RESUMO
Fluorescent probes in the NIR-II region provide high bioimaging quality. Optimizing the probe structure to achieve NIR-II imaging is ongoing, but remains challenging. Herein, increasing the electron withdrawing ability of the substituent in monochlorinated BODIPY greatly adjusted the emission wavelength from the NIR-I to NIR-II region, giving an efficient design strategy of NIR-II probes.
Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Animais , Elétrons , Células HCT116 , Halogenação , Células Hep G2 , Humanos , Camundongos , Neoplasias/diagnóstico por imagem , Imagem Óptica , Espectrometria de Fluorescência , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Nitroreductase (NTR) has been recognized as a biomarker for identifying the hypoxic status of cancers. Therefore, it is of high scientific interest to design effective fluorescent probes for tracking NTR activity. However, studies on elucidation of the structure-performance relationship of fluorescent probes and those providing valuable insight into optimized probe design have rarely been reported. Three BODIPY based fluorescent probes were made by conjugation of para-, ortho-, and meta-nitrobenzene to the BODIPY core via a thiolether bond, respectively. Our study revealed that the linkage and nitro substituent position significantly influence the capability of nitroreductase detection.
Assuntos
Biomarcadores Tumorais/análise , Compostos de Boro/química , Corantes Fluorescentes/química , Neoplasias/diagnóstico por imagem , Nitrorredutases/análise , Biomarcadores Tumorais/metabolismo , Compostos de Boro/síntese química , Corantes Fluorescentes/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Nitrobenzenos/química , Nitrorredutases/metabolismoRESUMO
An activatable and mitochondrial-targetable fluorescent probe was developed. This designed probe showed ratiometric fluorescence and light-up near-infrared emission responsiveness to nitroreductase, achieving precise imaging of mitochondria in cancer cells by real-time monitoring of nitroreductase activity.
Assuntos
Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Nitrorredutases/metabolismo , Imagem Óptica/métodos , Células A549 , HumanosRESUMO
We present an approach for constructing a H2S-specific nanoprobe by the entrapment of a small molecule probe within the hydrophobic interior of surface cross-linked micelles (SCMs), endowing the designed nanoprobes with good water solubility and biocompatibility. Importantly, the obtained nanoprobes displayed good responsiveness to H2S in both ratiometric fluorescence and light-up NIR emission modes, thus enabling accurate identification of H2S-rich colorectal cancer cells.
Assuntos
Materiais Biocompatíveis/química , Neoplasias Colorretais/diagnóstico por imagem , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Nanopartículas/química , Imagem Óptica , Materiais Biocompatíveis/síntese química , Corantes Fluorescentes/síntese química , Células HCT116 , Humanos , Micelas , Tamanho da Partícula , Propriedades de Superfície , Água/químicaRESUMO
We herein develop two ß-galactosidase (ß-Gal) activatable NIR fluorescent probes for visualizing ovarian cancers. Particularly, probe BOD-M-ßGal produced NIR-II emission light at 900-1300 nm upon ß-Gal activation. By using our activatable and target specific NIR-II probe for deep-tissue imaging of ß-Gal overexpressed ovarian cancer cells, rapid and accurate imaging of ovarian tumors in nude mice was achieved.
Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , beta-Galactosidase/química , Animais , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Corantes Fluorescentes/metabolismo , Células Endoteliais da Veia Umbilical Humana/química , Humanos , Raios Infravermelhos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Neoplasias Ovarianas/metabolismo , beta-Galactosidase/metabolismoRESUMO
DNA-dependent protein kinase (DNA-PK)-defective severe combined immunodeficient (SCID) mice have a greater sensitivity to ionizing radiation compared with wild-type mice due to deficient repair of DNA double-strand break. SCID cells were therefore studied to determine whether radiosensitization by the specific inhibitor of DNA-PK, IC87361, is eliminated in the absence of functional DNA-PK. IC87361 enhanced radiation sensitivity in wild-type C57BL6 endothelial cells but not in SCID cells. The tumor vascular window model was used to assess IC87361-induced radiosensitization of SCID and wild-type tumor microvasculature. Vascular density was 5% in irradiated SCID host compared with 50% in C57BL6 mice (P < 0.05). IC87361 induced radiosensitization of tumor microvasculature in wild-type mice that resembled the radiosensitive phenotype of tumor vessels in SCID mice. Radiosensitization by IC87361 was eliminated in SCID tumor vasculature, which lack functional DNA-PK. Irradiated LLC and B16F0 tumors implanted into SCID mice showed greater tumor growth delay compared with tumors implanted into either wild-type C57BL6 or nude mice. Furthermore, LLC tumors treated with radiation and IC87361 showed tumor growth delay that was significantly greater than tumors treated with radiation alone (P < 0.01 for 3 Gy alone versus 3 Gy + IC87361). DNA-PK inhibitors induced no cytotoxicity and no toxicity in mouse normal tissues. Mouse models deficient in enzyme activity are useful to assess the specificity of novel kinase inhibitors. DNA-PK is an important target for the development of novel radiation-sensitizing drugs that have little intrinsic cytotoxicity.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Radiossensibilizantes/farmacologia , Animais , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/enzimologia , Carcinoma Pulmonar de Lewis/radioterapia , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Proteína Quinase Ativada por DNA , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/enzimologia , Melanoma Experimental/radioterapia , Camundongos , Camundongos Nus , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/enzimologia , Neovascularização Patológica/patologia , Neovascularização Patológica/radioterapiaRESUMO
Expression of survivin is elevated in most malignancies, especially in radiation-resistant cell lines. In this study, we investigated how radiation affects survivin expression in primary endothelial cells as well as in malignant cell lines. We found that 3 Gy significantly reduced survivin protein level in human umbilical vein endothelial cells (HUVECs) but not in tumor cell lines. Flow cytometry studies suggest that the down-regulation of survivin is independent of cell cycle. In addition, survivin mRNA level was also down-regulatable by irradiation. However, it was abrogated by actinomycin D-mediated inhibition of gene transcription. Luciferase reporter gene assays suggest that irradiation suppressed the survivin promoter. p53 overexpression reduced survivin expression, but overexpression of a p53 mutant failed to abolish the radiation-induced down-regulation in HUVECs. Alteration of p53 status in Val138 lung cancer cell line also failed to restore the radiation-inducible down-regulation. Overexpression of survivin in 293 cells prevented apoptosis induced by irradiation and increased cell viability after irradiation. The inhibition of survivin using antisense oligonucleotides caused a significant decrease in cell viability of irradiated H460 lung cancer cells. These data suggest that radiation transcriptionally down-regulates survivin in HUVECs. This regulatory mechanism is defective in malignancies and is not mediated by p53. Survivin overexpression may lead to resistance to radiotherapy by inhibiting apoptosis and enhancing cell viability. The inhibition of survivin results in sensitization of H460 lung cancer cells to radiation. These studies suggest that survivin may be a target for cancer therapy.
Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Proteínas Associadas aos Microtúbulos/fisiologia , Proteínas Associadas aos Microtúbulos/efeitos da radiação , Tolerância a Radiação/fisiologia , Dano ao DNA/fisiologia , Regulação para Baixo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose , Neoplasias Pulmonares/genética , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Survivina , Ativação Transcricional , Transfecção , Proteína Supressora de Tumor p53/fisiologiaRESUMO
PURPOSE: Recent studies have demonstrated radiosensitization by inhibiting receptor tyrosine kinases (RTKs). Irradiation activates RTKs and their downstream prosurvival molecule, Akt. In this study, we investigated the mechanism by which SU6668, an inhibitor of RTKs involved in angiogenic pathways, enhances effects of irradiation. METHODS AND MATERIALS: Western blots were used to determine Akt phosphorylation. Clonogenic assays were performed to determine endothelial survival after combination of SU6668 and irradiation. This combination therapy was also tested in mouse models with Lewis lung carcinoma or glioblastoma multiforme (GL261) for inhibition of tumor growth and tumor vasculature by examining tumor volume, tumor vascular window, and blood flow. RESULTS: We found that SU6668 inhibited the Akt activation inducible by irradiation. Clonogenic survival of endothelial cells was decreased after the combined therapy compared with radiotherapy alone. In vivo studies demonstrated reduction of tumor vasculature and blood flow. In addition, 21 Gy in 7 fractions given concurrently with SU6668 resulted in tumor growth delay compared to either treatment alone. CONCLUSION: These data suggest that the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU6668 augments tumor-suppressive effects of radiotherapy in Lewis lung carcinoma and GL261 xenographs, possibly through reducing the survival of tumor endothelium.