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1.
Biochem Pharmacol ; 175: 113848, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32044354

RESUMO

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.

2.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302589

RESUMO

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Dicetopiperazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Chem Sci ; 10(11): 3315-3323, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30996918

RESUMO

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.

4.
J Med Chem ; 62(7): 3311-3322, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30816710

RESUMO

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.

5.
Dalton Trans ; 48(13): 4398-4404, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30864598

RESUMO

Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing ß-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carbolinas/farmacologia , Complexos de Coordenação/farmacologia , Lisossomos/efeitos dos fármacos , Rênio/química , Células A549 , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carbolinas/síntese química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Complexos de Coordenação/síntese química , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Camundongos Nus , Relação Estrutura-Atividade
6.
Chemistry ; 25(28): 7012-7022, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-30913329

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/métodos
7.
ACS Appl Mater Interfaces ; 11(14): 13123-13133, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30888144

RESUMO

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 Xenoenxerto
8.
Chem Sci ; 10(5): 1285-1293, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30809342

RESUMO

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.

9.
Nanoscale ; 10(47): 22252-22262, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30465053

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 X
10.
Adv Sci (Weinh) ; 5(10): 1800581, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30356964

RESUMO

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.

11.
Chemistry ; 24(71): 18971-18980, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30264929

RESUMO

Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip)2 (µ-bpm)PtCl2 ]Cl2 (RuPt; dip=4,7-diphenyl-1,10-phenanthroline; bpm=2,2'-bipyrimidine) and the corresponding mononuclear complex [Ru(dip)2 (bpm)]Cl2 (Ru) have been designed and synthesized. RuPt can bind to mtDNA and damage it both in the dark and upon visible light irradiation. By using a variety of methods, it was demonstrated that RuPt can interfere with the function of mtDNA by decreasing the amplification and copy number of mtDNA, and affecting the transcriptional level of mitochondria-encoded genes. Furthermore, RuPt can disturb the physiological processes of mitochondria and induce caspase-dependent apoptosis in the presence of light. In addition, RuPt shows low systemic toxicity and potent in vivo anticancer potency upon light irradiation. This study provides strong evidence that mtDNA is an important molecular target of RuPt, and photodamaging mtDNA is an effective strategy to overcome cisplatin resistance.


Assuntos
Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/genética , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Neoplasias/genética , Compostos Organoplatínicos/química , Fenantrolinas/química , Fenantrolinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Pirimidinas/química , Pirimidinas/farmacologia , Rutênio/química
12.
Dalton Trans ; 47(20): 6942-6953, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29721561

RESUMO

The development of iridium complexes as potent anticancer agents has received increasing attention in recent years. In this study, four cyclometalated Ir(iii) complexes with good photophysical properties and potent anticancer activity have been synthesized and characterized. They are taken up by human lung adenocarcinoma A549 cells very quickly and specifically target mitochondria. Mechanism studies reveal that one of them, namely IrM2, induces paraptosis accompanied by excessive mitochondria-derived cytoplasmic vacuoles. Meanwhile, IrM2 affects the ubiquitin-proteasome system (UPS) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, IrM2 rapidly induces a series of mitochondria-related dysfunctional events, including the loss of mitochondrial membrane potential, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The rapid loss of mitochondrial functions, elevation of ROS and impairment of the UPS induced by IrM2 lead to the collapse of mitochondria and the subsequent cytoplasmic vacuolation before the cells are ready to start the mechanisms of apoptosis and/or autophagy. Among the ROS, superoxide anion radicals play a critical role in IrM2-mediated cell death. In vivo studies reveal that IrM2 can significantly inhibit tumor growth in a mouse model. This work gives useful insights into the design and anticancer mechanisms of new metal-based anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Células HeLa , Humanos , Irídio/química , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina/metabolismo , Vacúolos/metabolismo
13.
Chem Commun (Camb) ; 54(21): 2635-2638, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29469156

RESUMO

Two cationic molecular rotors, 1 and 2, capable of real-time cell-cycle imaging by specifically dynamic monitoring of nucleolus and chromosome changes were developed. A further study shows that fluorescence enhancements in the nucleolus and chromosome are attributed to a combination effect of interaction with nucleic acid and high condensation of the nucleolus and chromosome.


