RESUMO
Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(iii), ruthenium(ii) and rhenium(i) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.
RESUMO
G-quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4-DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF-G4 (a promoter G4) shows that Pt1 matches 3'-G-tetrad of VEGF-G4 through Cl- -dissociation and loop rearrangement of VEGF-G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate-determining binding step, Cl- -dissociation upon G4-binding, is 2-3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4-binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
Assuntos
Antineoplásicos/farmacologia , Quadruplex G/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Células HeLa , Humanos , Cinética , Estrutura Molecular , Compostos Organoplatínicos/químicaRESUMO
The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6 -methyladenosine (m6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx -PEG NPs elevate RNA m6 A methylation levels to cause the m6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsSx -PEG NPs can regulate the expression of RNA m6 A methyltransferases and demethylases. Finally, DOX@OsSx -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.
Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Hipóxia , Metilação , PolietilenoglicóisRESUMO
Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Terapia Fototérmica , Pró-Fármacos/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cisplatino/química , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de SuperfícieRESUMO
Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.
Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Inibidores Enzimáticos/química , Platina/química , Pró-Fármacos/metabolismo , Timidilato Sintase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Liberação Controlada de Fármacos , Fluoruracila/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Assuntos
Complexos de Coordenação/química , Ferro/metabolismo , Mitocôndrias/metabolismo , Rênio/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Deferasirox/química , Avaliação Pré-Clínica de Medicamentos , Epigenômica , Histonas/metabolismo , Humanos , Quelantes de Ferro/química , Metilação/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , RNA Polimerase II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both inâ vitro and inâ vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70-90â times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects.
Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Hipóxia Celular , Complexos de Coordenação/química , Platina/química , Pró-Fármacos/química , Animais , Anidrase Carbônica IX/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Análise por Conglomerados , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Larva/efeitos dos fármacos , Larva/metabolismo , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Proteoma/análise , Proteoma/efeitos dos fármacos , Proteômica , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Cyclometalated iridium(III) complexes represent a promising approach to developing new anticancer metallodrugs. In this work, three phosphorescent cyclometalated iridium(III) complexes Ir1-Ir3 have been explored as mitochondria-targeted anticancer agents. All three complexes display higher antiproliferative activity than cisplatin against the cancer cells screened, and with the IC50 values ranging from 0.23 to 5.6 µM. Colocalization studies showed that these complexes are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy through initiating a series of events related to mitochondrial dysfunction, including depolarization of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS) levels, and induction of apoptosis. Mitochondria-targted cyclometalated iridium complexes induce apoptosis through depolarized mitochondria, elevation of intracellular ROS and activated caspase.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Mitocôndrias/metabolismo , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
G-quadruplex DNA show structural polymorphism, leading to challenges in the use of selective recognition probes for the accurate detection of G-quadruplexes inâ vivo. Herein, we present a tripodal cationic fluorescent probe, NBTE, which showed distinguishable fluorescence lifetime responses between G-quadruplexes and other DNA topologies, and fluorescence quantum yield (Φf ) enhancement upon G-quadruplex binding. We determined two NBTE-G-quadruplex complex structures with high Φf values by NMR spectroscopy. The structures indicated NBTE interacted with G-quadruplexes using three arms through π-π stacking, differing from that with duplex DNA using two arms, which rationalized the higher Φf values and lifetime response of NBTE upon G-quadruplex binding. Based on photon counts of FLIM, we detected the percentage of G-quadruplex DNA in live cells with NBTE and found G-quadruplex DNA content in cancer cells is 4-fold that in normal cells, suggesting the potential applications of this probe in cancer cell detection.
Assuntos
DNA/química , Quadruplex G , Linhagem Celular Tumoral , DNA/análise , Humanos , FótonsRESUMO
Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano-platform PDA-Pt-CD@RuFc formed by platinum-decorated and cyclodextrin (CD)-modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene-appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT-PTT) mediated by PDA-Pt-CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non-oxygen-dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near-infrared two-photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor-microenvironment-adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.
RESUMO
Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth.
