RESUMO
Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.
Assuntos
Cobre , Glutationa , Homeostase , Oxirredução , Animais , Camundongos , Humanos , Glutationa/metabolismo , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Estresse Oxidativo/efeitos dos fármacos , Sinergismo Farmacológico , Morte Celular Imunogênica/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismoRESUMO
Photocatalysis has found increasing applications in biological systems, for example, in localized prodrug activation; however, high-energy light is usually required without giving sufficient efficiency and target selectivity. In this work, we report that ion pairing between photocatalysts and prodrugs can significantly improve the photoactivation efficiency and enable tumor-targeted activation by red light. This is exemplified by a gold-based prodrug (1d) functionalized with a morpholine moiety. Such a modification causes 1d to hydrolyze in aqueous solution, forming a cationic species that tightly interacts with anionic photosensitizers including Eosin Y (EY) and Rose Bengal (RB), along with a significant bathochromic shift of absorption tailing to the far-red region. As a result, a high photoactivation efficiency of 1d by EY or RB under low-energy light was found, leading to an effective release of active gold species in living cells, as monitored by a gold-specific biosensor (GolS-mCherry). Importantly, the morpholine moiety, with pKa â¼6.9, in 1d brings in a highly pH-sensitive and preferential ionic interaction under a slightly acidic condition over the normal physiological pH, enabling tumor-targeted prodrug activation by red light irradiation in vitro and in vivo. Since a similar absorption change was found in other morpholine/amine-containing clinic drugs, photocages, and precursors of reactive labeling intermediates, it is believed that the ion-pairing strategy could be extended for targeted activation of different prodrugs and for mapping of an acidic microenvironment by low-energy light.
Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/química , Luz Vermelha , Morfolinas , Microambiente TumoralRESUMO
Over the past few decades, research on the chemistry of gold has progressed rapidly, encompassing topics like catalysis, supramolecular chemistry, molecular recognition, etc. These chemical properties are of great value in developing therapeutics or orthogonal catalysts in biology. However, the presence of concentrated nucleophiles and reductants, particularly thiol-containing serum albumin in blood and glutathione (GSH) inside cells that can strongly bind and quench the active gold species, makes it difficult to translate the chemistry of gold from test tubes into living systems. In this regard, modulating the chemical reactivity of gold complexes to conquer nonspecific interactions with thiols and meanwhile to controllably activate their reactivity in a spatiotemporal manner is of pivotal importance to develop gold complexes for biomedical applications. In this account, we aim to highlight the concept of developing stimuli-activatable gold complexes with masked chemical properties, the bioactivity of which can be spatiotemporally activated at the target site by leveraging approaches from classic structure design to recently emerged photo- and bioorthogonal-activation.A straightforward approach to tuning the reactivity of gold complexes is based on structure modification. This is achieved by introducing strong carbon donor ligands, such as N-heterocyclic carbene, alkynyl, and diphosphine, to improve the stability of gold(I) complexes against off-target thiols. Likewise, GSH-responsive gold(III) prodrug and supramolecular Au(I)-Au(I) interaction have been harnessed to keep a reasonable stability against serum albumin and confer tumor-targeted cytotoxicity by inhibiting thiol- and selenol-containing thioredoxin reductase (TrxR) for potent cancer treatment in vivo. To achieve better spatiotemporal controllability, photoactivatable prodrugs are developed. These complexes are equipped with cyclometalated pincer-type ligands and carbanion or hydride as ancillary ligands, rendering high thiol-stability in the dark, but upon photoirradiation, the complexes can undergo unprecedented photoinduced ligand substitution, ß-hydride elimination, and/or reduction to release active gold species for TrxR inhibition at the diseased tissue. To further improve the therapeutic activity, an oxygen-dependent conditional photoreactivity of gold(III) complexes by evolving from photodynamic into photoactivated chemotherapy has been achieved, resulting in highly potent antitumor efficacy in tumor-bearing mice. Of equal importance is harnessing the bioorthogonal activation approach by chemical inducers, as exemplified by a palladium-triggered transmetalation reaction to selectively activate the chemical reactivities of gold including its TrxR inhibition and catalytic activity in living cells and zebrafish. Collectively, strategies to modulate gold chemistry in vitro and in vivo are emerging, and it is hoped that this Account will spur the creation of better approaches to advance gold complexes closer to clinical application.
