RESUMO
Photodynamic therapy has been regarded as a noninvasive treatment for cancer with spatiotemporal control over drug activation. Bis-terpyridyl Ru(II) complexes exhibit a promising achiral structure but suffer from low photoreactivity due to deviation from the ideal octahedral geometry. Herein, we introduce the donor-acceptor-donor motif to construct a dinuclear bis-terpyridyl Ru(II) complex (Ru2). Ru2 exhibits superior light absorption properties compared with mononuclear complex Ru1. Importantly, upon 595 nm light excitation, Ru2 shows promising synergetic type I/II photosensitization and photocatalytic activity, while Ru1 is inactive. Anticancer mechanistic studies reflect that Ru2 induces intracellular redox imbalance and affects the biosynthetic and metabolic processes, leading to cell apoptosis. Overall, this work provides a simple strategy to rouse the PDT efficiency of bis-terpyridyl Ru(II) complexes.
Assuntos
Antineoplásicos , Complexos de Coordenação , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rutênio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Rutênio/química , Rutênio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Sonodynamic therapy (SDT), as a novel non-invasive cancer treatment modality derived from photodynamic therapy (PDT), has drawn much attention due to its unique advantages for the treatment of deep tumors. Zinc-based complexes have shown great clinical prospect in PDT due to their excellent photodynamic activity and biosafety. However, their application in SDT has lagged seriously behind. Exploring efficient zinc-based complexes as sono-sensitizers remains an appealing but significantly challenging task. Herein, we develop a hydrazone ligand-based zinc complex (ZnAMTC) for SDT of tumors in vitro and in vivo. ZnAMTC was facilely synthesized via a two-step reaction from low-cost raw materials without tedious purification. It shows negligible dark toxicity and can produce singlet oxygen (1O2) under ultrasound (US) irradiation, exhibiting high sono-cytotoxicity to various cancer cells. Mechanism studies show that ZnAMTC can effectively reduce the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) under US irradiation and later cause ferroptosis of cancer cells. In vivo studies further demonstrate that ZnAMTC exhibits efficient tumor growth inhibition under US irradiation and has good biosafety. This work provides useful insights into the design of first-row transition metal complexes for SDT application.
RESUMO
The design of the dinuclear Ru(II) complex (Ru2) with strong near-infrared (NIR) absorption properties has been reported for efficient anticancer phototherapy. Under 700 nm LED light excitation, Ru2 exhibited remarkable synergistic type I/II photosensitization ability and photocatalytic activity toward intracellular biomolecules. Ru2 showed impressive 700 nm light-triggered anticancer activity under normoxia and hypoxia compared with the clinically used photosensitizer Chlorin e6. The mechanistic studies showed that Ru2 induced intracellular redox imbalance and perturbed the energy metabolism and biosynthesis in A549 cancer cells. Overall, this work provides a new strategy for developing efficient metal-based complexes for anticancer phototherapy under NIR light.
Assuntos
Antineoplásicos , Complexos de Coordenação , Raios Infravermelhos , Fármacos Fotossensibilizantes , Rutênio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Rutênio/química , Rutênio/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Células A549 , Ensaios de Seleção de Medicamentos Antitumorais , Fotoquimioterapia , Proliferação de Células/efeitos dos fármacosRESUMO
The hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen-dependent photodynamic therapy (PDT). The development of hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop a "closed-loop" therapy based on PDT-induced ferroptosis and immune therapy is reported. Due to its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia-tolerant type I/II combined PDT capability, which can generate 1O2, O2 -, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4-dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon-γ (IFN-γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing "closed-loop" therapeutic approach.
Assuntos
Ferroptose , Imunoterapia , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rênio , Ferroptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Camundongos , Humanos , Imunoterapia/métodos , Fotoquimioterapia/métodos , Rênio/química , Rênio/farmacologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
The novel hetero-dinuclear complex trans,trans,trans-[PtIV(py)2(N3)2(OH)(µ-OOCCH2CH2CONHCH2-bpyMe)IrIII(ppy)2]Cl (Pt-Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt-OH) and donor photodynamic Ir(III) (Ir-NH2) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt-OH) to generate Pt(II) species, an azidyl radical and 1O2. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NADâ radicals and NAD+. Pt-Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465â nm, 4.8â mW/cm2), even with short light-exposure times (10-60â min). In contrast, the mononuclear Pt-OH and Ir-NH2 subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt-Ir compared to Pt-OH. Irradiation of Pt-Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron-XRF revealed ca. 4× higher levels of intracellular platinum compared to iridium in Pt-Ir treated cells under dark conditions. Luminescent Pt-Ir distributes over the whole cell and generates ROS and 1O2 within 1â h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt-Ir with a novel strategy for multimodal phototherapy.
