RESUMEN
Gold nanomaterials have been shown to augment radiation therapy both in vitro and in vivo. However, studies on these materials are mostly phenomenological due to nanoparticle heterogeneity and the complexity of biological systems. Even accurate quantification of the particle dose still results in bulk average biases; the effect on individual cells is not measured but rather the effect on the overall population. To perform quantitative nanobiology, we coated glass coverslips uniformly at varying densities with Au nanoparticle preparations with different morphologies (45 nm cages, 25 nm spheres, and 30 nm rods). Consequently, the effect of a specific number of particles per unit area in contact with breast cancer cells growing on the coated surfaces was ascertained. Gold nanocages showed the highest degree of radiosensitization on a per particle basis, followed by gold nanospheres and gold nanorods, respectively. All three materials showed little cytotoxic effect at 0 Gy, but clonogenic survival decreased proportionally with the radiation dose and particle coverage density. A similar trend was seen in vivo in the combined treatment antitumor response in 4T1 tumor-bearing animals. The presence of gold affected the type and quantity of reactive oxygen species generated, specifically superoxide and hydroxyl radicals, and the concentration of nanocages correlated with the development of more numerous double-stranded DNA breaks and increased protein oxidation as measured by carbonylation. This work demonstrates the dependence on morphology and concentration of radiation enhancement by gold nanomaterials and may lead to a novel method to differentiate intra- and extracellular functionalities of gold nanomedicine treatment strategies. It further provides insights that can guide the rational development of gold nanomaterial-based radiosensitizers for clinical use.
Asunto(s)
Nanopartículas del Metal , Nanoestructuras , Fármacos Sensibilizantes a Radiaciones , Animales , Oro/farmacología , Oro/metabolismo , Apoptosis , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have revolutionized the treatment of metastatic breast carcinoma. They currently form the first-line treatment, in combination with endocrine agents, for the management of locally advanced or metastatic hormone receptor-positive (HRâ¯+â¯), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the largest subtype of breast carcinoma. CDK 4/6 inhibitors have shown comparable efficacy outcomes with predictable and manageable adverse events. In this setting, dermatologic toxicity appears to be relatively frequent, accounting for up to 15% of all reported adverse events. It is usually mild to moderate in intensity and does not normally constitute a dose-limiting toxicity. The range of dermatologic adverse events includes both non-specific entities (maculopapular rash, pruritus, alopecia) and more characteristic toxicities related to CDK4/6 inhibitors, such as vitiligo-like lesions or cutaneous lupus erythematosus. Finally, more severe or life-threatening skin reactions can occasionally occur. The main dermatologic manifestations associated with CDK4/6 inhibitors, as well as management thereof, are described in this comprehensive review.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Quinasas Ciclina-Dependientes/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
High-Z metallic nanoparticles (NPs) are new players in the therapeutic arsenal against cancer, especially radioresistant cells. Indeed, the presence of these NPs inside malignant cells is believed to enhance the effect of ionizing radiation by locally increasing the dose deposition. In this context, the potential of platinum nanoparticles (PtNPs) as radiosensitizers was investigated in two breast cancer cell lines, T47D and MDA-MB-231, showing a different radiation sensitivity. PtNPs were internalized in the two cell lines and localized in lysosomes and multivesicular bodies. Analyses of cell responses in terms of clonogenicity, survival, mortality, cell-cycle distribution, oxidative stress, and DNA double-strand breaks did not reveal any significant enhancement effect when cells were pre-exposed to PtNPs before being irradiated, as compared to radiation alone. This result is different from that reported in a previous study performed, under the same conditions, on cervical cancer HeLa cells. This shows that the efficacy of radio-enhancement is strongly cell-type-dependent. Simulation of the early stage ionization processes, taking into account the irradiation characteristics and realistic physical parameters in the biological sample, indicated that PtNPs could weakly increase the dose deposition (by 3%) in the immediate vicinity of the nanoparticles. Some features that are potentially responsible for the biological effect could not be taken into account in the simulation. Thus, chemical and biological effects could explain this discrepancy. For instance, we showed that, in these breast cancer cell lines, PtNPs exhibited ambivalent redox properties, with an antioxidant potential which could counteract the radio-enhancement effect. This work shows that the efficacy of PtNPs for enhancing radiation effects is strongly cell-dependent and that no effect is observed in the case of the breast cancer cell lines T47D and MDA-MB-231. Thus, more extensive experiments using other relevant biological models are needed in order to evaluate such combined strategies, since several clinical trials have already demonstrated the success of combining nanoagents with radiotherapy in the treatment of a range of tumor types.
