RESUMEN
The particular characteristics of hypoxia, immune suppression in the tumor microenvironment, and the lack of accurate imaging guidance lead to the limited effects of stereotactic body radiotherapy (SBRT) in reducing the recurrence rate and mortality of hepatocellular carcinoma (HCC). This research developed a novel theranostic agent based on Bi/Se nanoparticles (NPs), synthesized by a simple reduction reaction method for in vivo CT image-guided SBRT sensitization in mice. After loading Lenvatinib (Len), the obtained Bi/Se-Len NPs had excellent performance in reversing hypoxia and the immune suppression status of HCC. In vivo CT imaging results uncovered that the radiotherapy (RT) area could be accurately labeled after the injection of Bi/Se-Len NPs. Under Len's unique and robust properties, in vivo treatment was then carried out upon injection of Bi/Se-Len NPs, achieving excellent RT sensitization effects in a mouse HCC model. Comprehensive tests and histological stains revealed that Bi/Se-Len NPs could reshape and normalize tumor blood vessels, reduce the hypoxic situation of the tumor, and upregulate tumor-infiltrating CD4+ and CD8+ T lymphocytes around the tumors. Our work highlights an excellent proposal of Bi/Se-Len NPs as theranostic nanoparticles for image-guided HCC radiotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Medios de Contraste/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas del Metal/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Animales , Bismuto/química , Bismuto/uso terapéutico , Bismuto/toxicidad , Vasos Sanguíneos/efectos de los fármacos , Carcinoma Hepatocelular/diagnóstico por imagen , Línea Celular Tumoral , Medios de Contraste/síntesis química , Medios de Contraste/toxicidad , Portadores de Fármacos/síntesis química , Portadores de Fármacos/uso terapéutico , Portadores de Fármacos/toxicidad , Femenino , Humanos , Hipoxia/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Linfocitos/efectos de los fármacos , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Ratones Endogámicos BALB C , Compuestos de Fenilurea/uso terapéutico , Medicina de Precisión , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Puntos Cuánticos/toxicidad , Quinolinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/toxicidad , Radiocirugia , Selenio/química , Selenio/uso terapéutico , Selenio/toxicidad , Tomografía Computarizada por Rayos XRESUMEN
While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Quitosano/química , Hipertermia Inducida/métodos , Nanopartículas de Magnetita/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Nanomedicina Teranóstica/métodos , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Medios de Contraste/síntesis química , Medios de Contraste/farmacología , Curcumina/química , Curcumina/farmacología , Sulfato de Dextran/química , Doxorrubicina/química , Doxorrubicina/farmacología , Composición de Medicamentos/métodos , Humanos , Cinética , Nanopartículas de Magnetita/ultraestructura , Oxígeno/química , Oxígeno/farmacología , Fármacos Sensibilizantes a Radiaciones/síntesis químicaRESUMEN
Due to conventional photodynamic therapy encountering serious problems of phototoxicity and low tissue-penetrating depth of light, other dynamic therapy-based therapeutic methods such as sonodynamic therapy (SDT) are expected to be developed. To improve the therapeutic response to SDT, more effective sonosensitizers are imperative. In this study, a novel water-soluble iridium(III)-porphyrin sonosensitizer (IrTMPPS) was synthesized and used for SDT. IrTMPPS generated ample singlet oxygen (1O2) under US irradiation and especially showed distinguished US-activatable abilities at more than 10 cm deep-tissue depths. Interestingly, under US irradiation, IrTMPPS sonocatalytically oxidized intracellular NADH, which would enhance SDT efficiency by breaking the redox balance in the tumor. Moreover, IrTMPPS displayed great sonocytotoxicity toward various cancer cells, and in vivo experiments demonstrated efficient tumor inhibition and anti-metastasis to the lungs in the presence of IrTMPPS and US irradiation. This report gives a novel idea of metal-based sonosensitizers for sonotherapy by fully taking advantage of non-invasiveness, water solubility, and deep tumor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Porfirinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Iridio/química , Iridio/uso terapéutico , Iridio/toxicidad , Ratones , NAD/química , NAD/metabolismo , Neoplasias/patología , Oxidación-Reducción , Porfirinas/síntesis química , Porfirinas/toxicidad , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/toxicidad , Oxígeno Singlete/metabolismo , Ondas Ultrasónicas , Pez CebraRESUMEN