Assuntos
Antineoplásicos , Irídio , Fotoquimioterapia , Fármacos Fotossensibilizantes , Platina , Irídio/química , Irídio/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Platina/química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacosRESUMO
Photoactivable chemotherapy (PACT) using metallic complexes provides spatiotemporal selectivity over drug activation for targeted anticancer therapy. However, the poor absorption in near-infrared (NIR) light region of most metallic complexes renders tissue penetration challenging. Herein, an NIR light triggered dinuclear photoactivable Ru(II) complex (Ru2) is presented and the antitumor mechanism is comprehensively investigated. The introduction of a donor-acceptor-donor (D-A-D) linker greatly enhances the intramolecular charge transition, resulting in a high molar extinction coefficient in the NIR region with an extended triplet excited state lifetime. Most importantly, when activated by 700 nm NIR light, Ru2 exhibits unique slow photodissociation kinetics that facilitates synergistic photosensitization and photocatalytic activity to destroy diverse intracellular biomolecules. In vitro and in vivo experiments show that when activated by 700 nm NIR light, Ru2 exhibits nanomolar photocytotoxicity toward 4T1 cancer cells via the induction of calcium overload and endoplasmic reticulum (ER) stress. These findings provide a robust foundation for the development of NIR-activated Ru(II) PACT complexes for phototherapeutic application.
RESUMO
Due to the antibiotics abuse, bacterial infection has become one of the leading causes of human death worldwide. Novel selective antimicrobial agents are urgently needed, with the hope of maintaining the balance of the microbial environment. Photo-activated chemotherapeutics have shown great potential to eliminate bacteria with appealing spatiotemporal selectivity. In this work, we reported the structural modification to enhance the triplet excited state property of Rhodamine B, synthesizing a rhodamine-based photosensitizer RBPy. Upon light activation, RBPy exhibited much stronger photosensitization ability than the parent compound Rhodamine B both in solution and in bacteria. Importantly, RBPy can selectively inactivate Staphylococcus aureus and inhibit biofilm formation with high biocompatibility. This work provides a new strategy to develop rhodamine-based photoactive chemotherapeutics for antimicrobial photodynamic therapy.
Assuntos
Fotoquimioterapia , Infecções Estafilocócicas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Superóxidos , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Infecções Estafilocócicas/tratamento farmacológico , Rodaminas/farmacologiaRESUMO
Due to cell mutation and self-adaptation, the application of clinical drugs with early epidermal growth factor receptor (EGFR)-targeted inhibitors is severely limited. To overcome this limitation, herein, the synthesis and in-depth biological evaluation of an erlotinib-platinum(II) complex as an EGFR-targeted anticancer agent is reported. The metal complex is able to self-assemble inside an aqueous solution and readily form nanostructures with strong photophysical properties. While being poorly toxic toward healthy cells and upon treatment in the dark, the compound was able to induce a cytotoxic effect in the very low micromolar range upon irradiation against EGFR overexpressing (drug resistant) human lung cancer cells as well as multicellular tumor spheroids. Mechanistic insights revealed that the compound was able to selectively degrade the EGFR using the lysosomal degradation pathway upon generation of singlet oxygen at the EGFR. We are confident that this work will open new avenues for the treatment of EGFR-overexpressing tumors.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Fotoquimioterapia , Humanos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Platina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/patologia , Receptores ErbB/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular TumoralRESUMO
The challenge of antibiotic resistance worldwide has brought an urgent need to explore novel drugs for bacterial infections. Antimicrobial photodynamic therapy has been proven to be a potential antimicrobial modality but is limited by biofilms. In this study, we synthesized three cationic photosensitizers with strong photoinduced antimicrobial and antibiofilm activities toward gram-positive Staphylococcus aureus. The indole-pyridine compounds illustrated multiple type I/II photosensitization and coenzyme NAD(P)H photocatalytic activity upon excitation. A mechanistic study showed that intracellular reactive oxygen generation and NAD(P)H oxidation caused membrane damage, leading to protein/nucleus acid leakage. This research provides insights into the development of novel chemotherapeutics with synergetic photodynamic and photocatalytic reactivity.