Assuntos
Antineoplásicos , Complexos de Coordenação , Camundongos , Animais , Ouro/química , Linhagem Celular Tumoral , Antineoplásicos/química , Ligantes , Peixe-Zebra/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Compostos de Sulfidrila , Complexos de Coordenação/químicaRESUMO
Hypoxia, as a prevalent feature of solid tumors, is correlated with tumorigenesis, proliferation, and invasion, playing an important role in mediating the drug resistance and affecting the cancer treatment outcomes. Due to the distinct oxygen levels between tumor and normal tissues, hypoxia-targeted therapy has attracted significant attention. The hypoxia-activated compounds mainly depend on reducible organic groups including azo, nitro, N-oxides, quinones and azide as well as some redox-active metal complex that are selectively converted into active species by the increased reduction potential under tumor hypoxia. In this review, we briefly summarized our current understanding on hypoxia-activated compounds with a particular highlight on the recently developed prodrugs and fluorescent probes for tumor treatment and diagnosis. We have also discussed the challenges and perspectives of small molecule-based hypoxia-activatable prodrug for future development.
Assuntos
Neoplasias , Pró-Fármacos , Humanos , Hipóxia/diagnóstico , Hipóxia/tratamento farmacológico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Hipóxia Celular , Hipóxia Tumoral , Linhagem Celular TumoralRESUMO
Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH2 even in limited O2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.
Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Humanos , Animais , Camundongos , Pró-Fármacos/uso terapêutico , Irídio , Espécies Reativas de Oxigênio , Neoplasias/tratamento farmacológico , Ácidos Borônicos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Microambiente TumoralRESUMO
The discovery of immunogenic cell death (ICD) by small molecules (e. g., chemotherapeutic drugs) intrigued medicinal chemists and led them to exploit anticancer agents with such a trait because ICD agents provoke anticancer immune responses in addition to their cytotoxicity. However, the unclear molecular mechanism of ICD hampers further achievements in drug development. Fortunately, increasing efforts have been made in this area in recent years by using either chemical or biological approaches. Here, we review the current achievements towards understanding the mechanisms of small molecule-induced ICD effects. Based on the established role of the unfolded protein response (UPR) in ICD, we classify the mechanisms of different inducers by their dependency on UPR. Key proteins and pathways with important implications are discussed in depth. We also give our perspectives on the research strategies for future investigation in this field.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/metabolismo , Morte Celular , Morte Celular Imunogênica , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , FenótipoRESUMO
Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.
Assuntos
Antineoplásicos , Morte Celular Imunogênica , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Irídio/farmacologia , Resposta a Proteínas não DobradasRESUMO
Photodynamic therapy (PDT) is a spatiotemporally controllable, powerful approach in combating cancers but suffers from low activity under hypoxia, whereas photoactivated chemotherapy (PACT) operates in an O2 -independent manner but compromises the ability to harness O2 for potent photosensitization. Herein we report that cyclometalated gold(III)-alkyne complexes display a PDT-to-PACT evolving photoactivity for efficient cancer treatment. On the one hand, the gold(III) complexes can act as dual photosensitizers and substrates, leading to conditional PDT activity in oxygenated condition that progresses to highly efficient PACT (Ï up to 0.63) when O2 is depleted in solution and under cellular environment. On the other hand, the conditional PDT-to-PACT reactivity can be triggered by external photosensitizers in a similar manner in vitro and in vivo, giving additional tumor-selectivity and/or deep tissue penetration by red-light irradiation that leads to robust anticancer efficacy.
Assuntos
Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Luz , Ouro , Neoplasias/tratamento farmacológicoRESUMO
Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo-induced ß-hydride elimination, releasing alkyl ligands and forming gold(III)-hydride intermediates that could be quickly converted into bioactive [AuIII -S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo-catalytically reduce [AuIII -S] into more bioactive AuI species. Such photo-reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal-biomacromolecule interactions. As a result, the gold(III) complexes containing glucose-functionalized alkyl ligands displayed efficient and tumor-selective uptake; notably, after one- or two-photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ouro , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tiorredoxina Dissulfeto RedutaseRESUMO
Controllably activating the bio-reactivity of metal complexes in living systems is challenging but highly desirable because it can minimize off-target bindings and improve spatiotemporal specificity. Herein, we report a new bioorthogonal activation approach by employing Pd(II)-triggered transmetallation reactions to conditionally activate the bio-reactivity of NHC-Au(I)-phenylacetylide complexes (1 a) inâ vitro and inâ vivo. A combination of 1 Hâ NMR, LC-MS, DFT calculation and fluorescence screening assays reveals that 1 a displays a reasonable stability against biological thiols, but its phenylacetylide ligand can be efficiently transferred to Pd(II), leading to inâ situ formation of labile NHC-Au(I) species that is catalytically active inside living cells and zebrafish, and can meanwhile effectively suppress the activity of thioredoxin reductase, potently inhibit the proliferation of cancer cells and efficiently suppress angiogenesis in zebrafish models.
