Silicon phthalocyanines: synthesis and resurgent applications.

The intense far-red absorption and emission features have made silicon phthalocyanines (SiPcs) distinct from the structurally related porphyrin analogues. Unlike most other phthalocyanines, SiPcs possess two additional axial bonds which reduce aggregation in solution and can be synthetically tailored, thereby creating further scope for modulation of optical, chemical and electronic properties. Multiple synthetic strategies have been employed for facile construction of symmetrical or unsymmetrical SiPc variants bearing desired substitutents at the axial and the aromatic ring positions. The overarching motive of this concise review article is to highlight and summarize the key synthetic routes and the fast-emerging applications of SiPcs in photouncaging techniques, photothermal and photoimmunotherapy, photovoltaics, optoelectronics and photocatalysis.

A Platinum(II) Complex of Heptamethine Cyanine for Photoenhanced Cytotoxicity and Cellular Imaging in Near-IR Light.

Controlled generation of cytotoxic agents with near-IR light is a current focus of photoactivated cancer therapy, including that involving cytotoxic platinum species. A heptamethine cyanine scaffolded PtII complex, IR797-Platin exhibits unprecedented Pt-O bond scission and enhancement in DNA platination in near-IR light. This complex also displayed significant singlet oxygen quantum yield thereby qualifying as a near-IR photodynamic therapeutic agent. The complex showed 30-60 fold enhancement of cytotoxicity in near-IR light in various cancer cell lines. The cellular imaging properties were also leveraged to observe its significant co-localization in cytoplasmic organelles. This is the first demonstration of a near-IR light-initiated therapy involving the cytotoxic effects of both active cisplatin and singlet oxygen.

Monofunctional BODIPY-Appended Imidazoplatin for Cellular Imaging and Mitochondria-Targeted Photocytotoxicity.

Monofunctional platinum(II) complexes of formulation cis-[Pt(NH3)2(L)Cl](NO3), where L is an imidazole base conjugated to 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) with emissive (L1 in 1) and nonemissive (L2 in 2) moieties were prepared and characterized, and their singlet oxygen-mediated photoinduced cytotoxicity was studied. The 1-methylimidazole (1-MeIm) complex 3 was prepared as a control and for structural characterization by X-ray crystallography. Complexes 1 and 2 showed strong visible absorption bands at 500 nm (ε = 2.7 × 104 M-1 cm-1) and 540 nm (1.4 × 104 M-1 cm-1). Complex 1 is emissive with a band at 510 nm (ΦF = 0.09) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH 7.2). Singlet oxygen generation upon photoirradiation with visible light (400-700 nm) was evidenced from 1,3-diphenylisobenzofuran titration experiments showing significant photosensitizing ability of the BODIPY complexes. Both 1 and 2 were remarkably photocytotoxic in visible light (400-700 nm, 10 J cm-2) in skin keratinocyte HaCaT and breast cancer MCF-7 cells giving IC50 values in nanomolar concentration. The complexes were, however, essentially nontoxic to the cells in the dark (IC50 > 80 µM). Complex 2 having a diiodo-BODIPY unit is nonemissive but an efficient photosensitizer with high singlet oxygen generation ability in visible light (400-700 nm). Confocal microscopy using the emissive complex 1 showed significant mitochondrial localization of the complex. Cell death via apoptotic pathway was observed from the Annexin-V-FITC/PI assay. The formation of Pt-DNA adducts was evidenced from the binding experiments of the complexes 1 and 2 with 9-ethylguanine as a model nucleobase from 1H NMR and mass spectral studies.

Biotinylated Platinum(II) Ferrocenylterpyridine Complexes for Targeted Photoinduced Cytotoxicity.

