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1.
Chem Commun (Camb) ; 57(72): 9100-9103, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498645

RESUMO

A rigid hemicyanine CSZ-J and a flexible molecule ESZ-J were synthesized. In particular, the conformationally restrained CSZ-J had higher fluorescence quantum yields, longer fluorescence lifetimes and higher triplet state quantum yields. CSZ-J could generate highly cytotoxic ROS simultaneously via type I and type II processes. This will contribute to the design and development of new photosensitizers in the future.


Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/química , Carbocianinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Conformação Molecular , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo
2.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299628

RESUMO

We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg)6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology.


Assuntos
Corantes Fluorescentes , Imagem Molecular , Peptidomiméticos , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-pim-1 , Carbocianinas/química , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo
3.
Angew Chem Int Ed Engl ; 60(41): 22441-22446, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34293228

RESUMO

Precise control of blood clotting and rapid reversal of anticoagulation are essential in many clinical situations. We were successful in modifying a thrombin-binding aptamer with a red-light photocleavable linker derived from Cy7 by Cu-catalyzed Click chemistry. We were able to show that we can successfully deactivate the modified aptamer with red light (660 nm) even in human blood-restoring the blood's natural coagulation capability.


Assuntos
Anticoagulantes/farmacologia , Benzotiazóis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Carbocianinas/farmacologia , Luz , Anticoagulantes/química , Benzotiazóis/química , Carbocianinas/química , Humanos , Estrutura Molecular
4.
Oncol Rep ; 45(3): 1306-1314, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650669

RESUMO

Non­small cell lung cancer (NSCLC) remains an intractable disease, which is primarily due to tumor metastasis and the acquisition of resistance to chemotherapy. Therefore, there is an urgent need for novel therapeutics to overcome these obstacles. It was recently demonstrated that upregulated expression of monoamine oxidase A (MAOA) contributes to the progression of NSCLC. G10, a tumor­targeting representative conjugate of heptamethine carbocyanine dye and an inhibitor of MAOA, was shown to exert potent cytotoxic effects, comparable to those of doxorubicin, against prostate cancer cell lines, as well as moderate MAOA inhibitory activity. The research described herein aimed to extend our previous study on the antitumor function of G10 in NSCLC in vitro and in vivo, and to elucidate the mechanisms through which G10 exerts its antineoplastic effects. G10 markedly inhibited the proliferation of paclitaxel­resistant NSCLC cells (H460/PTX) and reduced tumor cell migration and invasion. Gene expression profiling of paclitaxel­resistant NSCLC cells following treatment with G10 demonstrated that the expression of genes associated with the extracellular matrix was significantly affected, particularly the metastasis­related genes matrix metallopeptidase (MMP)2, MMP14 and COL6A, which exhibited notably reduced expression. Additionally, the results also demonstrated that MAOA­related pathways, including AKT and hypoxia­inducible factor­1α, were also inhibited by G10 treatment and, subsequently, the downstream molecules of these pathways, such as p21, MMP2 and vascular endothelial growth factor, were also downregulated, highlighting a possible mechanism through which G10 suppresses tumor cell migration, invasion and proliferation. Importantly, in mouse NSCLC xenografts, combined treatment with G10 and paclitaxel resulted in pronounced inhibition of tumor growth. Taken together, the results of the present study highlight the potential of G10 as a novel therapeutic targeting MAOA in paclitaxel­resistant NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carbocianinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Paclitaxel/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbocianinas/química , Carbocianinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Paclitaxel/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Mater Chem B ; 9(11): 2688-2696, 2021 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-33667292

