ABSTRACT
Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ â¼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 µM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.
Subject(s)
Antineoplastic Agents , Photochemotherapy , Porphobilinogen/analogs & derivatives , Prodrugs , Humans , Boron/pharmacology , Red Light , Coloring Agents , Prodrugs/pharmacology , Cobalt/pharmacology , Photosensitizing Agents/radiation effects , Antineoplastic Agents/radiation effects , Boron Compounds/pharmacology , Boron Compounds/radiation effects , Singlet Oxygen/metabolism , LightABSTRACT
Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Biodegradable Plastics/pharmacology , Fluorescent Dyes/pharmacology , Photosensitizing Agents/pharmacology , Polyesters/pharmacology , Polyethylene Glycols/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/radiation effects , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/pharmacology , Benzylidene Compounds/radiation effects , Biodegradable Plastics/chemical synthesis , Biodegradable Plastics/radiation effects , Boron Compounds/chemical synthesis , Boron Compounds/pharmacology , Boron Compounds/radiation effects , Cell Line, Tumor , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Humans , Light , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/radiation effects , Polyesters/chemical synthesis , Polyesters/radiation effects , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/radiation effects , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/pharmacology , Pyridinium Compounds/radiation effectsABSTRACT
Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable photoprotecting groups has the potential to further expand the established utility of the photoactivation strategy in biological applications by offering higher tissue penetration, diminished phototoxicity, and compatibility with other light-dependent techniques. Nevertheless, a critical barrier to such applications remains the significant hydrophobicity of most visible-light excitable photocaging groups. Here, we find that applying the conventional 2,6-sulfonation to meso-methyl BODIPY photocages is incompatible with their photoreaction due to an increase in the excited state barrier for photorelease. We present a simple, remote sulfonation solution to BODIPY photocages that imparts water solubility and provides control over cellular permeability while retaining their favorable spectroscopic and photoreaction properties. Peripherally disulfonated BODIPY photocages are cell impermeable, making them useful for modulation of cell-surface receptors, while monosulfonated BODIPY retains the ability to cross the cellular membrane and can modulate intracellular targets. This new approach is generalizable for controlling BODIPY localization and was validated by sensitization of mammalian cells and neurons by visible-light photoactivation of signaling molecules.
Subject(s)
Alkanesulfonates/metabolism , Boron Compounds/metabolism , Fluorescent Dyes/metabolism , Alkanesulfonates/chemical synthesis , Alkanesulfonates/radiation effects , Animals , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Cell Membrane/metabolism , Dopamine/chemistry , Dopamine/pharmacology , Drug Carriers/chemical synthesis , Drug Carriers/metabolism , Drug Carriers/radiation effects , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , HEK293 Cells , Hippocampus/drug effects , Histamine/chemistry , Histamine/pharmacology , Humans , Light , Microscopy, Confocal , Microscopy, Fluorescence , Molecular Structure , Neurons/drug effects , Rats , SolubilityABSTRACT
A synthetic strategy to BODIPY dyes is presented giving access to a range of new compounds relevant in the context of antimicrobial photodynamic therapy (aPDT). BODIPYs with the 8-(4-fluoro-3-nitrophenyl) and the 8-pentafluorophenyl substituents were used for the synthesis of new mono- and dibrominated BODIPYs. The para-fluorine atoms in these electron-withdrawing groups facilitate functional modification via nucleophilic aromatic substitution (SNAr) with a number of amines and thio-carbohydrates. Subsequently, the antibacterial phototoxic activity of these BODIPYs has been assessed in bacterial assays against the Gram-positive germ S. aureus and also against the Gram-negative germ P. aeruginosa. The bacterial assays allowed to identify substitution patterns which ensured antibacterial activity not only in phosphate-buffered saline (PBS) but also in the presence of serum, hereby more realistically modelling the complex biological environment that is present in clinical applications.
