RESUMEN
Reversible thiol-disulfide exchange chemistry is of particular interest in drug delivery systems. However, high levels of glutathione (GSH) in cancer cells are hard to distinguish from GSH in normal cells, resulting in unmanageable cytotoxic drug release. This study investigates the spatiotemporally-controlled irreversible degradation of Ir-based photosensitizer (TIr3)-encapsulating nanogels (IrNG) through the hyperoxidation of resulting intracellular thiols using reactive oxygen species (ROS). A highly cytotoxic TIr3 was stably encapsulated within IrNG through hydrophobic interactions and reversible crosslinking between its disulfide bonds and thiols in the absence of light, resulting in high biocompatibility under normal cellular conditions. However, upon photoirradiation, TIr3 generated high levels of ROS, irreversibly oxidizing the thiols to induce electrostatic repulsion between the polymer molecules, resulting in the TIr3 release and induction of cancer cell apoptosis.
Asunto(s)
Glutatión , Fármacos Fotosensibilizantes , Disulfuros/química , Glutatión/química , Nanogeles , Fármacos Fotosensibilizantes/farmacología , Polímeros , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Sulfhidrilo/químicaRESUMEN
Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, an iridium(III) complex, Ir-1, is reported as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including 1)â photoproperties leading to excitation by low-energy radiation; 2)â generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; and 3)â relatively easy incorporation of a ligand on the IrIII center for specific interactions with amyloidogenic peptides. Biochemical and biophysical investigations illuminate that the oxidation of representative amyloidogenic peptides (i.e., amyloid-ß, α-synuclein, and human islet amyloid polypeptide) is promoted by light-activated Ir-1, which alters the conformations and aggregation pathways of the peptides. Additionally, their potential oxidation sites are identified as methionine, histidine, or tyrosine residues. Overall, our studies on Ir-1 demonstrate the feasibility of devising metal complexes as chemical tools suitable for elucidating the nature of amyloidogenic peptides at the molecular level, as well as controlling their aggregation.
Asunto(s)
Péptidos beta-Amiloides/química , Complejos de Coordinación/química , Iridio/química , Secuencia de Aminoácidos , Péptidos beta-Amiloides/metabolismo , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Luz , Oxidación-Reducción , Agregado de Proteínas/efectos de la radiación , Espectrometría de Masa por Ionización de Electrospray , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMEN
Protein inactivation by reactive oxygen species (ROS) such as singlet oxygen ((1)O2) and superoxide radical (O2(â¢-)) is considered to trigger cell death pathways associated with protein dysfunction; however, the detailed mechanisms and direct involvement in photodynamic therapy (PDT) have not been revealed. Herein, we report Ir(III) complexes designed for ROS generation through a rational strategy to investigate protein modifications by ROS. The Ir(III) complexes are effective as PDT agents at low concentrations with low-energy irradiation (≤ 1 J cm(-2)) because of the relatively high (1)O2 quantum yield (> 0.78), even with two-photon activation. Furthermore, two types of protein modifications (protein oxidation and photo-cross-linking) involved in PDT were characterized by mass spectrometry. These modifications were generated primarily in the endoplasmic reticulum and mitochondria, producing a significant effect for cancer cell death. Consequently, we present a plausible biologically applicable PDT modality that utilizes rationally designed photoactivatable Ir(III) complexes.
Asunto(s)
Retículo Endoplásmico/metabolismo , Iridio/química , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Receptor Toll-Like 3/metabolismo , Transporte Biológico , Células HEK293 , Células HeLa , Humanos , Oxígeno Singlete/metabolismoRESUMEN
Reactive oxygen species have drawn attention owing to their strong oxidation ability. In particular, the singlet oxygen (1O2) produced by energy transfer is the predominant species for controlling oxidation reactions efficiently. However, conventional 1O2 generators, which rely on enhanced energy transfer, frequently suffer from poor solubility, low stability, and low biocompatibility. Herein, we introduce a hyperbranched aliphatic polyaminoglycerol (hPAG) as a 1O2 generator, which relies on spin-flip-based electron transfer. The coexistence of a lone pair electron on the nitrogen atom and a hydrogen-bonding donor (the protonated form of nitrogen and hydroxyl group) affords proximity between hPAG and O2. Subsequent direct electron transfer after photo-irradiation induces hPAGâ¢+-O2 â¢- formation, and the following spin-flip process generates 1O2. The spin-flip-based electron transfer pathway is analyzed by a series of photophysical, electrochemical, and computational studies. The 1O2 generator, hPAG, is successfully employed in photodynamic therapy and as an antimicrobial reagent.