Assuntos
Anti-Infecciosos , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , NAD , Piridinas/farmacologia , Biofilmes , Indóis/farmacologiaRESUMO
The hypoxic microenvironment and drug resistance of cancer cells have become a huge threat for clinical anticancer therapy. Anticancer phototherapy providing spatial and temporal control over drug activation may conquer this problem. Herein, we report a novel photoactivated Ru(II) complex (Ru2) with multiple activities including photochemotherapy, photodynamic and photocatalytic therapy, and endoperoxide formation. Upon white light irradiation, Ru2 can dissociate the coordinating ligands and form endoperoxides, produce diverse reactive oxygen species and catalytically oxidize cellular coenzymes. As a result, Ru2 shows promising antiproliferation activity toward cisplatin and 5-fluorouracil resistant tumor cell lines under normoxia and hypoxia. The multifunctional design strategy of metal-based anticancer drugs offers novel efficient therapeutics to combat drug-resistant cancer cells under hypoxia.
Assuntos
Antineoplásicos , Complexos de Coordenação , Fotoquimioterapia , Rutênio , Humanos , Oxigênio/metabolismo , Ligantes , Complexos de Coordenação/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Hipóxia , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de OxigênioRESUMO
An undescribed α-pyrone diaporpyrone E (1), and three known nucleotides, 5'-O-acetyl uridine (2), 5'-O-acetyl thymidine (3), and adenine (4), were identified from Diaporthe sp. CB10100, an endophytic fungus isolated from the medicinal plant Sinomenium acutum. The structure of 1 was determined by extensive analysis of its HRMS, 1D and 2D NMR spectroscopic data, as well as electronic circular dichroism calculations and comparison. The in vitro cytotoxic and antibacterial assays of 1 revealed that it has a 30.2% inhibitory effect on HepG2 cells at 50 µM, while no antibacterial activities against Staphylococcus aureus and Klebsiella pneumoniae at 64 µg/mL.
RESUMO
The rapid efflux of Pt-based chemotherapeutics by cancer cells is one of the major causes of drug resistance in clinically available drugs. Therefore, both the high cellular uptake as well as adequate retention efficiency of an anticancer agent are important factors to overcome drug resistance. Unfortunately, rapid and efficient quantification of metallic drug concentration in individual cancer cells still remains a tricky problem. Herein, with the help of newly developed single cell inductively coupled plasma mass spectrometry (SC-ICP-MS), we have found that the well-known Ru(II)-based complex, Ru3, displayed remarkable intracellular uptake and retention efficiency in every single cancer cell with high photocatalytic therapeutic activity to overcome cisplatin resistance. Moreover, Ru3 has shown sensational photocatalytic anticancer properties with excellent in-vitro and in-vivo biocompatibility under light exposure.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Rutênio , Humanos , Detecção Precoce de Câncer , Antineoplásicos/farmacologia , Antineoplásicos/química , Cisplatino/química , Rutênio/farmacologia , Rutênio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
Photoactive antibacterial therapy is one of the novel therapeutic methods that has great application potential and prospects for curbing bacterial infections. In this work, a photoactivated iridium complex (Ir-Cl) is synthesized for photoactive antibacterial research. Ir-Cl exhibits photoacidolysis, which can generate H+ and be converted into a photolysis product Ir-OH under blue light irradiation. At the meantime, this process is accompanied by 1O2 generation. Notably, Ir-Cl can selectively permeate S. aureus and exhibit excellent photoactive antibacterial activity. Mechanism studies show that Ir-Cl can ablate bacterial membranes and biofilms under light irradiation. Metabolomics analysis proves that Ir-Cl with light exposure mainly disturbs some amino acids' degradation (e.g., valine, leucine, isoleucine, arginine) and pyrimidine metabolism, which indirectly causes the ablation of biofilms and ultimately produces irreversible damage to S. aureus. This work provides guidance for metal complexes in antibacterial application.