Biotinylated platinum(II) ferrocenylterpyridine (Fc-tpy) complexes [Pt(Fc-tpy)(L(1))]Cl (1) and [Pt(Fc-tpy)(L(2))]Cl (2), where HL(1) and HL(2) are biotin-containing ligands, were prepared, and their targeted photoinduced cytotoxic effect in cancer cells over normal cells was studied. A nonbiotinylated complex, [Pt(Fc-tpy)(L(3))]Cl (3), was prepared as a control to study the role of the biotin moiety in cellular uptake properties of the complexes. Three platinum(II) phenylterpyridine (Ph-tpy) complexes, viz., [Pt(Ph-tpy)(L(1))]Cl (4), [Pt(Ph-tpy)(L(2))]Cl (5), and [Pt(Ph-tpy)(L(3))]Cl (6), were synthesized and explored to understand the role of a metal-bound Fc-tpy ligand over Ph-tpy as a photoinitiator. The Fc-tpy complexes displayed an intense absorption band near 640 nm, which was absent in their Ph-tpy analogues. The Fc-tpy complexes (1 mM in 0.1 M TBAP) showed an irreversible cyclic voltammetric anodic response of the Fc/Fc(+) couple near 0.25 V. The Fc-tpy complexes displayed photodegradation in red light of 647 nm involving the formation of a ferrocenium ion (Fc(+)) and reactive oxygen species (ROS). Photoinduced release of the biotinylated ligands was observed from spectral measurements, and this possibly led to the controlled generation of an active platinum(II) species, which binds to the calf-thymus DNA used for this study. The biotinylated photoactive Fc-tpy complexes showed significant photoinduced cytotoxicity, giving a IC50 value of ∼7 µM in visible light of 400-700 nm with selective uptake in BT474 cancer cells over HBL-100 normal cells. Furthermore, ferrocenyl complexes resulted in light-induced ROS-mediated apoptosis, as indicated by DCFDA, annexin V/FITC staining, and sub-G1 DNA content determined by fluorescent activated cell sorting analysis. The phenyl analogues 4 and 5 were photostable, served as DNA intercalators, and demonstrated selective cytotoxicity in the cancer cells, giving IC50 values of ∼4 µM.

2-(Phenylazo)pyridineplatinum(II) catecholates showing photocytotoxicity, nuclear uptake, and glutathione-triggered ligand release.

Platinum(II) complexes [Pt(pap)(an-cat)] (1) and [Pt(pap)(py-cat)] (2) with 2-(phenylazo)pyridine (pap), 4-[2-[(anthracen-9-ylmethylene)amino]ethyl]benzene-1,2-diol (H2an-cat), and 4-[2-[(pyren-1-ylmethylene)amino]ethyl]benzene-1,2-diol (H2py-cat) were prepared, and their photoinduced cytotoxicity was studied. The complexes were found to release catecholate ligand in the presence of excess glutathione (GSH), resulting in cellular toxicity in the cancer cells. The catecholate complex [Pt(pap)(cat)] (3) was prepared and used as a control. Complex 3, which is structurally characterized by X-ray crystallography, has platinum(II) in a distorted square-planar geometry. The complexes are redox-active, showing responses near 0.6 and 1.0 V versus SCE in N,N-dimethylformamide/0.1 M tetrabutylammonium perchlorate corresponding to a two-step catechol oxidation process and at -0.3 and -1.3 V for reduction of the pap ligand. Complex 1 showed remarkable light-induced cytotoxicity in HaCaT (human skin keratinocytes) and MCF-7 (human breast cancer) cells, giving IC50 value of ∼5 µM in visible light of 400-700 nm and >40 µM in the dark. The 2',7'-dichlorofluorescein diacetate (DCFDA) assay showed the generation of reactive oxygen species (ROS), which seems to trigger apoptosis, as is evident from the annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay. The fluorescence microscopic images showed significant nuclear localization of the complexes and free ligands. A mechanistic study revealed possible reduction of the coordinated azo bond of pap by cellular GSH, releasing the catecholate ligand and resulting in remarkable photochemotherapeutic action of the complexes.

The cis-Diammineplatinum(II) Complex of Curcumin: A Dual Action DNA Crosslinking and Photochemotherapeutic Agent.