The integration of multiple therapeutic and diagnostic functions into a single nanoplatform for image-guided cancer therapy has been an emerging trend in nanomedicine. We show here that multifunctional theranostic nanostructures consisting of superparamagnetic iron oxide (SPIO) and gold nanoparticles (AuNPs) scaffolded within graphene oxide nanoflakes (GO-SPIO-Au NFs) can be used for dual photo/radiotherapy by virtue of the near-infrared (NIR) absorbance of GO for photothermal therapy (PTT) and the Z element radiosensitization of AuNPs for enhanced radiation therapy (RT). At the same time, this nanoplatform can also be detected by magnetic resonance (MR) imaging because of the presence of SPIO NPs. Using a mouse carcinoma model, GO-SPIO-Au NF-mediated combined PTT/RT exhibited a 1.85-fold and 1.44-fold higher therapeutic efficacy compared to either NF-mediated PTT or RT alone, respectively, resulting in a complete eradication of tumors. As a sensitive multifunctional theranostic platform, GO-SPIO-Au NFs appear to be a promising nanomaterial for enhanced cancer imaging and therapy.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Carcinoma/tratamiento farmacológico , Imagen por Resonancia Magnética , Fototerapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Nanomedicina Teranóstica , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Férricos/química , Compuestos Férricos/farmacología , Oro/química , Oro/farmacología , Grafito/química , Grafito/farmacología , Masculino , Ensayo de Materiales , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Tamaño de la Partícula , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. METHODS: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. RESULTS: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. CONCLUSION: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.
Asunto(s)
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Pirimidinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
High atomic number Z, nanoparticles are able to enhance the photoelectric and Compton effects under X-Ray irradiation resulting the increase of radiation therapy efficacy. To achieve enhanced radiation therapy, Bi2S3 biocompatible particles coated with bovine serum albumin (BSA) (Bi2S3@BSA HNPs) were prepared through a BSA-mediated biomineralization procedure under green conditions. Then, to achieve improved chemo-radiation therapy against HT-29 cancer cells, curcumin (CUR) as natural anti-cancer therapy agent loaded on the Bi2S3@BSA (Bi2S3@BSA@CUR HNPs). Next, this synthesized nanodrug was evaluated for physical and chemical properties and in vitro cytotoxicity studies. Here, in vitro enhanced chemo-radiation combination therapy power was evaluated against HT-29 cell line under 2 Gy and 6 Gy X-ray irradiation doses. The Bi2S3@BSA HNPs without irradiation rarely affect cell viability which shown the non-toxicity of Bi2S3@BSA HNPs. The result of this study proved that Bi2S3@BSA@CUR HNPs can be used as both proficient vehicles for effective delivery of CUR and radiosensitizer in the treatment of cancer. In addition, the result of this study confirmed that the combination of high Z-element nanoradiosensitizer, Bi2S3@BSA HNPs, with a natural anti-cancer drug, CUR, enhanced therapeutic power against HT-29 cells.
Asunto(s)
Bismuto/farmacología , Quimioradioterapia , Minerales/química , Albúmina Sérica Bovina/química , Sulfuros/síntesis química , Sulfuros/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bismuto/química , Bovinos , Técnicas de Química Sintética , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Curcumina/química , Curcumina/farmacología , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Liberación de Fármacos , Tecnología Química Verde , Células HT29 , Humanos , Nanopartículas/química , Tamaño de la Partícula , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfuros/químicaRESUMEN
Emodin reduction to emodin anthrone comprise one of three process steps involved in the hypericin synthesis, a powerful natural photosensitiser found in plants of the genus Hypericum. In this communication, an optimized protocol was established for emodin reduction enabling an efficient multigram preparation of emodin anthrone. A screening of reducing agent (SnCl2·2H2O and HClconc) under different reaction times was employed in micro-scale and monitored by electronic absorption spectroscopy technique. Data showed lower yields of emodin anthrone when some experimental conditions previously described in the literature were reproduce. However, using the optimized protocol for the emodin reduction these yields were overcoming, and a gram-scale supply experiment was reproducible for the preparation of 10 grams of emodin anthrone with excellent yield.