Assuntos
Complexos de Coordenação/química , Ouro/química , Alcinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Teoria da Densidade Funcional , Embrião não Mamífero/química , Embrião não Mamífero/metabolismo , Humanos , Metano/análogos & derivados , Metano/química , Imagem Óptica , Paládio/química , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
Luminescent coinage metal complexes have shown promising applications as electroluminescent emitters, photocatalysts/photosensitizers, and bioimaging/theranostic agents, rendering them attractive alternatives to transition metal complexes based on iridium, ruthenium, and platinum that have extremely low earth abundance. In comparison to the widely studied Au(I) and Cu(I) complexes, Ag(I) complexes have seldom been explored in this field because of their inferior emission properties. Herein, we report a novel series of [Ag(N^N)(P^P)]PF6 complexes exhibiting highly efficient thermally activated delayed fluorescence by using easily accessible neutral diamine ligands and commercially available ancillary diphosphine chelates. The photoluminescence quantum yields (PLQYs) of the Ag(I) emitters are ≤0.62 in doped films. The high PLQY with a large delayed fluorescence ratio enabled the fabrication of solution-processed organic light-emitting diodes (OLEDs) with a high maximum external quantum efficiency of 8.76%, among the highest values for Ag(I) emitter-based OLEDs. With superior emission properties and an excited state lifetime in the microsecond regime, together with its potent cytotoxicity, the selected Ag(I) complex has been used for simultaneous cell imaging and anticancer treatment in human liver carcinoma HepG2 cells, revealing the potential of luminescent Ag(I) complexes for biological applications such as theranostics.
Assuntos
Complexos de Coordenação/química , Fluorescência , Luz , Semicondutores , Prata/química , Temperatura , Diaminas/química , Ligantes , Modelos Moleculares , Conformação Molecular , Teoria Quântica , SoluçõesRESUMO
The specific gold-sulfur binding interaction renders gold complexes as promising anti-cancer agents that can potentially overcome cisplatin resistance; while their unbiased binding towards non-tumoral off-target thiol-proteins has posed a big hurdle to clinical application. Herein we report that cyclometalated gold(III) complexes bearing hydride ligands are highly stable towards thiols in the dark but can efficiently dissociate the auxiliary hydride moiety and generate a gold-thiol adduct when excited with visible light. In consequence, the photo-activated gold(III) complexes potently inhibited thioredoxin reductase in association with up to >400-fold increment of photocytotoxicity (vs. dark condition) without deactivation by serum albumin and along with strong anti-angiogenesis activity in zebrafish embryos. Importantly, the gold(III)-hydride complexes could be activated by two-photon laser irradiation at the phototherapeutic window as effectively as blue-light irradiation.
Assuntos
Antineoplásicos/química , Ouro/química , Luz , Compostos de Sulfidrila/química , Animais , Linhagem Celular Tumoral , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Peixe-Zebra/embriologiaRESUMO
Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent inâ vitro and inâ vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and inâ vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Metano/análogos & derivados , Compostos Organoáuricos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Humanos , Ligantes , Metano/química , Metano/farmacologia , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos Organoáuricos/química , Relação Estrutura-AtividadeRESUMO
Gold complexes have recently gained increasing attention in the design of new metal-based anticancer therapeutics. Gold(III) complexes are generally reactive/unstable under physiological conditions via intracellular redox reactions, and the intracellular Au(III) to Au(I) reduction reaction has recently been "traced" by the introduction of appropriate fluorescent ligands. Similar to most Au(I) complexes, Au(III) complexes can inhibit the activities of thiol-containing enzymes, including thioredoxin reductase, via ligand exchange reactions to form Au-S(Se) bonds. Nonetheless, there are examples of physiologically stable Au(III) and Au(I) complexes, such as [Au(TPP)]Cl (H2TPP = 5,10,15,20-tetraphenylporphyrin) and [Au(dppe)2]Cl (dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent in vitro and in vivo anticancer activities. In this review, we summarize our current understanding of anticancer gold complexes, including their mechanisms of action and the approaches adopted to improve their anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologiaRESUMO
Two classes of pincer-type Pt(II) complexes containing tridentate N-donor ligands (1-8) or C-deprotonated N^C^N ligands derived from 1,3-di(2-pyridyl)benzene (10-13) and auxiliary N-heterocyclic carbene (NHC) ligand were synthesized. [Pt(trpy)(NHC)](2+) complexes 1-5 display green phosphorescence in CH2 Cl2 (Φ: 1.1-5.3 %; τ: 0.3-1.0â µs) at room temperature. Moderate-to-intense emissions are observed for 1-7 in glassy solutions at 77â K and for 1-6 in the solid state. The [Pt(N^C^N)(NHC)](+) complexes 10-13 display strong green phosphorescence with quantum yields up to 65 % in CHCl3 . The reactions of 1 with a wide variety of anions were examined in various solvents. The tridentate N-donor ligand of 1 undergoes displacement reaction with CN(-) in protic solvents. Similar displacement of the N^C^N ligand by CN(-) has been observed for 10, leading to a luminescence "switch-off" response. The water-soluble 7 containing anthracenyl-functionalized NHC ligand acts as a light "switch-on" sensor for the detection of CN(-) ion with high selectivity. The in vitro cytotoxicity of the Pt(II) complexes towards HeLa cells has been evaluated. Complex 12 showed high cytotoxicity with IC50 value of 0.46â µM, whereas 1-4 and 6-8 are less cytotoxic. The cellular localization of the strongly luminescent complex 12 traced by using emission microscopy revealed that it mainly localizes in the cytoplasmic structures rather than in the nucleus. This complex can induce mitochondria dysfunction and subsequent cell death.