Subject(s)
Anti-Bacterial Agents/pharmacology , Boron Compounds/pharmacology , Photosensitizing Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/radiation effects , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Light , Microbial Sensitivity Tests , Molecular Structure , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/radiation effects , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effectsABSTRACT
Photoacoustic (PA) dyes, which absorb near-infrared (NIR) light to generate an ultrasonic signal, can be detected at centimeter depths in tissues with significantly higher resolution than dyes imaged with fluorescence-based methods. As such, PA agents show great promise as research tools for the study of live-animal disease models. However, the development of activatable PA probes has been hampered by the relative scarcity of appropriate PA-active molecular platforms with properties that can be manipulated in a rational manner. Herein we synthesized and evaluated six modifications to the aza-BODIPY dye platform with respect to their absorbance, fluorescence, and PA properties. We identified a promising conformationally restricted aza-BODIPY (CRaB) scaffold that prioritizes three criteria necessary for the design of stimulus-responsive dyes with optimal ratiometric PA response: absorbance at NIR wavelengths, strong PA intensity, and large Δλ upon interaction with the desired stimulus. Using this scaffold, we synthesized three chemically diverse stimulus-responsive PA probes and demonstrated between 2- and 8-fold improvements in theoretical ratiometric response in vitro. This suggests that improvements in PA parameters are generalizable. Finally, we validated the in vitro turnover of each CRaB PA probe and demonstrated the in vivo potential of the CRaB scaffold by direct comparison to an established hypoxia-responsive probe for the detection of tumor hypoxia.
Subject(s)
Boron Compounds/chemistry , Fluorescent Dyes/chemistry , Animals , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Cell Line, Tumor , Female , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Infrared Rays , Male , Mice, Inbred BALB C , Molecular Conformation , Neoplasms/diagnostic imaging , Photoacoustic Techniques/methodsABSTRACT
We report the enantioselective [2+2] cycloaddition of simple cinnamate esters, the products of which are useful synthons for the controlled assembly of cyclobutane natural products. This method utilizes a cocatalytic system in which a chiral Lewis acid accelerates the transfer of triplet energy from an excited-state Ir(III) photocatalyst to the cinnamate ester. Computational evidence indicates that the principal role of the Lewis acid cocatalyst is to lower the absolute energies of the substrate frontier molecular orbitals, leading to greater electronic coupling between the sensitizer and substrate and increasing the rate of the energy transfer event. These results suggest Lewis acids can have multiple beneficial effects on triplet sensitization reactions, impacting both the thermodynamic driving force and kinetics of Dexter energy transfer.
Subject(s)
Cinnamates/chemistry , Lewis Acids/chemistry , Boron Compounds/chemistry , Boron Compounds/radiation effects , Catalysis , Coordination Complexes/chemistry , Coordination Complexes/radiation effects , Cycloaddition Reaction , Cyclobutanes/chemical synthesis , Density Functional Theory , Energy Transfer , Iridium/chemistry , Iridium/radiation effects , Lewis Acids/radiation effects , Light , Models, Chemical , StereoisomerismABSTRACT
A new N,O-based BODIPY ligand was synthesized and further utilized to develop highly fluorescent and photostable Ru(II), Rh(III), and Ir(III) metal complexes. The complexes were fully characterized by different analytical techniques including single-crystal XRD studies. The photostabilities and live cell imaging capabilities of the complexes were investigated via confocal microscopy. The complexes localized specifically in the mitochondria of live cells and showed negligible cytotoxicities at a concentration used for imaging purposes. They also exhibited high photostabilities, with fluorescence intensities remaining above 50% after 1800 scans.
Subject(s)
Boron Compounds/metabolism , Coordination Complexes/metabolism , Fluorescent Dyes/metabolism , Mitochondria/metabolism , Biological Transport , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Boron Compounds/toxicity , Coordination Complexes/chemical synthesis , Coordination Complexes/radiation effects , Coordination Complexes/toxicity , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Fluorescent Dyes/toxicity , HeLa Cells , Humans , Iridium/chemistry , Ligands , Microscopy, Confocal , Photobleaching , Rhodium/chemistry , Ruthenium/chemistryABSTRACT
A novel photosensitizer BDPI-lyso has been developed for photodynamic therapy (PDT). The photosensitizer BDPI-lyso showed a high singlet oxygen quantum yield (ΦΔ = 0.95) and low fluorescence quantum yield (ΦF = 0.05) in EtOH. Different singlet oxygen quantum yields were found in acidic solution (pH = 5, ΦΔ = 0.51) and in neutral solution (pH = 7, ΦΔ = 0.38). DFT and TD-DFT calculations of BDPI-lyso and its protonated product BDPI-lysoH+ indicated that the S1/T3 transition was responsible for the intersystem crossing (ISC) enhancement which would promote the production of singlet oxygen. The negligible dark cytotoxicity toward the hepatoma cell line Bel-7402 was confirmed by MTT assay, AO/EB dual staining, and cell images. Upon exposure to a low dose of light illumination, the disruption of the cell plasma membrane and the calculated half-maximal inhibitory concentration (IC50) of 0.4 µM showed a high phototoxicity of the photosensitizer BDPI-lyso. The light-induced intracellular ROS generation was verified as the PDT mechanism of BDPI-lyso. Colocalization experiments of LysoTracker Green and BDPI-lyso in the dark indicated the good lysosome-targeting ability of BDPI-lyso. The images of cells costained with LysoTracker Green and BDPI-lyso, and the appearance of intracellular and extracellular blebs with green fluorescence after light illumination revealed the light-induced dysfunction of lysosomes and cell apoptosis.