Asunto(s)
Emodina/análogos & derivados , Emodina/química , Hypericum/química , Perileno/análogos & derivados , Antracenos , Antraquinonas/química , Emodina/síntesis química , Perileno/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Sustancias ReductorasRESUMEN
Cancer radiotherapy suffers from drawbacks such as radiation resistance of hypoxic cells, excessive radiation that causes damage of adjacent healthy tissues, and concomitant side effects. Hence, radiotherapy sensitizers with improved radiotherapeutic performance and requiring a relatively small radiation dose are highly desirable. In this study, a nanosystem based on poly(lactic- co-glycolic acid) (PLGA) and ultrasmall black phosphorus quantum dots (BPQDs) is designed and prepared to accomplish precise tumor radiosensitization. The PLGA nanoparticles act as carriers to package the BPQDs to avoid off-target release and rapid degradation during blood circulation. The nanosystem that targets the polypeptide peptide motif Arg-Gly-Asp-Gys actively accumulates in tumor tissues. The 2,3-dimethylmaleic anhydride shell decomposes in an acidic microenvironment, and the nanoparticles become positively charged, thereby favoring cellular uptake. Furthermore, glutathione (GSH) deoxidizes the disulfide bond of cystamine and sequentially triggers release of BPQDs, rendering tumor cells sensitive to radiotherapy. The treatment utilizing the PLGA-SS-D@BPQDs nanosystem and X-ray induces cell apoptosis triggered by overproduction of reactive oxygen species. In the in vivo study, the nanosystem shows excellent radiotherapy sensitization efficiency but negligible histological damage of the major organs. This study provides insights into the design and fabrication of surface-charge-switching and pH-responsive nanosystems as potent radiosensitizers to achieve excellent radiotherapy sensitization efficacy and negligible toxic side effects.
Asunto(s)
Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Melanoma/terapia , Fósforo/química , Puntos Cuánticos/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Melanoma/metabolismo , Melanoma/patología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Desnudos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.
Asunto(s)
Bismuto/farmacología , Terapia Combinada/métodos , Medios de Contraste/farmacología , Nanocompuestos/química , Polietilenglicoles/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfuros/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Medios de Contraste/síntesis química , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células Epiteliales/efectos de la radiación , Femenino , Humanos , Hipertermia Inducida/métodos , Rayos Infrarrojos/uso terapéutico , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Nanocompuestos/administración & dosificación , Nanocompuestos/ultraestructura , Fármacos Sensibilizantes a Radiaciones/síntesis química , Sulfuros/síntesis química , Nanomedicina Teranóstica/métodos , Tomografía Computarizada por Rayos X , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Terapia por Rayos XRESUMEN
The extensive impact of antibiotic resistance has led to the exploration of new anti-bacterial modalities. We designed copper impregnated mesoporous silica nanoparticles (Cu-MSN) with immobilizing silver nanoparticles (SNPs) to apply photodynamic inactivation (PDI) of antibiotic-resistant E. coli. SNPs were decorated over the Cu-MSN surfaces by coordination of silver ions on diamine-functionalized Cu-MSN and further reduced to silver nanoparticles with formalin. We demonstrate that silver is capable of sensitizing the gram-negative bacteria E. coli to a gram-positive specific phototherapeutic agent in vitro; thereby expanding curcumin's phototherapeutic spectrum. The mesoporous structure of Cu-MSN remains intact after the exterior decoration with silver nanoparticles and subsequent curcumin loading through an enhanced effect from copper metal-curcumin affinity interaction. The synthesis, as well as successful assembly of the functional nanomaterials, was confirmed by various physical characterization techniques. Curcumin is capable of producing high amounts of reactive oxygen species (ROS) under light irradiation, which can further improve the silver ion release kinetics for antibacterial activity. In addition, the positive charged modified surfaces of Cu-MSN facilitate antimicrobial response through electrostatic attractions towards negatively charged bacterial cell membranes. The antibacterial action of the synthesized nanocomposites can be activated through a synergistic mechanism of energy transfer of the absorbed light from SNP to curcumin.