[Pt(cur)(NH3)2](NO3) (1), a curcumin-bound cis-diammineplatinum(II) complex, nicknamed Platicur, as a novel photoactivated chemotherapeutic agent releases photoactive curcumin and an active platinum(II) species upon irradiation with visible light. The hydrolytic instability of free curcumin reduces upon binding to platinum(II). Interactions of 1 with 5'-GMP and ct-DNA indicated formation of platinum-bound DNA adducts upon exposure to visible light (λ=400-700 nm). It showed apoptotic photocytotoxicity in cancer cells (IC50 ≈ 15 µM), thus forming (⋅)OH, while remaining passive in the darkness (IC50 >200 µM). A comet assay and platinum estimation suggest Pt-DNA crosslink formation. The fluorescence microscopic images showed cytosolic localization of curcumin, thus implying possibility of dual action as a chemo- and phototherapeutic agent.

SLC12A9 is a lysosome-detoxifying ammonium - chloride co-transporter.

Ammonia is a ubiquitous, toxic by-product of cell metabolism. Its high membrane permeability and proton affinity causes ammonia to accumulate inside acidic lysosomes in its poorly membrane-permeant form: ammonium (NH 4 + ). Ammonium buildup compromises lysosomal function, suggesting the existence of mechanisms that protect cells from ammonium toxicity. Here, we identified SLC12A9 as a lysosomal ammonium exporter that preserves lysosomal homeostasis. SLC12A9 knockout cells showed grossly enlarged lysosomes and elevated ammonium content. These phenotypes were reversed upon removal of the metabolic source of ammonium or dissipation of the lysosomal pH gradient. Lysosomal chloride increased in SLC12A9 knockout cells and chloride binding by SLC12A9 was required for ammonium transport. Our data indicate that SLC12A9 is a chloride-driven ammonium co-transporter that is central in an unappreciated, fundamental mechanism of lysosomal physiology that may have special relevance in tissues with elevated ammonia, such as tumors.

Development of a Cyclic, Cell Penetrating Peptide Compatible with In Vitro Selection Strategies.

A key limitation for the development of peptides as therapeutics is their lack of cell permeability. Recent work has shown that short, arginine-rich macrocyclic peptides containing hydrophobic amino acids are able to penetrate cells and reach the cytosol. Here, we have developed a new strategy for developing cyclic cell penetrating peptides (CPPs) that shifts some of the hydrophobic character to the peptide cyclization linker, allowing us to do a linker screen to find cyclic CPPs with improved cellular uptake. We demonstrate that both hydrophobicity and position of the alkylation points on the linker affect uptake of macrocyclic cell penetrating peptides (CPPs). Our best peptide, 4i, is on par with or better than prototypical CPPs Arg9 (R9) and CPP12 under assays measuring total cellular uptake and cytosolic delivery. 4i was also able to carry a peptide previously discovered from an in vitro selection, 8.6, and a cytotoxic peptide into the cytosol. A bicyclic variant of 4i showed even better cytosolic entry than 4i, highlighting the plasticity of this class of peptides toward modifications. Since our CPPs are cyclized via their side chains (as opposed to head-to-tail cyclization), they are compatible with powerful technologies for peptide ligand discovery including phage display and mRNA display. Access to diverse libraries with inherent cell permeability will afford the ability to find cell permeable hits to many challenging intracellular targets.

A DNA nanodevice for mapping sodium at single-organelle resolution.

Cellular sodium ion (Na+) homeostasis is integral to organism physiology. Our current understanding of Na+ homeostasis is largely limited to Na+ transport at the plasma membrane. Organelles may also contribute to Na+ homeostasis; however, the direction of Na+ flow across organelle membranes is unknown because organellar Na+ cannot be imaged. Here we report a pH-independent, organelle-targetable, ratiometric probe that reports lumenal Na+. It is a DNA nanodevice containing a Na+-sensitive fluorophore, a reference dye and an organelle-targeting domain. By measuring Na+ at single endosome resolution in mammalian cells and Caenorhabditis elegans, we discovered that lumenal Na+ levels in each stage of the endolysosomal pathway exceed cytosolic levels and decrease as endosomes mature. Further, we find that lysosomal Na+ levels in nematodes are modulated by the Na+/H+ exchanger NHX-5 in response to salt stress. The ability to image subcellular Na+ will unveil mechanisms of Na+ homeostasis at an increased level of cellular detail.