RESUMO

Due to the hydrophobicity of the cyanine dye and the huge conjugated plane, the cyanine dye is prone to H-aggregation in aqueous solution, and the ultraviolet absorption is blue-shifted. Here, a hydrophilic quaternary stereo-specific cyanine (HQS-Cy) dye has been synthesized and polypeptide based nanoparticles have been prepared, which improve the water solubility of the cyanine in two aspects. First, at the molecular level, the sulfonic acid group increases the water solubility of the dye molecule while the dimethyl-ammonium functional group repels the molecule through the charge-charge interaction, destroying the planar characteristics of the cyanine structure, increasing the molecular distance between the dye molecules, and preventing the accumulation of cyanine. Secondly, at the nano-micelle level, the use of amphiphilic polypeptide blocks to encapsulate the dye increases the water solubility of the dye while also increasing its biocompatibility. The HQS-Cy@P NPs prepared by the above methods exhibit the maximum absorption at 985 nm and maximum fluorescence emission at 1050 nm in aqueous solution. HQS-Cy@P exhibits good photothermal stability and significant photothermal conversion efficiency of about 35.5%, and both in vitro and in vivo studies revealed that it is an efficient system for NIR-II imaging-guided photothermal therapy of cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbocianinas/farmacologia , Corantes/farmacologia , Terapia Fototérmica , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Raios Infravermelhos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Imagem Óptica , Solubilidade , Neoplasias do Colo do Útero/diagnóstico por imagem
6.
J Photochem Photobiol B ; 217: 112171, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33711563

RESUMO

Dual phototherapy agents have attracted great interest in recent years as they offer enhanced cytotoxicity on cancer cells due to the synergistic effect of photodynamic and photothermal therapies (PDT/PTT). In this study, we demonstrate a brominated hemicyanine (HC-1), which is previously shown as mitochondria targeting PDT agent, can also serve as an effective photosensitizer for PTT for the first time under a single (640 nm or 808 nm) and dual laser (640 nm + 808 nm) irradiation. Generation of reactive oxygen species and photothermal conversion as a function of irradiation wavelength and power were studied. Both single wavelength irradiations caused significant phototoxicity in colon and cervical cancer cells after 5 min of irradiation. However, co-irradiation provided near-complete elimination of cancer cells due to synergistic action. This work introduces an easily accessible small molecule-based synergistic phototherapy agent, which holds a great promise towards the realization of local, rapid and highly efficient treatment modalities against cancer.


Assuntos
Apoptose/efeitos dos fármacos , Carbocianinas/farmacologia , Lasers , Fármacos Fotossensibilizantes/farmacologia , Apoptose/efeitos da radiação , Carbocianinas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citometria de Fluxo , Humanos , Neoplasias/patologia , Neoplasias/terapia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo
7.
J Med Chem ; 64(7): 4020-4033, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33745280

RESUMO

Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (20-Cy5.5) that retained desirable class I HDAC affinity and selectivity. Then, this probe could visualize epigenetic changes by class I HDACs in TNBC MDA-MB-231 cells and in xenograft tumor models in real time. Treatment with suberoylanilide hydroxamic acid (SAHA) significantly reduced the uptake of the probe in tumors, suggesting its potential use in evaluation of therapeutic responses of HDACi-mediated therapy. Moreover, 20-Cy5.5 could detect class I HDAC expression in TNBC lung metastasis. This novel NIR probe that achieves tumor class I HDAC imaging not only leads to a better understanding of epigenetic regulation in tumors but also has great potential for improving the TNBC diagnosis and treatment.


Assuntos
Carbocianinas/farmacologia , Depsipeptídeos/farmacologia , Epigênese Genética/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carbocianinas/síntese química , Linhagem Celular Tumoral , Depsipeptídeos/síntese química , Feminino , Fluorometria , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos/metabolismo , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/análise , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Nus , Neoplasias de Mama Triplo Negativas/patologia , Vorinostat/farmacologia
8.
J Orthop Res ; 39(4): 821-830, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33107629