Asunto(s)
Antibacterianos/química , Nanopartículas del Metal/química , Fototerapia/normas , Fármacos Sensibilizantes a Radiaciones/química , Antibacterianos/síntesis química , Cobre , Curcumina/uso terapéutico , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de la radiación , Sinergismo Farmacológico , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/efectos de la radiación , Luz , Nanopartículas del Metal/uso terapéutico , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Fototerapia/métodos , Fármacos Sensibilizantes a Radiaciones/síntesis química , Especies Reactivas de Oxígeno/efectos de la radiación , Dióxido de Silicio/química , PlataRESUMEN
Gold nanoparticles (GNPs) have been applied as radiosensitizer in radiotherapy. Limited reports have shown that GNPs may be effective as a dose enhancer agent for electron radiation therapy. Some Monte Carlo Simulation studies have shown that selecting suitable size of GNPs and electron energies are critical for effective dose enhancement. The aim of this study was to assess possible radiosensitization effect of GNPs on cancer cell treated with 4MeV electron beams. Approximately 10nm GNPs were synthesized and characterized by electron microscope and dynamic light scattering. MCF-7 and MDA-MB-231 breast cancer cells were used and their viability was measured by MTT assay. Radiosensitization effect of GNPs under 4MeV electron beams was measured by clonogenic assay. The result showed a concentration dependent uptake of GNPs without reducing cell viability at concentrations ≤50mg/L. Incubation of cancer cells with GNPs caused a significant decrease in their viability following exposure to electron beams as well as a decrease in their survival fraction when compared to control. The sensitizer enhancement ratio (SER) by electron beams in MCF-7 cells was 1.43 and 1.40 in presence of 25 and 50mg/L GNPs, respectively. For MDA-MB-231 cells, it was 1.62 in presence of 25mg/L GNPs. Our data demonstrated the significant dose enhancement of the GNPs in combination with 4MeV electron beams that could be applicable for the treatment of superficial tumors and intra operative radiation therapy.
Asunto(s)
Neoplasias de la Mama/radioterapia , Electrones/uso terapéutico , Oro , Nanopartículas del Metal/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Dispersión Dinámica de Luz , Humanos , Células MCF-7 , Microscopía Electrónica , Dosis de Radiación , Fármacos Sensibilizantes a Radiaciones/síntesis químicaRESUMEN
A novel series of sulfonamide derivatives 4-21 have been synthesized starting from the strategic starting material (E)-4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide 4. Two series of hydrazone 5-9, and pyridone 10-21 derivatives bearing a sulfonamide moiety were obtained. All the newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human liver cancer cell line (HepG2). Compounds 4-6, 8, 9, 10-14 and 16-18 showed higher activity compared to doxorubicin as a positive control. The radiosensitizing ability of the most promising compounds 4, 10 and 12 was studied which showed an increase in the cell killing effect of γ-radiation after combination with these derivatives. The molecular design was performed to predict the binding mode of the most promising compounds 4, 10 and 12 with the active site of hCA IX, that showed appropriate fitting with the relevant amino acids in the binding pocket on the basis of standard bond lengths, angles, S score and E conformation data.
Asunto(s)
Antineoplásicos/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Sulfonamidas/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Rayos gamma , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , BencenosulfonamidasRESUMEN
A novel selenium-containing ruthenium complex Ru(phtpy)(phenSe)Cl(ClO4) (phtpy = 4-phenyl-2,2':6',2''-terpyridine, phenSe = 2-selenicimidazole[4,5-f]1,10-phenanthroline) has been synthesized and found be able to enhance radiation-induced DNA damage through superoxide overproduction, which leads to G2/M arrest and apoptosis in cancer cells by activating ROS-mediated pathways.
