct formation on a guanine base of one ODN strand, followed by photoaddition of the same ruthenium complex onto a separate guanine base from the complementary strand. This leads to the irreversible cross-linkage of the two ODN strands by covalent bond formation. Further work by Le Gac et al. examined the unique property of complex 43, which is attached to a 14-mer ODN strand containing a guanine base.47 The Ru-ODN probe is G


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Inorganic Chemistry

complexes are similar to [Ru(tap)2(L)]2+, which can photooxidize guanine-containing ODNs.48 Noncovalent Probes for DNA. Complexes of the general structure [Ru(N^N)2(dppz)]2+ exhibit well-known molecular “light-switch” properties for double-stranded DNA.49 Gill et al. utilized a tetrapyridophenazine ligand, which exhibits similar properties, for cellular DNA staining.50 The dinuclear ruthenium(II) complex 47 (Chart 11) was shown to be nonemissive in aqueous environments but highly luminescent upon binding to duplex or quadruplex DNA. Cellular localization studies mainly indicated nuclear localization. Pierroz et al. have designed complex 48, utilizing dppz as the ancillary ligand.51 This complex possesses the ability to intercalate to DNA because of the ancillary ligand; however, surprisingly under biological conditions in HeLa cells, it specifically targets the mitochondria (Figure 6), which should be a result of the cationic and lipophilic nature of the complex. Friedman et al. reported the application of complex 49, which only exhibits luminescence when intercalated to the base pairs of DNA.49 Variations of the dppz ligand did not significantly affect the DNA intercalation properties, as seen in complexes 50 and 51.52 The derivative dppz complexes intercalated to DNA with larger binding constants than that of complex 49 and under irradiation could cleave supercoiled pBR322 DNA in vitro. Inspired by the DNA mismatch specificity of [Rh(bpy)2(chrysi)]3+ and light-switching properties of complex 49, McConnell et al. designed a family of ruthenium(II) complexes capable of exhibiting both properties by modifying the steric bulk of the dppz ligand or by replacing the dppz ligand with sterically expansive inserting ligands.53 Because of the large number of complexes, we will cover the most prominent complexes in the family. Complexes 52 and 53 with the chrysi modification show promising mismatch discrimination; however, because of their quenched luminescence from the exchangeable imino protons, their use as probes is limited. Complexes 54−59 were designed with the goal of increasing steric bulk of the dppz ligand. Complexes 54 and 57 contain narrower ligands and were able to display differential luminescence behavior. Overall, it was determined that increasing the steric bulk of the dppz ligand is more successful because the light-switching behavior is retained and capable of detecting mismatched sites. Recent work reported a sterically expansive ligand BNIQ to yield complex 60, which was found to be a highly selective probe for DNA mismatches and abasic sites.54 The complex acts as a metalloinsertor, capable of extruding destabilized bases of mismatch and abasic sites. Photoinduced Activation. Photoactivatable complexes usually can be characterized into three broad categories based on their mechanism: photorelease, photocage, and photosubstitution. In general, photoactivatable probes offer many advantages as therapeutics because of their inertness toward biological systems, controlled cytotoxicity, and noninvasive light for activation.55 The design of metallodrugs has often utilized ruthenium(II) photoactivable complexes owing to spatial and temporal control and the possibility of low-energy activation. Neuronal communication relies on the release and detection of neurotransmitters, molecules capable of stimulating the postsynaptic neuron.56 Zayat et al. have demonstrated the stimulation of neurons by the photorelease of 4-aminopyridine (4AP) from a ruthenium(II) polypyridine complex.57 Complex 61 (Chart 12) is functionalized with 4AP, a neurochemical

Chart 10. Ruthenium(II) Polypyridine Agents for Complexation with Guanine Bases of DNA

capable of gene silencing by photo-cross-linkage to the complementary strand containing a guanine base or by selfinhibition via photolinkage to the guanine base located on its own strand to form a less sterically hindered cyclic Ru-ODN photoadduct, as shown in Figure 5. Ruthenium(II) polypyridine complexes 44−46 were attached to gold nanoparticles by strong thiol−gold interactions. These probes containing multiple π-deficit ruthenium(II)