RESUMEN
Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations.
Asunto(s)
Iridio/farmacología , Mitocondrias/metabolismo , Fármacos Fotosensibilizantes/farmacología , Muerte Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Transferencia de Energía , Células HEK293 , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Oxidación-Reducción/efectos de los fármacos , Proteoma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ViscosidadRESUMEN
Efficient and selective production of CH4 through the CO2 reduction reaction (CO2RR) is a challenging task due to the high amount of energy consumption and various reaction pathways. Here, we report the synthesis of Zn-based polyoxometalate (ZnPOM) and its application in the photocatalytic CO2RR. Unlike conventional Zn-based catalysts that produce CO, ZnPOM can selectively catalyze the production of CH4 in the presence of an Ir-based photosensitizer (TIr3) through the photocatalytic CO2RR. Photophysical and computation analyses suggest that selective photocatalytic production of CH4 using ZnPOM and TIr3 can be attributed to (1) the exceptionally fast transfer of photogenerated electrons from TIr3 to ZnPOM through the strong molecular interactions between them and (2) effective transfer of electrons from ZnPOM to *CO intermediates due to significant hybridization of their molecular orbitals. This study provides insights into the design of novel CO2RR catalysts for CH4 production beyond the limitations in conventional studies that focus on Cu-based materials.
RESUMEN
Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [e.g., amyloid-ß (Aß) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of Aß peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(iii) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(iii) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main Aß isoforms, Aß40 and Aß42, as well as the production of toxic Aß species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes.
RESUMEN
Metal-organic framework (MOF) nanoparticles with high porosity and greater tunability have emerged as new drug delivery vehicles. However, premature drug release still remains a challenge in the MOF delivery system. Here, we report an enzyme-responsive, polymer-coated MOF gatekeeper system using hyaluronic acid (HA) and PCN-224 nanoMOF. The external surface of nanoMOF can be stably covered by HA through multivalent coordination bonding between the Zr cluster and carboxylic acid of HA, which acts as a gatekeeper. HA allows selective accumulation of drug carriers in CD44 overexpressed cancer cells and enzyme-responsive drug release in the cancer cell environment. In particular, inherent characteristics of PCN-224, which is used as a drug carrier, facilitates the transfer of the drug to cancer cells more stably and allows photodynamic therapy. This HA-PCN system enables a dual chemo and photodynamic therapy to enhance the cancer therapy effect.
Asunto(s)
Doxorrubicina , Portadores de Fármacos , Ácido Hialurónico , Estructuras Metalorgánicas , Nanopartículas , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
We developed three types of dithieno[3,2-b;2',3'-d]thiophene (DTT)-based organic sensitizers for high-performance thin photoactive TiO2 films and investigated the simple but powerful molecular engineering of different types of bonding between the triarylamine electron donor and the conjugated DTT π-bridge by the introduction of single, double, and triple bonds. As a result, with only 1.3 µm transparent and 2.5-µm TiO2 scattering layers, the triple-bond sensitizer (T-DAHTDTT) shows the highest power conversion efficiency (η = 8.4%; VOC = 0.73 V, JSC = 15.4 mA·cm-2, and FF = 0.75) in an iodine electrolyte system under one solar illumination (AM 1.5, 1000 W·m-2), followed by the single-bond sensitizer (S-DAHTDTT) (η = 7.6%) and the double-bond sensitizer (D-DAHTDTT) (η = 6.4%). We suggest that the superior performance of T-DAHTDTT comes from enhanced intramolecular charge transfer (ICT) induced by the triple bond. Consequently, T-DAHTDTT exhibits the most active photoelectron injection and charge transport on a TiO2 film during operation, which leads to the highest photocurrent density among the systems studied. We analyzed these correlations mainly in terms of charge injection efficiency, level of photocharge storage, and charge-transport kinetics. This study suggests that the molecular engineering of a triple bond between the electron donor and the π-bridge of a sensitizer increases the performance of dye-sensitized solar cell (DSC) with a thin photoactive film by enhancing not only JSC through improved ICT but also VOC through the evenly distributed sensitizer surface coverage.