Subject(s)
Boron Compounds/pharmacology , Lysosomes/drug effects , Photosensitizing Agents/pharmacology , Singlet Oxygen/chemistry , Apoptosis/drug effects , Boron Compounds/radiation effects , Cell Line, Tumor , Density Functional Theory , Humans , Hydrogen-Ion Concentration , Light , Models, Chemical , Photochemotherapy/methods , Photosensitizing Agents/radiation effects , Reactive Oxygen Species/metabolismABSTRACT
Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on "conventional" drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate 1O2 and NO with single photon excitation of biocompatible visible light, (ii) excellent 1O2 quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region. Furthermore, this compound together with its stable photoproduct, is well tolerated by both normal and cancer cells in the dark and exhibits bimodal photomortality of cancer cells under green light excitation due to the combined action of the cytotoxic 1O2 and NO.
Subject(s)
Boron Compounds/pharmacology , Nitric Oxide Donors/pharmacology , Nitrosamines/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/radiation effects , Antineoplastic Agents/toxicity , Boron Compounds/radiation effects , Boron Compounds/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Humans , Light , Nitric Oxide/metabolism , Nitric Oxide Donors/radiation effects , Nitric Oxide Donors/toxicity , Nitrosamines/radiation effects , Nitrosamines/toxicity , Photosensitizing Agents/radiation effects , Photosensitizing Agents/toxicity , Singlet Oxygen/metabolismABSTRACT
Light-emitting supramolecular coordination complexes (SCCs) have been widely studied for applications in the chemical and biological sciences. Herein, we report the coordination-driven self-assembly of two highly emissive platinum(II) supramolecular triangles (1 and 2) containing BODIPY-based bridging ligands. The metallacycles exhibit favorable anticancer activities against HeLa cells (IC50 of 6.41 and 2.11 µM). The characteristic â¼570 nm fluorescence of the boron dipyrromethene (BODIPY) moieties in the metallacycles permits their intracellular visualization using confocal microscopy. Additionally, the BODIPY fluorophore is an excellent photodynamic agent, making the metallacycles as ideal therapeutics for photodynamic therapy (PDT) and chemotherapy. In vitro studies demonstrate that the combination indexes against HeLa cells are 0.56 and 0.48 for 1 and 2, respectively, confirming their synergistic anticancer effect. More importantly, these SCCs also exhibit superior anticancer efficacy toward cisplatin-resistant A2780cis cell line by combining PDT and chemotherapy, showing promise in overcoming drug resistance. This study exploits a multicomponent approach to self-assembled metallacages that enables design of effective theranostic agents wherein the platinum acceptors are toxic chemotherapeutics and the BODIPY donors are imaging probes and photosensitizers. Since each piece may be independently tuned, i.e., Pt(II) polypyridyl fragment swapped for Pt(II) phosphine, the activity may be optimized without a total redesign of the system.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Coordination Complexes/pharmacology , Fluorescent Dyes/pharmacology , Organoplatinum Compounds/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Apoptosis/drug effects , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/radiation effects , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/radiation effects , Humans , Light , Microscopy, Confocal , Nanoparticles/chemistry , Necrosis/chemically induced , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/radiation effects , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Theranostic NanomedicineABSTRACT
Piperazine appended naphthalimide-BODIPYs (NPB1-NPB4) exhibiting solvatochromism and aggregation-induced emission with a large Stokes shift (up to 146 nm) have been described. Separation of naphthalimide and BODIPY fluorophores by piperazine in these conjugates creates a donor-acceptor system and induces twisted intramolecular charge transfer, in addition to photoinduced electron transfer. The crucial role of naphthalimide, the alkyl chain length, the piperazine ring, and the solid-state packing on AIE has been extensively investigated by various studies. Superior cell permeability coupled with bio-compatibility of these conjugates offers a unique opportunity for their potential applications in live cell lysosomal tracking.
