RESUMEN
Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (â¢OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting â¢OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent â¢OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.
Asunto(s)
Antineoplásicos/uso terapéutico , Cobre/química , Peróxido de Hidrógeno/metabolismo , Neoplasias/tratamiento farmacológico , Puntos Cuánticos/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Radical Hidroxilo/metabolismo , Lisosomas/efectos de los fármacos , Ratones , Puntos Cuánticos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Autofluorescence background in complex biological samples is a major challenge in achieving high sensitivity of fluorescence immunoassays (FIA). Here we report an X-ray luminescence-based immunoassay for high-sensitivity detection of biomarkers using X-ray scintillating nanotags. Due to the weak scattering and absorption of most biological chromophores by X-ray excitation, a low-dose X-ray source can be used to produce intense scintillating luminescence from the nanotags for autofluorescence-free biosensing. To demonstrate this concept, we designed and synthesized NaGdF4:Tb@NaYF4 core/shell nanoparticles as kind of high-efficiency X-ray scintillating nanotags, which are able to convert high-energy X-ray photons to visible light without autofluorescence in biological samples. Notably, strong X-ray absorption and minimized surface quenching arising from the heavy Gd3+/Tb3+ atoms and core/shell architecture of the nanoparticles were found to be critically important for high-efficiency X-ray excited luminescence for high-sensitivity biosensing. Our method allows for sensing alpha-fetoprotein (AFP) biomarkers with a detection limit down to 0.25 ng/mL. Moreover, the as-described X-ray luminescence immunoassay exhibited an excellent biological specificity, high stability, and sample recovery, implying an opportunity for applications in complex biological samples. Consequently, our method can be readily extended for multiplexing sensing and medical diagnosis.
Asunto(s)
Inmunoensayo , Nanopartículas/química , Rayos X , alfa-Fetoproteínas/análisis , Animales , Biomarcadores/sangre , Células Cultivadas , Fluorescencia , Humanos , Inyecciones Subcutáneas , Mediciones Luminiscentes , Ratones , Ratones Desnudos , Nanopartículas/administración & dosificación , Neoplasias Experimentales/diagnóstico por imagen , Imagen Óptica , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Hypoxic tumor microenvironment (TME) is closely linked to tumor progression, heterogeneity and immune suppression. Therefore, the development of effective methods to overcome hypoxia and substantially enhance the immunotherapy efficacy remains a desirable goal. Herein, we engineered a biocompatible Au core/Pt shell nanoparticles (Au@Pt NPs) to reoxygenate the TME by reacting with endogenous H2O2. Treatment with Au@Pt NPs appeared to improve oxygen in intracellular environments and decrease hypoxia-inducible factor-1α expression. Furthermore, the integration of high catalytic efficiency of Au@Pt NPs with cytokine-induced killer (CIK) cell immunotherapy, could lead to significantly improve the effect of CIK cell-mediated cytotoxicity. These results suggest great potential of Au@Pt NPs for regulation of the hypoxic TME and enhance immune cell mediated anti-tumor immunity.