Figure 5. Complex 43 conjugated to an ODN strand under irradiation which can photo-cross-link with a complementary ODN strand (green and blue) or self-inhibit to form a cyclized Ru-ODN product (blue). Reproduced from ref 47. Copyright 2009 Wiley-VCH. H


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Inorganic Chemistry Chart 11. Ruthenium(II)-Based Intercalators Exhibiting Emission Turn-On for DNA

formation after irradiation with visible light.60 The ruthenium(II) octahedral geometry is distorted from the sterically bulky biq ligand and upon irradiation is expelled. Interestingly, an electrophillic ruthenium(II) complex has been designed for an inverse approach, photodeactivation. 61 Complex 68 is functionalized with a basic region leucine zipper (bZIP) peptide and acetamidobenzoyl (Aba), a chromophore included to quantify the peptide. Upon visible light irradiation, the DNA binding properties of the bZIP-conjugated complex are deactivated due to the release of one the peptides. Ruthenium(II)-based photocages provide versatile delivery and localization of bioactive molecules, in which the metal center offers the structural protection and low activation energy needed for targeted release.62 A ruthenium(II) bipyridine complex, 69 (Chart 13), has been utilized for the

capable of blocking K+ channels and increasing neuronal activity. Two dinuclear ruthenium(II) arene complexes 62 and 63 were designed for specific DNA binding.58 Upon irradiation with UV-A light, these complexes release arene, and subsequent fluorescence is detected from the free arene. Complex 62 exhibits guanine cross-linkage and after irradiation displays enhanced DNA binding. Howerton et al. demonstrated the capability of ruthenium(II) complexes for controllable cytotoxicity.59 Complexes 64 and 65 have been utilized for the steric clash between the ancillary ligands to induce ligand expulsion and covalent modification of DNA. The complexes are inert, and activation by visible light leads to an increase in the cytotoxicity by 2 orders of magnitude. Similarly, complexes 66 and 67 bind to DNA by covalent adduct I


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Inorganic Chemistry

Chart 13. Ruthenium(II)-Based Photocages for the Delivery of Bioactive Molecules

Figure 6. Confocal microscopy images of HeLa cells incubated with complex 48 (20 μM, 2 h) and various commercially available dyes: (a) DAPI staining; (b) cellular staining; (c) Mitotracker green FM staining; (d) an overlaid image. Reproduced from ref 51. Copyright 2012 American Chemical Society.

photocaging of a variety of amines, 2 equiv of the amine ligand are caged by the metal center, and following irradiation by visible light, one molecule of ligand is released.63 Further

improvement on the caging of amines demonstrated a monodentate caging of γ-aminobutyric acid (GABA) in

Chart 12. Photoactivatable Ruthenium(II) Polypyridine Complexes for Photorelease

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Inorganic Chemistry

Chart 14. Ruthenium(II) Polypyridine Complexes Exhibiting DNA Binding Properties Similar to Those of Cisplatin via Photosubstitution