Subject(s)
Boron Compounds/chemistry , Fluorescent Dyes/chemistry , Lysosomes/metabolism , Naphthalimides/chemistry , Piperazines/chemistry , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Boron Compounds/toxicity , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Fluorescent Dyes/toxicity , HeLa Cells , Humans , Hydrogen-Ion Concentration , Light , Molecular Structure , Naphthalimides/chemical synthesis , Naphthalimides/radiation effects , Naphthalimides/toxicity , Piperazines/chemical synthesis , Piperazines/radiation effects , Piperazines/toxicity , Spectrometry, FluorescenceABSTRACT
A fluorescence probe, Cz-BDP-NBD, for detecting biothiols with two photon excited fluorescence has been designed and used under irradiation from sapphire pulsed lasers at 800 nm. Upon addition of biothiols, NBD was removed through a SNAr reaction and the fluorophore Carbazyl BODIPY (Cz-BDP) was released simultaneously. A two photon excited fluorescence was turned on and accompanied by a strong red emission at 660 nm, the two-photon absorption (TPA) cross section of the Cz-BDP reached a value of 198.5 GM at 800 nm. Moreover, Hcy/Cys and GSH could be distinguished between by a two emission channel, which resulted from the different mechanisms. For Hcy and Cys, N-NBD-Hcy and N-NBD-Cys were formed through a 5/6-membered cyclic transition, they displayed distinct fluorescent turn-on signal changes at 540 nm (Φ = 0.28, Φ = 0.24) and 670 nm, while GSH only has a single emission channel at 670 nm. Therefore, the Cz-BDP-NBD can distinguish GSH, Hcy and Cys with a fast response time (within one minute), high selectivity and sensitivity. In addition, it has been successfully applied for the detection of Cys/Hcy and GSH in living cells and ratio imaging. The Cz-BDP-NBD probe could be used for discriminative sensing of intracellular Cys, Hcy and GSH, and has the potential for use in biological applications.
Subject(s)
Cysteine/analysis , Fluorescent Dyes/chemistry , Glutathione/analysis , Homocysteine/analysis , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Boron Compounds/toxicity , Carbazoles/chemical synthesis , Carbazoles/chemistry , Carbazoles/radiation effects , Carbazoles/toxicity , Cysteine/metabolism , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/radiation effects , Fluorescent Dyes/toxicity , Glutathione/metabolism , Homocysteine/metabolism , Humans , Limit of Detection , MCF-7 Cells , Microscopy, Confocal/methods , Microscopy, Fluorescence/methods , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/radiation effects , Oxadiazoles/toxicity , PhotonsABSTRACT
Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500â¯nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light.
Subject(s)
Benzylamines/pharmacology , Boron Compounds/pharmacology , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Fatty Acids/pharmacology , Benzylamines/chemical synthesis , Benzylamines/chemistry , Benzylamines/radiation effects , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Calcium/metabolism , Capsaicin/chemical synthesis , Capsaicin/radiation effects , Fatty Acids/chemical synthesis , Fatty Acids/chemistry , Fatty Acids/radiation effects , HEK293 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Light , Solvents/chemistry , TRPV Cation Channels/agonistsABSTRACT
A novel, photochromic N^C-chelate organoboron functionalized dipicolinic acid (H2L) has been designed and synthesized. Lanthanide(III) complexes based on this ligand (L) with the general formula [NBu4]3[LnL3] (Ln = Eu or Tb) were prepared. The new ligand was found to be effective in both sensitizing and photomodulating the emission of a Eu(III) ion. The photoisomerization conversion of the boryl chromophore attached to the ligand of the lanthanide complex was determined to be quantitative by NMR analysis of the La(III) analogue.