Asunto(s)
Neoplasias de la Mama/radioterapia , Simulación por Computador , Nanopartículas del Metal/administración & dosificación , Platino (Metal)/química , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Técnicas In Vitro , Nanopartículas del Metal/química , Estrés Oxidativo , Fármacos Sensibilizantes a Radiaciones/química , Células Tumorales CultivadasRESUMEN
Cavities are the building blocks for multiple photonic applications from linear to nonlinear optics and from classical optics to quantum electrodynamics. Hyperbolic metamaterial cavities are one class of optical cavities that have recently been realized and shown to possess desirable characteristics such as engineered refractive indices and ultrasmall mode volumes, both beneficial for enhancement of light-matter interactions at the nanoscale. We hereby report the design, fabrication, and experimental characterization of nanoscale hyperbolic metamaterial cavities at the visible frequency. We show experimentally that these nanocavities enhance the light-matter interaction at the nanoscale and demonstrate increased photonic density of states and enhanced free space radiation efficiency of quantum dots coupled to such cavities, thus demonstrating the importance of hyperbolic metamaterial cavities for applications in solid-state light sources, quantum technologies, and cavity quantum electrodynamics.
RESUMEN
Infrared gas sensors have been proven promising for broad applications in Internet of Things and Industrial Internet of Things. However, the lack of miniaturized light sources with good compatibility and tunable spectral features hinders their widespread utilization. Herein, a strategy is proposed to increase the radiated power from microelectromechanical-based thermal emitters by coating with graphene oxide (GO). The radiation can be substantially enhanced, which partially stems from the high emissivity of GO coating demonstrated by spectroscopic methods. Moreover, the sp2 structure within GO may induce plasmons and thus couple with photons to produce blackbody radiation and/or new thermal emission sources. As a proof-of-concept demonstration, the GO-coated emitter is integrated into a multifunctional monitoring platform and evaluated for gas detection. The platform exhibits sensitive and highly selective detection toward CO2 at room temperature with a detection limit of 50 ppm and short response/recovery time, outperforming the state-of-the-art gas sensors. This study demonstrates the emission tailorability of thermal emitters and the feasibility of improving the associated gas sensing property, offering perspectives for designing and fabricating high-end optical sensors with cost-effectiveness and superior performance.
Asunto(s)
Dióxido de Carbono/análisis , Grafito/química , Acetona/análisis , Monóxido de Carbono/análisis , Humedad , Rayos Infrarrojos , Metano/análisis , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
The potential of gold nanoparticles (GNPs) as radiosensitizers for the treatment of malignant tumors has been limited by the large quantities of GNPs that must be administered and the requirement for low-energy X-ray irradiation to optimize radiosensitization. In this study, we enhance the radiosensitivity of HCT116 human colorectal cells with tiopronin-coated GNPs (Tio-GNPs) combined with a low-energy X-ray (26 keV effective energy) source, similar to the Papillon 50 clinical irradiator used for topical irradiation of rectal tumors. Sensitizer enhancement ratios of 1.48 and 1.69 were measured in vitro, when the HCT116 cells were incubated with 0.1 mg/mL and 0.25 mg/mL of Tio-GNPs, respectively. In nude mice bearing the HCT116 tumor, intra-tumoral (IT) injection of Tio-GNPs allowed a 94 times higher quantity of Tio-GNPs to accumulate than was possible by intravenous injection and facilitated a significant tumor response. The time following irradiation, for tumors growing to four times their initial tumor volume (4Td) was 54 days for the IT injection of 366.3 µg of Tio-GNPs plus 10 Gy, compared to 37 days with radiation alone (P=0.0018). Conversely, no significant improvement was obtained when GNPs were injected intravenously before tumor irradiation (P=0.6547). In conclusion, IT injection of Tio-GNPs combined with low-energy X-rays can significantly reduce the growth of colorectal tumors.