RESUMO
Understanding the mechanism of action of anti-cancer agents is of paramount importance for drug development. NMR spectroscopy can provide insights into the kinetics and thermodynamics of the binding of metallodrugs to biomolecules. NMR is most sensitive for highly abundant I=1/2 nuclei with large magnetic moments. Polarization transfer can enhance NMR signals of insensitive nuclei at physiologically-relevant concentrations. This paper reviews NMR methods for speciation of precious metal anti-cancer complexes, including platinum-group and gold-based anti-cancer agents. Examples of NMR studies involving interactions with DNA and proteins in particular are highlighted.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Espectroscopia de Ressonância Magnética/métodos , Metais Pesados/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Ouro/química , Ouro/uso terapêutico , Humanos , Metais Pesados/uso terapêutico , Platina/química , Platina/uso terapêutico , Ródio/química , Ródio/uso terapêuticoRESUMO
In the design of anticancer gold(I) complexes with high inâ vivo efficacy, tuning the thiol reactivity to achieve stability towards blood thiols yet maintaining the thiol reactivity to target cellular thioredoxin reductase (TrxR) is of pivotal importance. Herein we describe a dinuclear gold(I) complex (1-PF6) utilizing a bridging bis(N-heterocyclic carbene) ligand to attain thiol stability and a diphosphine ligand to keep appropriate thiol reactivity. Complex 1-PF6 displays a favorable stability that allows it to inhibit TrxR activity without being attacked by blood thiols. Inâ vivo studies reveal that 1-PF6 significantly inhibits tumor growth in mice bearing HeLa xenograft and mice bearing highly aggressive mouse B16-F10 melanoma. It inhibits angiogenesis in tumor models and inhibits sphere formation of cancer stem cells inâ vitro. Toxicology studies indicate that 1-PF6 does not show systemic anaphylaxis on guinea pigs and localized irritation on rabbits.
Assuntos
Ouro/farmacologia , Metano/análogos & derivados , Compostos de Sulfidrila/farmacologia , Tiorredoxina Dissulfeto Redutase/química , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células HeLa , Humanos , Ligantes , Metano/química , Camundongos , Neovascularização Patológica , Coelhos , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Compostos Organoáuricos/administração & dosagem , Porfirinas/administração & dosagem , Dióxido de Silício/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Organoáuricos/farmacologia , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
Luminescent metallo-intercalators are potent biosensors of nucleic acid structure and anticancer agents targeting DNAs. There are few examples of luminescent metallo-intercalators which can simultaneously act as emission probes of nucleic acid structure and display promising anticancer activities. Herein, we describe a luminescent platinum(II) complex, [Pt(C^N^N)(C≡NtBu)]ClO4 (1 a, HC^N^N= 6-phenyl-2,2'-bipyridyl), that intercalates between the nucleobases of nucleic acids, accompanied by an increase in emission intensity and/or a significant change in the maximum emission wavelength. The changes in emission properties measured with double-stranded RNA (dsRNA) are different from those with dsDNA used in the binding reactions. Complex 1 a exhibited potent anticancer activity towards cancer cells inâ vitro and inhibited tumor growth in a mouse model. The stabilization of the topoisomeraseâ I-DNA complex with resulting DNA damage by 1 a is suggested to contribute to its anticancer activity.
Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Luminescência , Neoplasias Experimentais/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , RNA de Cadeia Dupla/efeitos dos fármacos , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/química , RNA de Cadeia Dupla/química , Relação Estrutura-AtividadeRESUMO
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.