RESUMO

γ-Tilmanocept (99m Tc-tilmanocept) is a receptor-directed, radiolabeled tracer that is FDA-approved for guiding sentinel lymph node biopsy. Tilmanocept binds the C-type lectin mannose receptor (MR, CD206) on macrophages. In this study, nonradioactive, fluorescently-labeled Cy3-tilmanocept was used to detect CD206+ mononuclear cells in the cartilage of mice with antibody-induced arthritis and in the synovial fluid and tissue of human subjects with rheumatoid arthritis (RA) for comparison with osteoarthritis (OA), and healthy volunteer (HV) controls. Murine arthritis was induced by injection of monoclonal anti-cartilage antibody followed by injection of Escherichia coli lipopolysaccharide. Post-arthritis development (7-11 days), the mice were injected intravenously with Cy3-tilmanocept followed by in vivo and ex vivo epifluorescence imaging. Two-photon imaging, immunofluorescence, and immunohistochemistry were used to identify articular and synovial macrophages (CD206, F4/80, and Cy3-tilmanocept binding) in murine tissues. Cy3-tilmanocept epifluorescence was present in arthritic knees and elbows of murine tissues; no radiographic changes were noted in the skeletons. However, inflammatory arthritic changes were apparent by histopathology and immunohistochemistry (F4/80), immunofluorescence (CD206) and Cy3-tilmanocept binding. In human RA synovial fluid, Cy3-tilmanocept staining correlated with CD206+ /CD16+ cells; negligible labeling was observed in OA samples. Cy3-tilmanocept colocalized with CD206 and staining was significantly higher in RA synovial tissue compared to OA or HV. Our results demonstrate that imaging with Cy3-tilmanocept can detect in vivo inflammatory, CD206+ macrophages in an early arthritis animal model and in human RA patients. These data establish a novel tool for preclinical research of early arthritis and have implications for early RA detection and monitoring of therapeutic efficacy in humans.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Articulações/diagnóstico por imagem , Macrófagos/imunologia , Membrana Sinovial/diagnóstico por imagem , Animais , Anticorpos Monoclonais , Artrite Reumatoide/imunologia , Carbocianinas/farmacologia , Dextranos/química , Escherichia coli/metabolismo , Voluntários Saudáveis , Humanos , Inflamação , Articulações/imunologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/imunologia , Lectinas Tipo C/química , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/química , Masculino , Mananas/química , Lectinas de Ligação a Manose/química , Camundongos , Camundongos Endogâmicos DBA , Microscopia de Fluorescência , Osteoartrite/diagnóstico por imagem , Osteoartrite/imunologia , Fótons , Receptores de Superfície Celular/química , Membrana Sinovial/imunologia , Tecnécio/química , Pentetato de Tecnécio Tc 99m/análogos & derivados , Pentetato de Tecnécio Tc 99m/química
9.
Arch Pharm (Weinheim) ; 354(3): e2000186, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33169870

RESUMO

In this study, some novel cyanine dyes, 1, 3, and 5-15, were synthesized by a one-pot step reaction of pyridinium salts 2 and/or 4 with benzenaminium salt 1. N-{[1-Chloro-3,4-dihydronaphthalen-2-yl)methylene]benzenaminium} chloride 1 was obtained by the reaction of α-tetralone with Vilsmeier-Haack reagent, followed by a mixture of an equimolar ratio of anilin/ethanol (1:1). All new cyanine dyes were evaluated in vitro for their anticancer activity against two cell lines, that is, HepG2 (human hepatocellular liver carcinoma) and MCF-7 (breast cancer). The obtained results were compared with human lung fibroblasts (WI-38) and Vero cells (derived from the kidney of an African green monkey) as normal cells. In particular, some of these compounds, 6, 9, 13, and 14, were found to be the most potent derivatives against all the cancer cell lines, without effect on the normal cells. According to the structure-activity relationship, compound 13 (IC50 = 8.8 µg/ml) exhibited a higher activity against HepG2 cells, as it contains the azo group and two phenyl rings and due to the presence of the π-conjugated system attached to the two pyridine rings. Compound 6 (IC50 = 8 µg/ml) exhibited a higher activity against MCF-7 cells, as it contains two chlorine atoms and the π-conjugated system of the pyridine rings.


Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
10.
J Mater Chem B ; 9(3): 857-863, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33367439

RESUMO

A near-infrared fluorescent probe (AH+) has been prepared by incorporating an oxazolidine switch into a near-infrared hemicyanine dye. The probe shows fast and sensitive responses to pH from an oxazolidine switch to the hemicyanine dye upon pH decreases from 10.0 to 5.0. The probe shows good photostability, low cytotoxicity, and reversible fluorescence responses to pH changes with a pKa value of 7.6. It has been successfully used to determine pH changes in mitochondria.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Oxazóis/química , Carbocianinas/síntese química , Carbocianinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Oxazóis/farmacologia , Tamanho da Partícula , Espectrometria de Fluorescência , Propriedades de Superfície
11.
Bioorg Chem ; 104: 104196, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911188

RESUMO

The core of the tau fibrils in Alzheimer disease is a hexapeptide sequence organized in paired helical filaments (PHF). This sequence AcPHF6 can be used as tau fibrils model for the fast screening of potential therapeutic inhibitors of fibril formation or their disruption. The assay is usually performed by monitoring the fluorescence increase of Thioflavin T (ThT), well-known reporter dye for fibrillation. However, the ThT assay is not faultless, and here we present novel fluorescent dye, cyanine attached to amino acid side-chain (Cy-aa) that shows several advantages over ThT. The fibrillation kinetics of AcPHF6 was monitored via Cy-aa at twenty times lower concentration compared to ThT and successfully reported the presence of fibrillation inhibitor by Cy-aa fluorescence decrease. Additionally, spectral properties of Cy-aa are red-shifted in comparison to ThT allowing screening of a wider range of potential fibrillation inhibitors. Moreover, in the mixture with the pre-formed fibrils, Cy-aa shows strong fluorescence light-up proportional to fibrils concentration. We also successfully coupled this fluorescent amino acid to PHF in order to completely avoid the possibility of dye displacement with screening compound, and this newly designed conjugate showed to be a reliable intrinsic fluorescent probe for monitoring fibrillation kinetics of amyloid peptides.


Assuntos
Doença de Alzheimer/diagnóstico , Aminoácidos/química , Peptídeos beta-Amiloides/análise , Carbocianinas/química , Corantes Fluorescentes/química , Doença de Alzheimer/tratamento farmacológico , Aminoácidos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/farmacologia , Carbocianinas/farmacologia , Fluorescência , Corantes Fluorescentes/farmacologia , Humanos , Cinética , Estrutura Molecular
12.
Bioconjug Chem ; 31(7): 1724-1739, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32530288

RESUMO

This review covers the application of heptamethine cyanine dye (HMCD) mediated drug delivery. A relatively small number of HMCDs possess tumor targeting abilities, and this has spurred interest from research groups to explore them as drug delivery systems. Their tumor selectivity is primarily attributed to their uptake by certain isoforms of organic anion transporting polypeptides (OATPs) which are overexpressed in cancer tissues, although there are other possible mechanisms for the observed selectivity still under investigation. This specificity is confirmed using various cancer cell lines and is accompanied by moderate cytotoxicity. Their retention in tumor tissue is facilitated by the formation of albumin adducts as revealed by published mechanistic studies. HMCDs are also organelle selective dyes with specificity toward mitochondria and lysosomes, and with absorption and emission in the near-infrared region. This makes them valuable tools for biomedical imaging, especially in the field of fluorescence-guided tumor surgery. Furthermore, conjugating antitumor agents to HMCDs is providing novel drugs that await clinical testing. HMCD development as theranostic agents with dual tumor targeting and treatment capability signals a new approach to overcome drug resistance (mediated through evasion of efflux pumps) and systemic toxicity, the two parameters which have long plagued drug discovery.


Assuntos
Antineoplásicos/administração & dosagem , Carbocianinas/administração & dosagem , Corantes/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológico , Carbocianinas/farmacologia , Carbocianinas/uso terapêutico , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Medicina de Precisão , Neoplasias da Próstata/tratamento farmacológico
13.
Bioorg Med Chem Lett ; 30(14): 127252, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527552

RESUMO

We describe the synthesis and in vitro activity of drug-dye conjugate 1, which is a combination of the PARP inhibitor rucaparib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed strong cytotoxic activity with nanomolar potency (EC50: 128 nM), which was a 780 fold improvement over rucaparib itself. We also observe a synergistic effect of 1 with temozolomide (TMZ), the standard drug for treatment for glioblastoma even though these cell lines were resistant to TMZ treatment. We envisage such conjugates to be worth exploring for their utility in the treatment of various brain cancers.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Carbocianinas/farmacologia , Glioblastoma/tratamento farmacológico , Indóis/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carbocianinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Indóis/química , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Relação Estrutura-Atividade
14.
ACS Appl Mater Interfaces ; 12(29): 32388-32396, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32597630