Assuntos
Antineoplásicos , Complexos de Coordenação , Irídio , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Irídio/química , Irídio/farmacologia , Metano/análogos & derivados , Metano/síntese química , Metano/química , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We have proposed a facile and cheap cancer therapeutic strategy by in-cell synthesizing theranostic Zn Schiff base complexes with nuclear targeting and DNA damaging capability. The in-cell synthesis can be traced via a green-to-blue fluorescence shift, and the subsequent cytoplasm-to-nucleus translocation realizes cancer-specific therapy both in vitro and in vivo.
Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Bases de Schiff/uso terapêutico , Nanomedicina Teranóstica/métodos , Zinco/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cloretos/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/toxicidade , Citoplasma/metabolismo , DNA/química , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/uso terapêutico , Corantes Fluorescentes/toxicidade , Humanos , Hidrólise , Camundongos Endogâmicos BALB C , Microscopia Confocal/métodos , Bases de Schiff/síntese química , Bases de Schiff/metabolismo , Bases de Schiff/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto , Compostos de Zinco/químicaRESUMO
Harsh photothermal temperatures, long-term body retention of nanoagents, elevated ROS and inflammation induction all threaten the normal tissues, thus hindering the translation of photothermal therapy (PTT) from bench to clinical practice. To resolve these problems, we have developed a disassembled theranostic nanodrug Qu-FeIIP based on the quercetin coordination. Herein, quercetin is not only the heat shock protein (Hsp 70) inhibitor but also the skeleton of Qu-FeIIP, realizing near-infrared light induced low-temperature PTT (45⯰C) to ablate tumor completely without heat stress to normal tissues. Owing to the ROS scavenging ability of quercetin, Qu-FeIIP effectively reduces intracellular ROS and in vivo inflammatory factors (TNF-α, IL-6, IFN-γ) levels. Simultaneously, quercetin-Fe coordination is weakened when scavenging ROS, which triggers the Qu-FeIIP disassembling, resulting in effective clearance of nanoparticles from main organs 168â¯h post intravenous injection. Additionally, the photoacoustic and magnetic resonance dual-imaging capability of Qu-FeIIP offers excellent spatial resolution and imaging depth not only for precise tumor diagnosis but also for monitoring the nanodrug disassembling in vivo. Thus, Qu-FeIIP intrinsically integrates precise diagnosis, excellent low-temperature PTT efficacy, ROS elimination and anti-inflammatory action, dynamic disassembly and renal clearance ability into a single nanodrug, which is very promising for future clinical cancer treatment.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Compostos Ferrosos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/terapia , Quercetina/uso terapêutico , Animais , Temperatura Baixa , Crioterapia , Feminino , Humanos , Células MCF-7 , Imageamento por Ressonância Magnética , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Técnicas Fotoacústicas , Fototerapia , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina TeranósticaRESUMO
Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.
RESUMO
The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Aspirina/uso terapêutico , Complexos de Coordenação/uso terapêutico , Imunomodulação/efeitos dos fármacos , Irídio/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Aspirina/química , Aspirina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Feminino , Humanos , Irídio/química , Irídio/farmacologia , Medições Luminescentes/métodos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Imagem Óptica/métodosRESUMO
Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.
Assuntos
Carcinogênese/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Rênio/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/química , Rênio/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Dano ao DNA , DNA Mitocondrial/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Irídio/química , Células A549 , Animais , Complexos de Coordenação/química , Cristalografia por Raios X , DNA Mitocondrial/metabolismo , Células HeLa , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental changes of a chromophore in a quantitative manner. Phosphorescent iridium complexes are potential TPPLIM probes due to their rich photophysical properties including environment-sensitive long-lifetime emission and high two-photon absorption (TPA) properties. In this work, a series of iridium(iii) complexes containing rotatable groups are developed as mitochondria-targeting anticancer agents and quantitative viscosity probes. Among them, Ir6 ([Ir(ppy-CHO)2(dppe)]PF6; ppy-CHO: 4-(2-pyridyl)benzaldehyde; dppe: cis-1,2-bis(diphenylphosphino)ethene) shows satisfactory TPA properties and long lifetimes (up to 1 µs). The emission intensities and lifetimes of Ir6 are viscosity-dependent, which is mainly attributed to the configurational changes in the diphosphine ligand as proved by 1H NMR spectra. Ir6 displays potent cytotoxicity, and mechanism investigations show that it can accumulate in mitochondria and induce apoptotic cell death. Moreover, Ir6 can induce mitochondrial dysfunction and monitor the changes in mitochondrial viscosity simultaneously in a real-time and quantitative manner via TPPLIM. Upon Ir6 treatment, a time-dependent increase in viscosity and heterogeneity is observed along with the loss of membrane potential in mitochondria. In summary, our work shows that multifunctional phosphorescent metal complexes can induce and precisely detect microenvironmental changes simultaneously at the subcellular level using TPPLIM, which may deepen the understanding of the cell death mechanisms induced by these metallocompounds.