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THERAPEUTIC LUMINESCENT COMPLEXES Photodynamic Therapeutic Drugs. PDT is one of the most extensively utilized techniques for the noninvasive treatment of cancer, involving a PS agent with greater accumulation in cancerous cells.73,74 The ideal PS should be nontoxic in the dark but upon excitation should be able to undergo electron/energy transfer processes, leading to the generation of ROS such as 1O2, peroxides (ROOR), and hydroxyl radicals (•OH). These ROS are highly cytotoxic and able to induce cancer cell death. The ruthenium(II) porphyrin compound 80 (Chart 15) has been designed as a PS agent; upon irradiation at 652 nm, the complex exhibits toxicity toward melanoma cells.75 Cloonan et al. functionalized a ruthenium(II) complex with a derivative of the dppz ligand to yield complex 81 to enhance the cellular uptake.76 Cellular studies indicated that the complex induces ROS apoptosis in HeLa cells under excitation. Recent work has demonstrated an organelle-specific-targeting PS in the form of a macromolecule.77 The synthetic scheme involves the conjugation of complex 82 and mitochondria-targeting groups to blood plasma protein serum albumin. The macromolecular PS is localized in the mitochondria and exhibits excellent photocytotoxicity toward the myeloid leukemic cell line OCI-AML3. Because of the high loading of ruthenium(II) complexes onto the nanotransporter, favorable properties could be enhanced such as an increase in the cellular uptake efficiency and greater 1 O2 generation. Liu et al. demonstrated complex 83 capable of one- or two-photon activation to address the low efficiency of activation and penetrative depth limitations in PDT.78 In 3D multicellular spheroids (MCs), the complex displays IC50 values of 9.6 μM in one-photon PDT and 1.9 μM in twophoton PDT. Hess et al. continued the investigation of ruthenium(II) polypyridine complexes as one- and two-photon PSs.79 The photocytotoxicity of complex 84 can be achieved by two-photon irradiation and under one-photon irradiation exhibits greater photocytotoxicity than complex 85. Subsequent cellular studies in HeLa cell monolayers after light treatment depict the relocalization of complex 84 toward the

complex 70, in which one of the ligands is replaced with a triphenylphosphine (PPh3) moiety.64 Upon irradiation by visible light, the GABA ligand is released, and the complex is confirmed to exhibit higher quantum yields than its predecessor. Respondek et al. have designed complex 71 for the caging of a protease inhibitor.65 The nitrile moiety of the ligand is caged by the ruthenium(II) center, and upon irradiation, the ligand is released. The release of the ligand leads to the inhibition of cysteine proteases papain and cathepsins B, K, and L. Recently, a new ruthenium(II) complex, 72, that can cage abiraterone has been synthesized and undergoes expulsion when irradiated with visible light.66 Because the abiraterone ligand is a potent inhibitor of cytochrome P450 enzymes (CYPs), the complex was demonstrated to inhibit the enzyme cytochrome CYP17A1 in DU145 cells with reduced off-target effects. After the widespread development of cisplatin and its derivatives as therapeutics for cancer, other metal-based therapeutics have been designed to combat the severe toxic side effects and cisplatin-resistant cells.67,68 Many ruthenium(II) polypyridine complexes exhibit photosubstitution to form the aqua species of ruthenium.69 The diaqua ruthenium(II) species exhibits a mechanism similar to that of cisplatin, capable of binding together DNA strands. Goldbach et al. have designed the thioether complexes 73 and 74 (Chart 14), which are stable in the dark but upon irradiation yield the aqua complex 75.70 The acetonitrile ligands of complex 76 undergo photosubstitution with water under low-energy irradiation.71 Gel electrophoresis studies indicated that photoactivation leads to the decreased mobility of linearized DNA. Barragán et al. demonstrated two ruthenium(II) complexes with a dual mechanism of selectivity.72 Complexes 77 and 78 are conjugated with a peptide, and under visible-light irradiation, the pyridine-derivatized peptides are selectively photodissociated. The complexes yield an aqua complex, 79, after dissociation of the peptide conjugate. Interestingly, the subsequent loss of the p-cymene ligand from the aqua species led to the formation of a ruthenium adduct bonded to two guanine nucleotides. K


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Inorganic Chemistry Chart 15. Ruthenium(II) PSs for PDT

nucleus, whereas complex 85 is retained in the cell membranes, as shown in Figure 7. Pierroz et al. demonstrated that a small modification to complex 86 leads to localization in the nucleus of various cancer cells via intercalation with DNA.80 Upon UVA-light irradiation, the complex promotes guanine oxidation, thus resulting in DNA fragmentation. Further experimentation demonstrated the ability of the complex to induce cell cycle

arrest and cell death in mitotic cells. Ramu et al. reported two new apoptotic ruthenium(II) complexes, 87 and 88, functionalized with tyrosine and tryptophan, respectively.81 In cellular studies, the PSs are able to induce apoptosis in A549 cells. A new strategy was reported on the ability of ruthenium(II) PSs capable of damaging two different sites of the cell.82 Complexes 89−93 incubated in HeLa cells for a short period L