Asunto(s)
Neoplasias Colorrectales/radioterapia , Oro/química , Nanopartículas del Metal/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Células HCT116/efectos de los fármacos , Células HCT116/efectos de la radiación , Humanos , Inyecciones Intralesiones , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Ratones Desnudos , Fármacos Sensibilizantes a Radiaciones/química , Tiopronina/química , Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To evaluate the enhancement effect of two combined radiation-sensitizing agents in mammalian cells at small doses as compared to large doses using the linear-quadratic (LQ) mathematical model. METHODS AND MATERIALS: Data on clonogenic assays concerning the radio-enhancement effects of combined halogenated pyrimidines and hyperthermia or combined cisplatin and hyperthermia, as published in earlier reports, were analyzed according to the LQ-formula: S(D)/S(0) = exp-(αD + ßD(2)). Effects of sensitizing agents on the linear parameter α and the quadratic parameter ß are compared in order to evaluate differences depending on the applied dose, the possible relations to mechanisms of radiation sensitization and to derive suggestions for applications. RESULTS: The values of the linear parameter α, which determines the effectiveness at low doses, are for all cell lines and all conditions more increased than the values of the parameter ß which has a higher contribution at larger radiation doses. The combination of hyperthermia with halogenated pyrimidines to radiation as well as the combination of hyperthermia and cisplatin to radiation significantly increases the value of the linear parameter α, as compared to radiation alone or radiation combined with a single agent. CONCLUSIONS: The radiation enhancement factors of the values of linear and quadratic parameters demonstrate that the sensitizing agents have a larger effect on the linear parameter which is dominant at low radiation doses as is used in fractionated-radiation treatment in the clinic. Moreover, the effect is even further increased when two radiation sensitizers are used.
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Supervivencia Celular/fisiología , Supervivencia Celular/efectos de la radiación , Modelos Biológicos , Modelos Estadísticos , Fármacos Fotosensibilizantes/administración & dosificación , Tolerancia a Radiación/efectos de los fármacos , Animales , Simulación por Computador , Relación Dosis-Respuesta en la Radiación , Combinación de Medicamentos , Humanos , Dosis de RadiaciónRESUMEN
Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by secondary electrons. In this work, polyethylene glycol-capped AuNPs were conjugated with tirapazamine (TPZ) moiety, and then thioctyl TPZ (TPZs)-modified AuNPs (TPZs-AuNPs) were synthesized. The TPZs-AuNPs were characterized by transmission electron microscopy, ultraviolet-visible spectra, dynamic light scattering, and inductively coupled plasma mass spectrometry to have a size of 16.6±2.1 nm in diameter and a TPZs/AuNPs ratio of ~700:1. In contrast with PEGylated AuNPs, the as-synthesized TPZs-AuNPs exhibited 20% increment in hydroxyl radical production in water at 2.0 Gy, and 19% increase in sensitizer enhancement ratio at 10% survival fraction for human hepatoma HepG2 cells under X-ray irradiation. The production of reactive oxygen species in HepG2 cells exposed to X-rays in vitro demonstrated a synergistic radiosensitizing effect of AuNPs and TPZ moiety. Thus, the reductive drug-conjugated TPZs-AuNPs as a kind of AuNP radiosensitizer with low gold loading provide a new strategy for enhancing the efficacy of radiation therapy.
Asunto(s)
Células Hep G2/efectos de la radiación , Nanopartículas del Metal , Fármacos Sensibilizantes a Radiaciones/farmacología , Triazinas/farmacología , Oro/química , Células Hep G2/efectos de los fármacos , Humanos , Radical Hidroxilo/metabolismo , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Microscopía Electrónica de Transmisión , Polietilenglicoles/química , Fármacos Sensibilizantes a Radiaciones/química , Tirapazamina , Triazinas/administración & dosificación , Triazinas/química , Microambiente Tumoral/efectos de los fármacos , Rayos XRESUMEN
AIM: Gold nanoparticles have attracted significant interest in cancer diagnosis and treatment. Herein, we evaluated the theranostic potential of dithiolated diethylenetriamine pentaacetic acid (DTDTPA) conjugated AuNPs (Au@DTDTPA) for CT-contrast enhancement and radiosensitization in prostate cancer. MATERIALS & METHODS: In vitro assays determined Au@DTDTPA uptake, cytotoxicity, radiosensitizing potential and DNA damage profiles. Human PC3 xenograft tumor models were used to determine CT enhancement and radiation modulating effects in vivo. RESULTS: Cells exposed to nanoparticles and radiation observed significant additional reduction in survival compared with radiation only. Au@DTDTPA produced a CT enhancement of 10% and a significant extension in tumor growth delay from 16.9 days to 38.3 compared with radiation only. CONCLUSION: This study demonstrates the potential of Au@DTDTPA to enhance CT-image contrast and simultaneously increases the radiosensitivity of prostate tumors.