Asunto(s)
Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Selenio/química , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: We previously designed the boron tracedrugs UTX-42, UTX-43, and UTX-44, which possess antioxidant potency. In order to explore their destructive dynamic effects when bombarded by weak thermal neutrons, we performed thermal neutron irradiation of bovine serum albumin (BSA) treated with the boron tracedrugs. MATERIALS AND METHODS: Boron tracedrugs, including the boron dipyrromethene (BODIPY)-containing compounds UTX-42, UTX-44, and UTX-47 and the curcuminoid compounds UTX-50 and UTX-51, were designed for neutron dynamic therapy based on their molecular orbital calculation. Newly designed UTX-47, UTX-50, and UTX-51 were synthesized. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed to detect decomposition by thermal neutron irradiation of BSA treated with these boron tracedrugs. RESULTS: The combination of 1.0 µM BSA with 100 µM of each of the boron tracedrugs showed a decrease in band intensity after irradiation. CONCLUSION: All boron tracedrugs tested caused destructive dynamic damage of BSA during thermal neutron irradiation, suggesting that boron tracedrugs could be used as dynamic drugs for neutron dynamic therapy.
Asunto(s)
Compuestos de Boro/efectos de la radiación , Terapia por Captura de Neutrón de Boro/métodos , Curcumina/efectos de la radiación , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Animales , Compuestos de Boro/química , Bovinos , Curcumina/análogos & derivados , Curcumina/química , Diseño de Fármacos , Electroforesis en Gel de Poliacrilamida , Rayos gamma , Estructura Molecular , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Albúmina Sérica Bovina/efectos de los fármacos , Albúmina Sérica Bovina/efectos de la radiación , Relación Estructura-ActividadRESUMEN
A novel fully automated radiosynthesis procedure for [(18)F]Fluoromisonidazole using a simple alumina cartridge-column for purification instead of conventionally used semi-preparative HPLC was developed. [(18)F]FMISO was prepared via a one-pot, two-step synthesis procedure using a modified nuclear interface synthesis module. Nucleophilic fluorination of the precursor molecule 1-(2'-nitro-1'-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulphonylpropanediol (NITTP) with no-carrier added [(18)F]fluoride followed by hydrolysis of the protecting group with 1M HCl. Purification was carried out using a single neutral alumina cartridge-column instead of semi-preparative HPLC. The maximum overall radiochemical yield obtained was 37.49+/-1.68% with 10mg NITTP (n=3, without any decay correction) and the total synthesis time was 40+/-1 min. The radiochemical purity was greater than 95% and the product was devoid of other chemical impurities including residual aluminum and acetonitrile. The biodistribution study in fibrosarcoma tumor model showed maximum uptake in tumor, 2h post injection. Finally, PET/CT imaging studies in normal healthy rabbit, showed clear uptake in the organs involved in the metabolic process of MISO. No bone uptake was observed excluding the presence of free [(18)F]fluoride. The reported method can be easily adapted in any commercial FDG synthesis module.
Asunto(s)
Radioisótopos de Flúor , Misonidazol/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/síntesis química , Óxido de Aluminio , Animales , Automatización , Cromatografía , Fibrosarcoma/diagnóstico , Humanos , Misonidazol/síntesis química , Misonidazol/aislamiento & purificación , Misonidazol/farmacocinética , Tomografía de Emisión de Positrones/métodos , Conejos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/aislamiento & purificación , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Eight d-ribo-phytosphingosine derivatives were synthesized from d-ribo-phytosphingosine and diverse acyl chlorides with N,N-diisopropylethylamine in tetrahydrofuran for 1h at room temperature. Effect of these compounds on IR-induced cell death was evaluated on blood cancer cells (Jurkat). Among these, 3d showed the highest enhancement of radiosensitizing effect.