An activity-based fluorescent sensor for the detection of the phenol sulfotransferase SULT1A1 in living cells.

Human phenol sulfotransferases mediate the transfer of a sulfuryl moiety from the activated sulfate donor PAPS to hydroxy-containing substrates, altering substrate solubility and charge to affect phase II metabolism and cell signaling. Here, we present the development, computational modeling, in vitro enzymology, and biological application of STS-3, an activity-based fluorescent sensor for the SULT1A1 isoform.

Photocontrolled activation of small molecule cancer therapeutics.

Cancer remains one of the leading causes of death worldwide. Conventional treatment of the disease is comprised of chemotherapy, radiation and surgery among other treatment approaches. Chemotherapy is plagued by multiple side-effects caused due to non-specific drug action. Light-based therapies offer an alternative treatment approach that can be fine tuned to achieve the desired effect to treat the disease and address challenges posed by chemotherapeutic side-effects. Photodynamic therapy (PDT) is one of the light mediated treatment modalities that has been successfully applied to treat superficial malignancies with high-efficiency, although its dependence on normoxic conditions limits its efficiency to treat deep-seated tumors. On the other hand, light-sensitive drug-mimetics and drug-release platforms have been deemed efficient in preclinical settings to induce cancer cell death with minimal collateral damage. Drawing from about a decade's worth of examples, we highlight the application of photosensitive molecules as an alternative therapeutic option to PDT and describe their designs that influence the biology of the cancer cells, in turn affecting their viability with high spatio-temporal control.

Photo-controlled delivery of a potent analogue of doxorubicin.

Highly cytotoxic agents have found an important niche in targeted anticancer therapy. Here we develop a new light release strategy for the targeting of one of these agents, 2-pyrrolinodoxorubicin, showing dramatic enhancements in toxicity with light and single digit nM potency.

Targeted photodynamic therapy in visible light using BODIPY-appended copper(ii) complexes of a vitamin B6 Schiff base.

Copper(ii) complexes [Cu(L1/L2/L3)(A)] (1-3), where H2A·HCl is a vitamin B6 Schiff base, viz. 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-1-ium chloride, L1 and L2 are 2-(2-pyridyl)benzimidazole based borondipyrromethene (BODIPY) ligands and L3 is 2-(2-pyridyl)benzimidazole, were prepared, characterized and their visible light-induced anti-cancer activity was studied. Complex 3, characterized by X-ray crystallography, exhibits a distorted square-pyramidal geometry for copper (τ = 0.33). Complexes 1 and 2 showed absorption bands at 500 and 535 nm, respectively, in 20% DMSO/Dulbecco's phosphate buffered saline (DPBS) medium. Complex 1 exhibited emission at ∼510 nm (λexc = 480 nm) (ΦF = 0.1) in 20% DMSO/DPBS, while the non-emissive diiodo-BODIPY complex 2 is an efficient photosensitizer. The green fluorescent complex 1 enabled us to study its cellular uptake and localization. It showed selective uptake in proliferating cancer cells and significant mitochondrial localization (Pearson's coefficient = 0.7). Complex 2 showed excellent photocytotoxicity (400-700 nm, 10 J cm-2) in HeLa, MCF-7 and HepG2 cancer cells with IC50 values within 0.4-0.6 µM, while remaining less toxic in the dark and in non-cancerous HPL1D cells (photocytotoxic index ∼50). Complex 2, remarkable in targeting cancer cells over non-cancerous cells, showed photoinduced generation of singlet oxygen, causing apoptotic cell death, thus satisfying the major requirements of targeted photodynamic therapy.

Hyaluronic Acid Grafted Nanoparticles of a Platinum(II)-Silicon(IV) Phthalocyanine Conjugate for Tumor and Mitochondria-Targeted Photodynamic Therapy in Red Light.

Herein, we report novel hyaluronic acid formulated nanoparticles containing a platinum(II) conjugated silicon(IV) phthalocyanine (SiPc-Pt-HA) for tumor targeted red light photodynamic therapy and chemotherapy. The SiPc-Pt-HA conjugate showed specific uptake, photo-enhanced cytotoxicity (~1500 fold) and mitochondrial accumulation in breast cancer over normal cells.