Assuntos
Ciclo Celular , Nucléolo Celular/metabolismo , Cromossomos/metabolismo , Corantes Fluorescentes/química , Imagem Óptica , Nucléolo Celular/química , Cromossomos/química , Células HeLa , Humanos , Estrutura Molecular , Fatores de Tempo
14.
J Biomater Appl ; 32(9): 1253-1264, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29448866

RESUMO

A multimodal nanocarrier based on mesoporous silica nanoparticles (MSNs) is developed to co-delivery photosensitizer chlorin e6 (Ce6) and chemotherapeutic agent doxorubicin (Dox) for cancer combination therapy. Ce6 was covalently conjugated with mesoporous silica nanoparticles, which could increase the loading efficiency, and allowed for photodynamic therapy. Doxorubicin was loaded into the pores of mesoporous silica nanoparticles to afford the dual drug delivery system Dox@MSNs-Ce6. These hybrid nanoparticles have an average diameter of about 100 nm and slightly negative charge of about -17 mV. The Dox@MSNs-Ce6 nanoparticles could efficiently enter into cancer cells. The cellular reactive oxygen species level in treated cells increased about 17 times, upon 660 nm light irradiation (10 mW/cm2, 2 min). More importantly, Dox@MSNs-Ce6 exhibited excellent synergistic effect through combining chemotherapy and photodynamic therapy against A549 lung cancer cells. Our work provides an effective strategy for anticancer drug delivery and combination therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Dióxido de Silício/química , Células A549 , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Nanoconjugados/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porosidade , Porfirinas/farmacocinética , Porfirinas/farmacologia
15.
ACS Appl Mater Interfaces ; 9(49): 42471-42481, 2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29140069

RESUMO

Four phosphorescent cyclometalated iridium(III) complexes containing benzimidazole moiety have been designed and synthesized. These Ir(III) complexes can effectively inhibit several cancerous processes, including cell migration, invasion, colony formation, and angiogenesis. Interestingly, they show a much higher singlet oxygen quantum yield in an acidic solution than in a neutral solution. Upon irradiation at 425 nm with low energy (1.2 J cm-2), they can induce apoptosis through lysosomal damage, evaluation of reactive oxygen species level, and activation of caspase-3/7. The highest phototoxicity index is >476, with almost no dark cytotoxicity observed for Ir4. Ir4 can also inhibit tumor growth effectively in nude mice in vivo after photodynamic therapy. An in vitro assay against 70 kinases indicates that maternal embryonic leucine zipper kinase (MELK), PIK3CA, and AMPK are the possible molecular targets. The half maximal inhibitory concentration of Ir4 toward MELK is 1.27 µM. Our study demonstrates that these Ir(III) complexes are promising anticancer agents with dual functions, including metastasis inhibition and lysosome-damaged photodynamic therapy.


Assuntos
Irídio/química , Animais , Complexos de Coordenação , Células HeLa , Humanos , Lisossomos , Camundongos , Camundongos Nus , Fotoquimioterapia
16.
Nanoscale ; 9(47): 18966-18976, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29181479

RESUMO

Nanohybrids can in most cases kill cancer cells more efficiently as compared with free photosensitizers. In this work, we constructed nanohybrid Ru1@CDs composed of carbon nanodots (CDs) and a phosphorescent Ru(ii) complex (Ru1) for one- and two-photon photodynamic therapy of cancer. The photosensitizer and imaging agent Ru1 is decorated onto the nanocarrier CDs covalently. Ru1 and Ru1@CDs can penetrate into cancer cells through an energy-dependent mechanism and endocytosis, respectively. Both Ru1 and Ru1@CDs are capable of lysosome-targeted phosphorescence imaging and photodamage under either 450 nm (one-photon) or 810 nm (two-photon) excitation. Conjugation with CDs can increase the cellular uptake efficacy of Ru1. Mechanism investigations show that both Ru1 and Ru1@CDs can induce apoptosis through generation of reactive oxygen species and cathepsin-initiated apoptotic signaling pathways. Upon two-photon excitation, Ru1@CDs show better penetrability, as well as higher inhibitory effects on cancer cell growth in both 2D cell and 3D multicellular tumor spheroid models. Our work provides an effective strategy for the construction of multifunctional imaging and phototherapeutic nanohybrids for the treatment of cancer.


Assuntos
Carbono , Lisossomos , Nanoestruturas , Fotoquimioterapia , Rutênio/química , Células A549 , Animais , Apoptose , Complexos de Coordenação , Embrião não Mamífero , Endocitose , Humanos , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares , Peixe-Zebra
17.
Dalton Trans ; 46(39): 13482-13491, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28951916