Assuntos
Complexos de Coordenação , Irídio , Irídio/farmacologia , Staphylococcus aureus , Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , LuzRESUMO
A novel axisymmetric bis-tridentate Ir(III) photocatalyst (Ir3) with synergetic type I/II photosensitization and photocatalytic activity was reported. Ir3 exhibited high photocytotoxicity toward drug-resistant cancer cells under normoxia and hypoxia. The photoactivated anticancer mechanism of Ir3 were investigated in detail. Overall, this new photo-redox catalyst can overcome hypoxia and drug resistance-related problems in clinical anticancer therapy.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fototerapia , Catálise , Hipóxia/tratamento farmacológicoRESUMO
The photoisomerization-induced cytotoxicity in photopharmacology provides a unique pathway for phototherapy because it is independent of endogenous oxygen. In this study, we developed a biosafe photoisomerizable zinc(II) complex (Zn1), which releases its trans ligand (trans-L1) after being irradiated with blue light. This causes the complex to undergo photoisomerization and produce the toxic cis product (cis-L1) and generate singlet oxygen (1 O2 ). The resulting series of events caused impressive phototoxicity in hypoxic A431 skin cancer cells, as well as in a tumor model in vivo. Interestingly, Zn1 was able to inhibit tumor microtubule polymerization, while still showing good biocompatibility and biosafety in vivo. This photoisomerizable zinc(II) complex provides a novel strategy for addressing the oxygen-dependent limitation of traditional photodynamic therapy.
Assuntos
Fotoquimioterapia , Zinco , Polimerização , Fototerapia , Oxigênio , MicrotúbulosRESUMO
Recently, interest has been given to developing photocatalytic anticancer drugs. This area of research is dominated by metal complexes. Here, we report the potential of lysosome/mitochondria targeting cyanine appended bipyridine compounds as the organic photocatalytic anticancer agents. The organocatalyst (bpyPCN) not only exhibits light-induced NADH oxidation but also generates intracellular ROS to demonstrate anticancer activity. This is the first example of organic compound induced catalytic NADH photo-oxidation in an aqueous solution and in cancer cells.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , 2,2'-Dipiridil/farmacologia , Oxirredução , NAD , Antineoplásicos/farmacologiaRESUMO
Photodynamic therapy (PDT) for cancer treatment has garnered tremendous attention with its promising non-invasiveness, low side effects, and spatiotemporal selectivity. However, the hypoxic microenvironment in solid tumours remains a serious resistant factor to reducing the effects of PDT. Endoperoxides are successfully utilized as the chemical storage or supplier of singlet oxygen (1 O2 ), the active substance for PDT in materials and other domains. Recent reports indicated that this type of compound could remarkably enhance the therapeutic effects of PDT under hypoxia. This concept mainly introduces a few representative endoperoxides and the outlook of their potent application for treating hypoxic cancer cells.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Hipóxia/tratamento farmacológico , Oxigênio Singlete , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes , Linhagem Celular Tumoral , Oxigênio , Microambiente TumoralRESUMO
Rationally-designed glucose-appended Ir(III) photo-catalysts ([Ir(N,C)2(N,N-Glc)]+, Ir1-Ir3) show visible light-induced catalytic NAD(P)H oxidation in aqueous solution. The highly in vivo biocompatible complex, Ir3, shows lysosome and mitochondria targeting necro-apoptotic photo-cytotoxicity against various cancer cell lines and multicellular spheroids, while remaining non-toxic in the dark.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Glucose , Humanos , Irídio/farmacologia , Mitocôndrias , Neoplasias/tratamento farmacológicoRESUMO
Immunotherapy has made great progress in clinical cancer treatment in recent years, but its therapeutic efficacy is significantly limited by the lack of immunogenicity in the tumor microenvironment. Pyroptosis is a type of programmed cell death in which the dying cancer cells produce inflammatory cytokines to relieve the immuno-suppressive microenvironment and thus increase anti-tumor immunity. Reactive oxygen species (ROS) produced during photodynamic therapy (PDT) are one of the efficient activators that induce pyroptosis. Recently, a few photosensitizers have emerged with the ability to induce immunogenic cancer cell death via pyroptosis, opening a new field for PDT. This highlight introduces the latest research on antitumor strategies achieved by the combination of immunotherapy and photodynamic therapy through photo-pyroptosis.
Assuntos
Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Piroptose , Microambiente TumoralRESUMO
Photodynamic therapy (PDT), a non-/minimally invasive cancer treatment method, has the advantages of low side effects, high selectivity, and low drug resistance. It is currently a popular cancer treatment method. However, given the shortcomings of photosensitizers such as poor photostability, poor water solubility, and short half-life inâ vivo when used alone, the development of photosensitizer nano-delivery platforms has always been a research hotspot to overcome these shortcomings. In the human body, various types of cells generally release bilayer extracellular vesicles known as exosomes. Compared with traditional materials, exosomes are currently an ideal drug delivery platform due to their homology, low immunogenicity, easy modification, high biocompatibility, and natural carrying capacity. Therefore, in this concept, we focus on the research status and prospects of engineered exosome-based photosensitizer nano-delivery platforms in cancer PDT.