Correction: Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation.

Correction for 'Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation' by Koushambi Mitra, et al., Dalton Trans., 2016, 45, 19157-19171.

Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation.

Site-specific delivery and amenable activation of prodrugs are indispensible criteria for designing novel anticancer agents. Platinum based drugs vanguard the chemotherapeutic regimes and over the years significant attention has been paid to achieve more efficacious drugs with fewer adverse effects. The switch from platinum(ii) drugs to the inert platinum(iv) analogues proved advantageous but the new prodrugs still suffered from unspecific cytotoxic actions. Thus the photoactivation of an inert platinum prodrug specifically within neoplastic cells provided the desired spatio-temporal control over drug activation by means of illumination, thereby limiting the cytotoxic events to only at the targeted tumors. This article collates research on platinum complexes which exhibit potential light mediated anticancer effects and provides insights into the underlying mechanisms of activation. Fine tuning of the coordination sphere results in dramatic alteration of the redox and spectral properties of both ground and excited states and the cellular properties of the molecules. This concise article highlights the various light promoted strategies employed to attain a controlled release of active platinum(ii) and/or reactive oxygen species such as photoreduction, photocaging, photodissociation and photosensitization. Such dual action photoactive metal complexes with improved aqueous solubility and versatility are promising candidates for combination therapy which is likely to be the future of anticancer research.

BODIPY-Appended 2-(2-Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria-Targeted Photocytotoxicity.

Platinum(II) complexes of the type [Pt(L)(cat)] (1 and 2), in which H2 cat is catechol and L represents two 2-(2-pyridyl)benzimidazole ligands with 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) pendants, were synthesized to achieve mitochondria-targeted photocytotoxicity. The complexes showed strong absorptions in the range λ=510-540 nm. Complex 1 exhibited intense emission at λ=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di-iodinated complex 2. The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3-diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC50 ≈3 µm, λ=400-700 nm, light dose=10 J cm(-2) ), but they remained non-toxic in the dark (IC50 >100 µm). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis.

Photoactive platinum(ii) ß-diketonates as dual action anticancer agents.

Platinum(ii) complexes, viz. [Pt(L)(cur)] (1), [Pt(L)(py-acac)] (2) and [Pt(L)(an-acac)] (3), where HL is 4,4'-bis-dimethoxyazobenzene, Hcur is curcumin, Hpy-acac and Han-acac are pyrenyl and anthracenyl appended acetylacetone, were prepared, characterized and their anticancer activities were studied. Complex [Pt(L)(acac)] (4) was used as a control. Complex 1 showed an absorption band at 430 nm (ε = 8.8 × 10(4) M(-1) cm(-1)). The anthracenyl and pyrenyl complexes displayed bands near 390 nm (ε = 3.7 × 10(4) for 3 and 4.4 × 10(4) M(-1) cm(-1) for 2). Complex 1 showed an emission band at 525 nm (Φ = 0.017) in 10% DMSO-DPBS (pH, 7.2), while 2 and 3 were blue emissive (λem = 440 and 435, Φ = 0.058 and 0.045). There was an enhancement in emission intensity on glutathione (GSH) addition indicating diketonate release. The platinum(ii) species thus formed acted as a transcription inhibitor. The released ß-diketonate base showed photo-chemotherapeutic activity. The complexes photocleaved plasmid DNA under blue light of 457 nm forming ∼75% nicked circular (NC) DNA with hydroxyl radicals and singlet oxygen as the ROS. Complexes 1-3 were photocytotoxic in skin keratinocyte HaCaT cells giving IC50 of 8-14 µM under visible light (400-700 nm, 10 J cm(-2)), while being non-toxic in the dark (IC50: ∼60 µM). Complex 4 was inactive. Complexes 1-3 generating cellular ROS caused apoptotic cell death under visible light as evidenced from DCFDA and annexin-V/FITC-PI assays. This work presents a novel way to deliver an active platinum(ii) species and a phototoxic ß-diketone species to the cancer cells.