RESUMO

Organometallic iridium complexes have emerged as potent anticancer agents in recent years. In this work, three cyclometalated iridium(iii) complexes Ir1-Ir3 containing monodentate five-membered heterocyclic ligands have been synthesized and characterized. Upon visible light (425 nm) irradiation, the five-membered heterocyclic ligands will dissociate from the metal centre. Moreover, Ir1-Ir3 can also act as effective singlet oxygen photosensitizers. Thus, Ir1-Ir3 can exert their light-mediated activation of anticancer effects by dual modes including ligand exchange reactions and generation of singlet oxygen (1O2) upon visible light irradiation. Notably, Ir1 displays a high phototoxicity index of 61.7 against human cancer cells. Further studies show that light-mediated anticancer properties exerted by Ir1-Ir3 occur through reactive oxygen species (ROS) generation, caspase activation, and eventually apoptosis induction. Our study demonstrates that these complexes can act as novel dual-mode light-mediated anticancer agents.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Compostos Heterocíclicos/química , Irídio/química , Fármacos Fotossensibilizantes/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Luz , Microscopia Confocal , Conformação Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/metabolismo
18.
Dalton Trans ; 46(34): 11395-11407, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28813052

RESUMO

Many phosphorescent iridium complexes are potent candidates as photodynamic therapeutic agents. In this work, a series of mixed-ligand phosphorescent iridium complexes (Ir1: [Ir(L1)(bpy)Cl](PF6)2; Ir2: [Ir(L1)(ppy)Cl](PF6); Ir3: [Ir(L2)(bpy)Cl](PF6)2; Ir4: [Ir(L2)(ppy)Cl](PF6). L1 = 2,6-bis(2-benzimidazolyl)pyridine; bpy = 2,2'-bipyridine; L2 = 2,6-bis(1-methyl-benzimidazol-2-yl)pyridine; ppy = 2-phenylpyridine) have been synthesized and characterized. These complexes display high luminescence quantum yields and long phosphorescence lifetimes. All the complexes are resistant to hydrolysis in aqueous solutions, and can produce singlet oxygen (1O2) effectively upon irradiation. Ir1 and Ir2 show pH-sensitive emission properties. Interestingly, higher cellular uptake efficiency is observed for Ir2 and Ir4 with the cyclometalated ppy ligand in human lung adenocarcinoma A549 cells. Ir2 with pH-sensitive emission properties can selectively image lysosomes, and Ir4 can specifically target mitochondria. Both Ir2 and Ir4 exhibit potent photodynamic therapy (PDT) effects, with Ir2 displaying a higher phototoxicity index (PI) especially in A549 cells (PI > 54). Mechanism studies indicate that Ir2 and Ir4 can induce apoptosis through reactive oxygen species (ROS) generation and caspase activation upon visible light (425 nm) irradiation. As expected, Ir2 can damage lysosomes more effectively with a pH-sensitive singlet oxygen (1O2) yield, while Ir4 tends to impair mitochondrial function. Nevertheless, the practical application of Ir2 and Ir4 for PDT may be limited to superficial tumors due to the short excitation wavelength (425 nm). Our study gives insights into the design and anticancer mechanisms of new metal-based PDT anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Irídio/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Transporte Biológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Espaço Intracelular/efeitos da radiação , Ligantes , Lisossomos/efeitos dos fármacos , Lisossomos/efeitos da radiação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/efeitos da radiação , Compostos Organometálicos/síntese química , Compostos Organometálicos/metabolismo , Oxigênio Singlete/metabolismo , Água/química
19.
Chemistry ; 23(60): 15166-15176, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28833658

RESUMO

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1 a-3 a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death-related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.


Assuntos
Antineoplásicos/toxicidade , Complexos de Coordenação/química , Irídio/química , Mitocôndrias/efeitos dos fármacos , Ácido Valproico/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cisplatino/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Humanos , Microscopia de Fluorescência por Excitação Multifotônica , Conformação Molecular , Espécies Reativas de Oxigênio/metabolismo
20.
ACS Appl Mater Interfaces ; 9(15): 13304-13314, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28345337

RESUMO

Phosphorescent Ir(III) complexes are expected to be new multifunctional theranostic platforms that enable the integration of imaging capabilities and anticancer properties. Mitophagy is an important selective autophagic process that degrades dysfunctional mitochondria. Until now, the regulation of mitophagy is still poorly understood. Herein, we present two phosphorescent cyclometalated iridium(III) complexes (Ir1 and Ir2) that can accumulate in mitochondria and induce mitophagy. Because of their intrinsic phosphorescence, they can specially image mitochondria and track mitochondrial morphological alterations. Mechanism studies show that Ir1 and Ir2 induce mitophagy by depolarization of mitochondrial membrane potential, depletion of cellular ATP, perturbation in mitochondrial metabolic status, and induction of oxidative stress. Moreover, no sign of apoptosis is observed in Ir1- and Ir2-treated cells under the same conditions that an obvious mitophagic response is initiated. We demonstrate that Ir1 is a promising theranostic agent that can induce mitophagy and visualize changes in mitochondrial morphology simultaneously.

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