Subject(s)
Boron Compounds/chemistry , Coordination Complexes/chemistry , Lanthanoid Series Elements/chemistry , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Coordination Complexes/chemical synthesis , Coordination Complexes/radiation effects , Isomerism , Ligands , Luminescence , Models, Chemical , Quantum Theory , Ultraviolet RaysABSTRACT
We report herein a new ZIF-90-based PDT agent which was synthesized by in situ assembly of imidazole-2-carboxaldehyde (IcaH), Zn(NO3)2, and heavy atom iodine-attached Bodipy. The obtained 2I-BodipyPhNO2@ZIF-90 (1) host-guest photosensitive system featured low cytotoxicity, good biocompatibility, pH-driven selective cancer cell uptake and release, mitochondria targeting, and highly efficient pH-triggered 1O2 generation. Therefore, it can be used as a high-performing PDT agent to selectively kill tumor cells. In comparison to free 2I-BodipyPhNO2, 1 exhibits a much higher antitumor efficacy and selectivity, which was confirmed by in vitro cell experiments.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Metal-Organic Frameworks/pharmacology , Nanoparticles/chemistry , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/radiation effects , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Boron Compounds/toxicity , Cell Line, Tumor , Drug Stability , Humans , Hydrogen-Ion Concentration , Metal-Organic Frameworks/chemical synthesis , Metal-Organic Frameworks/radiation effects , Metal-Organic Frameworks/toxicity , Mitochondria/metabolism , Nanoparticles/radiation effects , Nanoparticles/toxicity , Photochemotherapy/methods , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/radiation effects , Photosensitizing Agents/toxicity , Singlet Oxygen/metabolismABSTRACT
Monofunctional pyriplatin analogues cis-[Pt(NH3)2(L)Cl](NO3) (1-3) having boron-dipyrromethene (BODIPY) pendants (L) with 1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4'-difluoroboradiazaindacene moieties were designed and synthesized, and their photocytotoxic properties were studied. The Pt-BODIPY conjugates displayed an absorption band within 505-550 nm and a green emissive band near 535 nm in 1% DMSO/DMEM (Dulbecco's modified Eagle's medium) buffer. Complex cis-[Pt(NH3)2(4-Me-py)Cl](NO3) (4) was used as a control for determining the structural aspects by X-ray crystallography. The mono- and diiodinated BODIPY complexes 2 and 3 showed generation of singlet oxygen on light activation as evidenced from the 1,3-diphenylisobenzofuran (DPBF) titration experiments. The cytotoxicity of the BODIPY complexes was tested against A549 (human lung cancer), MCF-7 (human breast cancer), and HaCaT (human skin keratinocyte) cells in dark and visible light (400-700 nm, 10 J cm-2). While complexes 2 and 3 showed excellent photocytotoxicity (IC50 ≈ 0.05 µM), they remained essentially nontoxic in the dark (IC50 > 100 µM). The emissive bands of 1 and 2 were used for cellular imaging by confocal microscopy study, which showed their mitochondrial localization. This was further supported by platinum estimation from isolated mitochondria and mitochondrial depolarization through a JC-1 assay. The photomediated apoptotic cell death was evidenced from flow cytometric assays, annexin-V/FITC-PI (fluorescein isothiocyanate-propidium iodide) and cell cycle arrest in sub-G1 and G2/M phases. The complexes bind to 9-ethylguanine as a model nucleobase to form monoadducts. A mechanistic study on DNA photocleavage activity using pUC19 DNA showed singlet oxygen as the reactive oxygen species (ROS). The combination of photodynamic therapy with DNA cross-linking property enhanced the anticancer potential of the monofunctional BODIPY-conjugates of pyriplatins.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Mitochondria/metabolism , Organoplatinum Compounds/pharmacology , Photosensitizing Agents/pharmacology , Porphobilinogen/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Apoptosis/drug effects , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Cattle , Cell Line, Tumor , DNA/chemistry , G1 Phase Cell Cycle Checkpoints/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Light , Membrane Potential, Mitochondrial/drug effects , Microscopy, Confocal , Microscopy, Fluorescence , Mitochondria/drug effects , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/radiation effects , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Porphobilinogen/chemical synthesis , Porphobilinogen/chemistry , Porphobilinogen/pharmacology , Porphobilinogen/radiation effects , Singlet Oxygen/metabolismABSTRACT