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Oro/uso terapéutico , Nanopartículas del Metal/uso terapéutico , Ácido Pentético/uso terapéutico , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Línea Celular Tumoral , Tomografía Computarizada de Haz Cónico , Oro/química , Oro/farmacocinética , Humanos , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/ultraestructura , Ratones SCID , Ácido Pentético/análogos & derivados , Ácido Pentético/farmacocinética , Fantasmas de Imagen , Próstata/patología , Próstata/efectos de la radiación , Neoplasias de la Próstata/patología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacocinética , Compuestos de Sulfhidrilo/uso terapéutico , Nanomedicina TeranósticaRESUMEN
Ultrasound-stimulated microbubbles have been demonstrated to mechanically perturb cell membranes, resulting in the activation of biological signaling pathways that significantly enhance the effects of radiation. The underlying mechanism involves augmented ceramide production following both microbubble stimulation and irradiation, leading to rapid and extensive endothelial apoptosis and tumor cell death as a result of vascular collapse. Endothelial cells are particularly sensitive to ceramide-induced cell death due to an enriched presence of sphingomyelinase in their membranes. In tumors, this consequent rapid vascular shutdown translates to an overall increase in tumor responses to radiation treatments. This review summarizes the groundwork behind endothelial-based radiation enhancement with ultrasound-stimulated microbubbles, and presents ongoing research on the use of microbubbles as therapeutic agents in cancer therapy.
Asunto(s)
Fenómenos Biomecánicos/fisiología , Microburbujas , Neoplasias/radioterapia , Terapia por Ultrasonido , Supervivencia Celular/efectos de la radiación , Ceramidas/metabolismo , Humanos , Transducción de Señal/fisiologíaRESUMEN
Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-(177)Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [mean±SEM]: 2.7±0.2µM vs. 11.3±1.2µM against 4T1 cells; 1.8±0.2 vs. 17.1±1.26µM against Miapaca-2 cells; p<0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p<0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-(177)Lu radiotherapy as measured by clonogenic assay (p<0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-(177)Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-(177)Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.
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Antineoplásicos/administración & dosificación , Lutecio/administración & dosificación , Neoplasias Mamarias Experimentales/terapia , Nanopartículas/administración & dosificación , Neoplasias Pancreáticas/terapia , Radioisótopos/administración & dosificación , Alcaloides de Veratrum/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Quimioradioterapia , Terapia Combinada , Femenino , Humanos , Lutecio/farmacocinética , Lutecio/uso terapéutico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Distribución Tisular , Carga Tumoral/efectos de los fármacos , Alcaloides de Veratrum/farmacocinética , Alcaloides de Veratrum/uso terapéuticoRESUMEN
We examined the dependence of hydroxyl radical production on the concentration of 15 nm citrate-capped AuNPs and dose using coumarin-3-carboxylic acid in phosphate buffered saline (PBS), and investigated the radiosensitisation of different concentration AuNPs on human cervix carcinoma HeLa cells through clonogenic survival assay for X-rays and carbon ions. The enhancement factor of AuNPs for hydroxyl radical production reached a maximum 3.66 for X-rays at the concentration of 0.1 µg/mL while the maximum was 5.52 for carbon ions in presence of 1.0 µg/mL AuNPs in PBS. At 50% survival level, the sensitizer enhancement ratios of X-rays and carbon ions varied from 1.14 to 2.88 and from 1.27 to 1.44, respectively, when cells were co-cultured with 1.5-15.0 µg/mL AuNPs. Our data indicate AuNPs showed radiosensitisation in terms of hydroxyl radical production and cell killing for low- and high-LET radiations. The concentration of AuNPs in PBS and cells played an important role in radiosensitizing effect. Based on the fact-the AuNPs in PBS could improve the production of hydroxyl radical and no accumulation of cells in the G2/M phase was observed, we deduce that the increment of hydroxyl radical production with AuNPs provided a mechanism for radiosensitisation.