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Inorganic Chemistry

transfer state to promote reaction with oxygen and biological substrates. From the promising photocytotoxic results in microorganisms,93 the complex was tested for their efficacy against colon and glioma cancer cells (CT26.WT, CT26.CL25, F98, and U87).94 In vitro studies in normoxic conditions induced complete cell death of these cancer cell models; however, under hypoxic conditions, the PDT effect was lost for U87 cells. In vivo PDT study on a rodent model indicated a maximum tolerated dose of 103 mg kg−1 (MTD50), where 50% of the animals survive the dose. Complex 99 at 1/2 MTD50 dose was injected into mice with subcutaneous cancer and subsequently irradiated, resulting in the destruction of tumors. The mechanism of this PS is still being elucidated, but a recent study indicated that the complex may localize in the endosomal or lysosomal organelles.95 Ruthenium(II) complexes can undergo receptor-mediated transport into cells by association with transferrin; hence, in a study, complex 99 was premixed with transferrin to allow for the formation of Rutherrin before administration into AY27 cells and subcutaneous CT26.CL25 tumor mice models.96 Rutherrin was found to improve cellular uptake and maintain the structural integrity to produce an increase in the defining PDT effect of complex 99. Interestingly, the binding of complex 99 to transferrin would also bestow photobleaching resistance, reduced toxicity, and increased extinction coefficient (400−850 nm).

Figure 7. Confocal microscopy images depicting the cellular localization of complex 84 (50 μM, 4 h) without light irradiation (A) and after irradiation (B). Confocal microscopy images depicting the cellular localization of complex 85 (50 μM, 4 h) without light irradiation (C) and after irradiation (D). Reproduced from ref 79. Copyright 2017 Wiley-VCH on behalf of ChemPubSoc Europe.

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OVERVIEW AND FUTURE OUTLOOK Ruthenium(II) polypyridine complexes have been extensively developed, yet there is still room for improvement and investigation. Targeted delivery with conjugated biomolecules has been shown to be specific to malignant cells with overexpressed receptors. Bioorthogonal ruthenium(II) probes have been shown to exhibit chemoselective ligation to complementary modified substrates for site-specific localization, without disruption of biological activities. In terms of the photophysical properties, one- and two-photon absorption techniques have been studied and produced promising results for ruthenium(II) probes capable of functioning in the therapeutic window. The development of two-photon ruthenium(II) agents able to absorb longer wavelengths of light will allow for treatment in deeper regions of tissue and exhibit less damage to healthy cells. The field of inorganic medicinal chemistry is growing, and the design of ruthenium(II) PSs capable of specific organelle targeting has been a great success. However, there have been some concerns over the optimization and side effects of the PSs. Mitochondria localization of the PSs could have implications of high dark cytotoxicity, and nucleus localization is unfavorable because of potential DNA mutation. A concerning issue with traditional PSs is the photosensitivity of patients after PDT treatment resulting from off-site accumulation in healthy cells. Possible solutions could exist, such as PSs bound to protein carriers as a means of delivery or novel ruthenium(II) bioorthogonal probes able to provide specific localization and exert a PDT effect. The introduction of complex 99 opens new and promising possibilities for the development of dual-versatile PSs. An area that was not discussed in detail is that most of the studies on ruthenium(II) polypyridine complexes exist as a mixture of optical isomers. Enantiomers have been shown in the past to display different binding, photophysical, and photochemical properties, which may influence their mode of action and organelle targeting.