RESUMO

Organic small-molecule-based photothermal agents such as cyanine dyes have received increasing attention in developing novel cancer therapies with potential clinical utility but suffer from poor stability, low photothermal efficiency, and limited accumulation at tumor sites in molecular forms. Self-assembly of small-molecule dyes into supramolecular assemblies may address these concerns by controlling the molecular organization of dye monomers to form structures of a higher order. Among them, H-aggregates of dyes favor face-to-face contacts with strongly overlapping areas, which always have a negative connotation to exhibit low or no fluorescence in most cases but may emanate energy in nonradiative forms such as heat for photothermal cancer therapy applications. Here, the synergistic self-assembly of cyanine dyes into H-aggregates is developed as a new supramolecular strategy to fabricate small-molecule-based photothermal nanomaterials. Compared to the free cyanine dyes, the H-aggregates assembled from pyrene or tetraphenylethene (TPE) conjugating cyanine exhibit the expected absorption spectral blue shift and fluorescence self-quenching but unique photothermal properties. Remarkably, the obtained H-aggregates are saucer-shaped nanoparticles that exhibit passive tumor-targeting properties to induce imaging-guided photothermal tumor ablation under irradiation. This supramolecular strategy presented herein may open up new opportunities for constructing next-generation small-molecule-based self-assembly nanomaterials for PTT cancer therapy in clinics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbocianinas/farmacologia , Corantes Fluorescentes/farmacologia , Pirenos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Estilbenos/farmacologia , Animais , Antineoplásicos/química , Carbocianinas/química , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/química , Camundongos , Camundongos Nus , Tamanho da Partícula , Terapia Fototérmica , Pirenos/química , Bibliotecas de Moléculas Pequenas/química , Estilbenos/química , Propriedades de Superfície
15.
Photodiagnosis Photodyn Ther ; 30: 101775, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32330609

RESUMO

Photodynamic therapy (PDT) is currently one of the cancer treatment options. PDT requires the application of a photosensitizer (such as: porphyrins, chlorines, and phthalocyanines) that selectively targets malignant cells. It is a dilemma to find a proper photosensitizer. In our study, we have tested a new in-vitro group of cyanine dyes. These dyes are widely applied in biotechnology as fluorescent markers. Two malignant adenocarcinoma cell lines (MCF-7/WT and MCF-7/DOX) were investigated using photodynamic reaction (PDR) with four cyanine dyes (KF-570, HM-118, FBF-749, and ER-139). KF-570 and HM-118 were irradiated with red light (630 nm), whereas FBF-749 and ER-139 with green light (435 nm). To evaluate PDR efficiency, a clonogenic test was conducted. Apoptosis was investigated by TUNEL and NCA (neutral comet) assays. Proteins selected as indicators of the apoptotic pathway (AIF, sPLA2, Smac/Diablo) and intracellular response markers (SOD-1 and GST-pi) were detected using western blot. The highest number of apoptotic cells (ca. 100%) was observed after PDR with HM-118 and KF-570 in both conducted tests, in both cell lines. The results showed that HM-118 and KF-570 cyanine dyes demonstrated a major phototoxic effect causing apoptosis in doxorubicin-resistant and sensitive cell lines.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Carbocianinas/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Células MCF-7
16.
Nanoscale ; 12(20): 11008-11025, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32301458