Sensitizing the antitumor activity of monofunctional PtII complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional PtII complexes, in this study, the photosensitizing monofunctional PtII complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the PtII center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional PtII complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional PtII complex and renders the possibility of monofunctional PtII prodrugs for precise chemotherapy via only short time photoactivation.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Organoplatinum Compounds/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Cell Line, Tumor , Cell Membrane/drug effects , Fluorescence , Humans , Light , Microscopy, Confocal , Microscopy, Fluorescence , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/radiation effects , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Reactive Oxygen SpeciesABSTRACT
Ternary oxidovanadium(IV) complexes of curcumin (Hcur), dipicolylamine (dpa) base, and its derivatives having pendant noniodinated and di-iodinated boron-dipyrromethene (BODIPY) moiety (L1 and L2, respectively), namely, [VO(dpa)(cur)]ClO4 (1), [VO(L1)(cur)]ClO4 (2), and [VO(L2)(cur)]ClO4 (3) and their chloride salts (1a-3a) were prepared, characterized, and studied for anticancer activity. The chloride salts were used for biological studies due to their aqueous solubility. Complex 1 was structurally characterized by single-crystal X-ray crystallography. The complex has a VO2+ moiety bound to dpa ligand showing N,N,N-coordination in a facial mode, and curcumin is bound in its mono-anionic enolic form. The V-O(cur) distances are 1.950(18) and 1.977(16) Å, while the V-N bond lengths are 2.090(2), 2.130(2), and 2.290(2) Å. The bond trans to VâO is long due to trans effect. The complexes are stable in a solution phase over a long period of time of 48 h without showing any apparent degradation of the curcumin ligand. The diiodo-BODIPY ligand (L2) or Hcur alone showed limited solution stability in dark. The emissive BODIPY (L1) containing complex 2a showed preferential mitochondrial localization in MCF-7 cells in cellular imaging experiments. The cytotoxicity of the complexes was studied by MTT assay. The BODIPY complex 3a showed excellent photodynamic therapy effect in visible light (400-700 nm) giving IC50 values of 2-6 µM in HeLa and MCF-7 cancer cells, while being less toxic in dark (â¼100 µM). The cell death was apoptotic in nature involving reactive oxygen species (ROS). Mechanistic data from pUC19 DNA photocleavage studies revealed photogenerated ROS as primarily 1O2 from the BODIPY moiety and ·OH radicals from the curcumin ligand.
Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Coordination Complexes/pharmacology , Curcumin/analogs & derivatives , Curcumin/pharmacology , Mitochondria/metabolism , Photosensitizing Agents/pharmacology , Vanadium/chemistry , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Apoptosis/drug effects , Boron Compounds/chemical synthesis , Boron Compounds/chemistry , Boron Compounds/radiation effects , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/radiation effects , Curcumin/chemical synthesis , Curcumin/radiation effects , DNA Cleavage , Drug Stability , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Ligands , Light , Mitochondria/genetics , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Picolinic Acids/chemical synthesis , Picolinic Acids/chemistry , Picolinic Acids/pharmacology , Reactive Oxygen Species/metabolism , Singlet Oxygen/chemistryABSTRACT
We report a discovery that perfunctionalized icosahedral dodecaborate clusters of the type B12(OCH2Ar)12 (Ar = Ph or C6F5) can undergo photo-excitation with visible light, leading to a new class of metal-free photooxidants. Excitation in these species occurs as a result of the charge transfer between low-lying orbitals located on the benzyl substituents and an unoccupied orbital delocalized throughout the boron cluster core. Here we show how these species, photo-excited with a benchtop blue LED source, can exhibit excited-state reduction potentials as high as 3 V and can participate in electron-transfer processes with a broad range of styrene monomers, initiating their polymerization. Initiation is observed in cases of both electron-rich and electron-deficient styrene monomers at cluster loadings as low as 0.005 mol%. Furthermore, photo-excitation of B12(OCH2C6F5)12 in the presence of a less activated olefin such as isobutylene results in the production of highly branched poly(isobutylene). This work introduces a new class of air-stable, metal-free photo-redox reagents capable of mediating chemical transformations.
Subject(s)
Boron Compounds/chemistry , Light , Oxidants/chemistry , Polyenes/chemistry , Polymers/chemistry , Boron Compounds/radiation effects , Electron Transport , Models, Molecular , Molecular Structure , Oxidation-Reduction , Photochemical Processes , PolymerizationABSTRACT
Investigation of the unexpected photo-instability of 2,6-sulfonamide-substituted derivatives of the boron dipyrromethene (BODIPY) fluorophore led to the discovery of a photoreaction accompanied by multiple bond scissions. We characterized the photoproducts and utilized the photoreaction to design a caged γ-aminobutyric acid (GABA) derivative that can release GABA upon irradiation in the visible range (>450â nm). This allowed us to stimulate neural cells in mouse brain slices.