Asunto(s)
Leucemia de Células T/radioterapia , Fármacos Sensibilizantes a Radiaciones/síntesis química , Esfingosina/análogos & derivados , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Terapia Combinada , Evaluación Preclínica de Medicamentos/métodos , Humanos , Células Jurkat , Leucemia de Células T/tratamiento farmacológico , Leucemia de Células T/patología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Esfingosina/síntesis química , Esfingosina/uso terapéuticoRESUMEN
Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers. (Z)-(+/-)-2-(1-Benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation.
Asunto(s)
Neoplasias del Colon/terapia , Hipertermia Inducida/métodos , Indoles/química , Indoles/farmacología , Mitosis/fisiología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Proteínas de Unión al ADN/metabolismo , Células HCT116 , Factores de Transcripción del Choque Térmico , Humanos , Indoles/síntesis química , Mitosis/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/síntesis química , Relación Estructura-Actividad , Factores de Transcripción/metabolismoRESUMEN
Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline hydrochloride (8a) and 10-[3-(2-nitroimidazolyl)propylamino]-2-methyl-1,2,3,4-tetrahydro-benzo[b]-1,6-naphthyridine hydrochloride (8b) have been synthesized and evaluated in V79 cells as hypoxia-selective cytotoxins and radiosensitizers that target DNA through weak intercalation. Both compounds were relatively good radiosensitizers (C(1.6) values of 40.0+/-0.8 and 59.0+/-0.4 microM for 8a and 8b, respectively) but neither of the compounds was superior to 2 which does not carry a second heteroatom in the DNA-intercalating chromophore.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Nitroimidazoles/síntesis química , Quinolinas/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Animales , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Cricetinae , Evaluación Preclínica de Medicamentos/métodos , Compuestos Heterocíclicos/toxicidad , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/toxicidad , Nitroimidazoles/toxicidad , Quinolinas/toxicidad , Fármacos Sensibilizantes a Radiaciones/toxicidadRESUMEN
The sulfur analogues of psoralen and 8-methoxypsoralen (8-MOP) in the pyrone moiety were synthesized and compared to the parent compounds in terms of photoreactivity with viral M13mp19 RF DNA. The damaged viral DNA was transfected into Escherichia coli and scored for infectivity toward Ca-treated wild-type E. coli. This allowed a comparative study of the sulfur and oxygen analogues to be made in terms of photoreactivity. Furthermore, the DNA sequence specificity for the formation of monoadducts and cross-links of the four analogues was determined with 32P-labeled oligonucleotides containing thymidine in different sequences. The most site specific of the studied psoralens is 8-MOP, while 1-thiopsoralen is the most reactive analogue. This new thio analogue of psoralen leads to the efficient formation of monoadducts and cross-links in any pyrimidine-purine site.
Asunto(s)
Daño del ADN , ADN Viral/efectos de los fármacos , ADN Viral/metabolismo , Furocumarinas/síntesis química , Furocumarinas/farmacología , Metoxaleno/análogos & derivados , Terapia PUVA , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/farmacología , Secuencia de Bases , Sitios de Unión , Calcio/farmacología , Reactivos de Enlaces Cruzados , Aductos de ADN/biosíntesis , ADN Viral/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/virología , Metoxaleno/síntesis química , Metoxaleno/farmacología , Datos de Secuencia Molecular , Oxígeno/farmacología , Radioisótopos de Fósforo , Fotobiología , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta , TransfecciónRESUMEN
A convenient in vitro screening test using E. coli B/r for evaluating a variety of hypoxic cell radiosensitizers/hypoxic cell cytotoxins has been developed for the initial selection of candidates in medicinal/organic chemistry laboratories. E. coli cells were used for convenience since: (1) the bacterium is grown using commercially available broths, where it multiplies rapidly, and requires little specialized equipment for growth and handling. (2) More is known about the genetics and biochemistry of the radiation damage to these cells and their repair than any other organism.