RESUMO

Photodynamic therapy (PDT), as one of the most powerful photo-therapeutic strategies for cancer treatment with minimum invasiveness, can effectively damage local tumor cells and significantly induce systemic antitumor immunity. However, current nanotechnology-assisted PDT-immunomodulators have either poor penetration for deep tumors or low singlet oxygen generation. Herein, we construct a novel theranostic nanocarrier (HA-PEG-CyI, HPC) by inducing the self-assembly of PEGylated CyI and attaching the ligand HA to its surface. The prepared HPC can be used as an ideal PDT-immunomodulator for synergistic cancer therapy. CyI is an iodinated-cyanine dye with enhanced singlet oxygen generation ability as well as excellent photo-to-photothermal and near-infrared fluorescence imaging properties. Under 808 nm laser irradiation, the prepared HPC can generate both reactive oxygen species (ROS) and elevate temperature which can subsequently result in apoptosis and necrosis at tumor sites. Moreover, the HPC-induced cell death can generate a series of acute inflammatory reactions, leading to systemic immunity induction and secondary death of tumor cells, which further results in reducing tumor recurrence. In vitro and in vivo results show that HPC can enhance the tumor targeting efficacy, generate ROS efficiently and exhibit a high temperature response under NIR irradiation, which working together can activate immune responses for synergistic phototherapy on tumor cells. Accordingly, the proposed multi-functional HPC nanocarriers represent an important advance in PDT and can be used as a superior cancer treatment strategy with great promise for clinical applications.


Assuntos
Carbocianinas , Portadores de Fármacos , Hidrocarbonetos Iodados , Fatores Imunológicos , Nanoestruturas , Neoplasias Experimentais , Fotoquimioterapia , Animais , Apoptose/efeitos dos fármacos , Carbocianinas/química , Carbocianinas/farmacocinética , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Feminino , Humanos , Hidrocarbonetos Iodados/química , Hidrocarbonetos Iodados/farmacocinética , Hidrocarbonetos Iodados/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Células RAW 264.7
17.
Anal Chem ; 92(10): 6977-6983, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32314575

RESUMO

Mitochondria plays pivotal roles in energy production and apoptotic pathways. Mitochondria-targeting strategy has been recognized as a promising way for cancer theranostics. Thus, spatiotemporally manipulating the prolonged retention of theranostic agents within mitochondria is considerably significant in cancer diagnosis and therapy. Herein, as a proof-of concept, we for the first time report a sulfenic acid-responsive platform on controlled immobilization of probes within mitochondria for prolonged tumor imaging. A novel near-infrared (NIR) probe DATC constructed with a NIR dye (Cy5) as signal unit, a cationic triphenylphosphonium (TPP) for mitochondria targeting, and a sulfenic acid-reactive group (1,3-cyclohexanedione) for mitochondrial fixation was rationally designed and synthesized. This probe displayed good target ability to mitochondria and could act as a promising fluorescent probe for specific visualization of endogenous protein sulfenic acids expressed in the mitochondria. Moreover, the probe could be spontaneously fixed on site through the specific reaction and covalent binding to the sulfenic acids of oxidized proteins under oxidative stress, resulting in enhanced intracellular uptake and prolonged retention. We thus believe that this mitochondria-targeted and locational immobilization strategy may offer a new insight for long-term tumor imaging and effective therapy.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carbocianinas/química , Corantes Fluorescentes/química , Mitocôndrias/química , Ácidos Sulfênicos/química , Células 3T3 , Animais , Carbocianinas/metabolismo , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/farmacologia , Raios Infravermelhos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Imagem Óptica , Ácidos Sulfênicos/metabolismo
18.
Biomater Sci ; 8(8): 2111-2119, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31967117

RESUMO

Gram-negative bacteria are a significant cause of infections acquired in both hospital and community settings, resulting in a high mortality rate worldwide. Currently, a Gram-negative infection is diagnosed by symptom evaluation and is treated with empiric antibiotics which target both Gram-negative and Gram-positive bacteria. A rapid and simple diagnostic method would enable immediate and targeted treatment, while dramatically reducing antibiotic overuse. Herein, we introduce a method utilizing a fluorescent derivative of colistin (COL-FL), that can directly label the Gram-negative cell wall of live bacteria and universally detect the targets within 10 min. By using the COL-FL assay, we achieved the differential labeling of various Gram-negative pathogens related to hospital-acquired infections, which could be subsequently detected via spectrofluorometry and microscopy. Further, we determined that our method can be used for complex samples, such as combinations of multiple bacterial types; bacteria in the presence of mammalian cells; and bacteria with serum components. This assay can be integrated into a simple diagnostic platform for rapid screening tests and the stratification of Gram-negative bacterial infections in the clinic.