RESUMO
Nano-drug delivery systems with multi-modality imaging capacities are worth pursuing because they integrate diagnostic and therapeutic functions. Herein, we report the design, synthesis and evaluation of modified iridium sulfide (IrSx) nanoparticles (NPs) for cancer therapy in vitro and in vivo. This nanosystem was prepared by modifying IrSx with polyethylene glycol (PEG) conjugated to the targeting ligand folate (FA) for multimodal imaging-guided combined chemo-photothermal therapy. Upon PEG modification, the small IrSx NPs (about 4 nm) self-assembled into much larger (about 120 nm) IrSx-PEG-FA NPs, which exhibited high photostability, ideal photothermal effect, high drug loading and pH-/photothermal-responsive drug release properties. By using the model anticancer drug camptothecin (CPT), we demonstrated that CPT@IrSx-PEG-FA can effectively target FA-receptor-positive cancer cells in vitro and show efficient tumor accumulation in vivo. The combination of CPT@IrSx-PEG-FA treatment and irradiation with an 808 nm laser resulted in complete tumor elimination. Moreover, photothermal/photoacoustic (PA)/computed tomography (CT) imaging provided an effective means to monitor the therapeutic effects. Interestingly, the nanoparticles can be cleared, resulting in low systematic toxicity of CPT@IrSx-PEG-FA. Our work demonstrates that the as-prepared IrSx-PEG-FA NPs present a promising platform for the construction of multifunctional theranostic agents for cancer therapy.
Assuntos
Camptotecina/administração & dosagem , Receptor 1 de Folato/química , Nanopartículas/química , Fototerapia , Polietilenoglicóis/química , Animais , Antineoplásicos/administração & dosagem , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ácido Fólico , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Hipertermia Induzida , Irídio , Células MCF-7 , Camundongos , Imagem Multimodal , Nanopartículas/uso terapêutico , Técnicas Fotoacústicas , Sulfetos , Nanomedicina Teranóstica , Tomografia Computadorizada por Raios XRESUMO
Recently, phosphorescent iridium complexes have demonstrated great potential as anticancer and imaging agents. Dopamine is a melanin-like mimic of mussel adhesive protein that can self-polymerize to form polydopamine (PDA) nanoparticles that demonstrate favorable biocompatibility, near-infrared absorption, and photothermal effects. Herein, PDA nanoparticles are functionalized with ß-cyclodextrin (CD) substitutions, which are further assembled with adamantane-modified arginine-glycine-aspartic acid (Ad-RGD) tripeptides to target integrin-rich tumor cells. The thus formed PDA-CD-RGD nanoparticles can deliver a phosphorescent iridium(III) complexes LysoIr ([Ir(ppy)2(l)]PF6, ppy = 2-phenylpyridine, L = (1-(2-quinolinyl)-ß-carboline) to form a theranostic platform LysoIr@PDA-CD-RGD. It is demonstrated that LysoIr@PDA-CD-RGD can be applied for targeted combined cancer photothermal-chemotherapy and thermal/photoacoustic/two-photon phosphorescence lifetime imaging under both in vitro and in vivo conditions. This work provides a useful strategy to construct multifunctional nanocomposites for the optimization of metal-based anticancer agents for further biomedical applications.