(0.5 h) reside on the cytomembranes first; a longer incubation time (4 h) leads to accumulation in both the mitochondria and cytomembranes. Upon two-photon irradiation, the complexes show good 1O2 quantum yields, thus leading to the destruction of HeLa cells. Huang et al. have designed complexes that are specifically localized in the lysosomes of HeLa cells.83 The octacationic complexes 94−96 exhibit good 1O2 quantum yields and induce cell necrocytosis upon two-photon irradiation. Zhang et al. have also designed one- and twophoton excitable ruthenium(II)-containing carbon nanodots (CNDs) for lysosome targeting.84 Various molecules of complex 97 are attached to the CNDs, and the functionalized RuII-CNDs are able to penetrate into cancer cells via endocytosis. Upon irradiation under 450 nm (one-photon) or 810 nm (two-photon), the conjugated RuII-CNDs generate ROS to induce apoptotic cell death. Type II PDT relies on a high concentration of oxygen and is a severe limitation in hypoxic cancer cells because of the rapid consumption of oxygen.85 Lv et al. have designed a ruthenium(II) PS 98, which undergoes a type I photochemical process, through direct electron transfer between the excited PS and substrate to form • OH radicals to damage tumor cells.86 Further work demonstrated that the complex is effective in tumor-bearing mice and inhibits growth of the tumor. Ruthenium(II)-based therapeutics have entered clinical trials, such as the three well-known ruthenium anticancer agents: NAMI-A, KP1019, and KP1339.87−90 As of the writing of this Article, there is a luminescent ruthenium(II)-based PDT drug, TLD-1433 (99), that has completed a phase 1b clinical study for non-muscle invasive bladder cancer and is currently in preparation for phase II studies.91 Complex 99 was designed with the intention of creating a highly efficient and dual-versatile type I/type II PS.92 The π-expansive α-terthienyl moiety was specifically chosen for its triplet intraligand chargeM


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Inorganic Chemistry Future studies to determine the different characteristics that these enantiomers exhibit could be of importance. In conclusion, many ruthenium(II) polypyridine complexes have been successfully developed as diagnostic and therapeutic agents. However, we have merely scratched the surface on the possible applications of these highly promising probes.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Justin Shum: 0000-0001-5080-0792 Peter Kam-Keung Leung: 0000-0002-6050-5276 Kenneth Kam-Wing Lo: 0000-0002-2470-5916

Kenneth Kam-Wing Lo obtained his B.Sc. and Ph.D. degrees at The University of Hong Kong in 1993 and 1997, respectively. He then worked as a Croucher Foundation Postdoctoral Research Fellow at the Inorganic Chemistry Laboratory, University of Oxford. In 1999, he joined the Department of Biology and Chemistry (currently the Department of Chemistry), City University of Hong Kong, as an Assistant Professor and has been a Professor since 2011. He received an APA Prize for Young Scientist from the Asian and Oceanian Photochemistry Association in 2005, a Distinguished Lectureship Award from the Chemical Society of Japan in 2011, and a Croucher Senior Research Fellowship from the Croucher Foundation in 2015. He was one of the Chairs of the Gordon Research Conference Metals in Medicine 2018 and will be the Chair of the 23rd International Symposium on the Photochemistry and Photophysics of Coordination Compounds (ISPCC 2019) at City University of Hong Kong in 2019. He is currently an Associate Editor of RSC Advances. His research interest is the utilization of luminescent inorganic and organometallic transition-metal complexes as biomolecular probes, cellular imaging reagents, and photocytotoxic agents.

Notes

The authors declare no competing financial interest. Biographies

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ACKNOWLEDGMENTS We thank the Hong Kong Research Grants Council (Projects CityU 11300318, CityU 11300017, CityU 11302116, and T42103/16-N) and the Hong Kong Research Grants Council, National Natural Science Foundation of China (Project N_CityU113/15), for financial support. P.K.-K.L. acknowledges the receipt of a Postgraduate Studentship administered by the City University of Hong Kong. K.K.-W.L. is grateful to the Croucher Foundation for the award of a Croucher Senior Research Fellowship.

Justin Shum received his B.Sc. in biochemistry in 2018 from the University of Toronto. From 2017 to 2018, he worked as a research assistant for the evaluation of luminescent transition-metal complexes for biological applications. His current research interest is the development of transition-metal complexes as bioorthogonal probes.

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REFERENCES

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