Assuntos
Antibacterianos/farmacologia , Benzenossulfonatos/farmacologia , Carbocianinas/farmacologia , Colistina/farmacologia , Corantes Fluorescentes/farmacologia , Bactérias Gram-Negativas/isolamento & purificação , Antibacterianos/química , Benzenossulfonatos/química , Bioensaio , Carbocianinas/química , Linhagem Celular Tumoral , Colistina/análogos & derivados , Colistina/química , Fluorescência , Corantes Fluorescentes/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Bactérias Gram-Positivas/metabolismo , Humanos , Microscopia Confocal , Espectrometria de Fluorescência
19.
Biochemistry ; 59(5): 717-726, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31967788

RESUMO

Up to 20% of solid tumors are characterized by DNA mismatch repair (MMR) deficiency and microsatellite instability that confer resistance to standard of care chemotherapy. MMR-deficient cancers have an increased mutation rate, and DNA mismatches accumulate as part of these cancers. We previously described a class of compounds, rhodium metalloinsertors, that bind DNA mismatches with high specificity and selectivity and have potential as targeted therapy. [Rh(chrysi)(phen)(PPO)]2+ (RhPPO) is the most potent, selective compound in this class and acts by targeting DNA mismatches, resulting in preferential cytotoxicity to MMR-deficient cancers. To explore further the cellular mechanism of action of RhPPO, we conjugated the metal complex to a fluorescent probe, cyanine 3 (Cy3). RhPPO-Cy3 binds DNA mismatches and retains the selectivity and potent cytotoxic activity of RhPPO for MMR-deficient cell lines. RhPPO-Cy3 forms discrete foci in the cell nucleus that overlap with sites of DNA damage, suggesting that the lesions occur at or near DNA mismatch sites. RhPPO-Cy3 foci persist over time, despite initial processing of the lesion and recruitment of repair proteins, consistent with the idea that the complex binding to a mismatch prevents repair. RhPPO-Cy3 binding does not lead to activation of p53 and the apoptotic pathway. Together, these findings support the idea that RhPPO-Cy3 binding leads to irreversible DNA damage at DNA mismatches that enables selective cytotoxicity to MMR-deficient cells.


Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Complexos de Coordenação/farmacologia , Dano ao DNA , Corantes Fluorescentes/farmacologia , Ródio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carbocianinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Células HCT116 , Humanos , Estrutura Molecular , Imagem Óptica , Ródio/química
20.
Macromol Biosci ; 20(2): e1900279, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31885210

RESUMO

Because of the high mortality of coronary atherosclerotic heart diseases, it is necessary to develop novel early detection methods for vulnerable atherosclerotic plaques. Phenotype transformation of vascular smooth muscle cells (VSMCs) plays a vital role in progressed atherosclerotic plaques. Osteopontin (OPN) is one of the biomarkers for phenotypic conversion of VSMCs. Significant higher OPN expression is found in foam cells along with the aggravating capacity of macrophage recruitment due to its arginine-glycine-aspartate sequence and interaction with CD44. Herein, a dual-modality imaging probe, OPN targeted nanoparticles (Cy5.5-anti-OPN-PEG-PLA-PFOB, denoted as COP-NPs), is constructed to identify the molecular characteristics of high-risk atherosclerosis by ultrasound and optical imaging. Characterization, biocompatibility, good binding sensibility, and specificity are evaluated in vitro. For in vivo study, apolipoprotein E deficien (ApoE-/- ) mice fed with high fat diet for 20-24 weeks are used as atherosclerotic model. Ultrasound and optical imaging reveal that the nanoparticles are accumulated in the vulnerable atherosclerotic plaques. OPN targeted nanoparticles are demonstrated to be a good contrast agent in molecular imaging of synthetic VSMCs and foam cells, which can be a promising tool to identify the vulnerable atherosclerotic plaques.


Assuntos
Carbocianinas , Meios de Contraste , Sistemas de Liberação de Medicamentos , Nanopartículas , Imagem Óptica , Osteopontina/metabolismo , Placa Aterosclerótica/diagnóstico por imagem , Animais , Carbocianinas/química , Carbocianinas/farmacologia , Meios de Contraste/química , Meios de Contraste/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo
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