RESUMEN
Biosynthesis offers opportunities for cost-effective and sustainable production of semiconductor quantum dots (QDs), but is currently restricted by poor controllability on the synthesis process, resulting from limited knowledge on the assembly mechanisms and the lack of effective control strategies. In this work, we provide molecular-level insights into the formation mechanism of biogenic QDs (Bio-QDs) and its connection with the cellular substrate metabolism in Escherichia coli. Strengthening the substrate metabolism for producing more reducing power was found to stimulate the production of several reduced thiol-containing proteins (including glutaredoxin and thioredoxin) that play key roles in Bio-QDs assembly. This effectively diverted the transformation route of the selenium (Se) and cadmium (Cd) metabolic from Cd3(PO4)2 formation to CdS xSe1- x QDs assembly, yielding fine-sized (2.0 ± 0.4 nm), high-quality Bio-QDs with quantum yield (5.2%) and fluorescence lifetime (99.19 ns) far exceeding the existing counterparts. The underlying mechanisms of Bio-QDs crystallization and development were elucidated by density functional theory calculations and molecular dynamics simulation. The resulting Bio-QDs were successfully used for bioimaging of cancer cells and tumor tissue of mice without extra modification. Our work provides fundamental knowledge on the Bio-QDs assembly mechanisms and proposes an effective, facile regulation strategy, which may inspire advances in controlled synthesis and practical applications of Bio-QDs as well as other bionanomaterials.
Asunto(s)
Cadmio/química , Imagen Molecular/métodos , Puntos Cuánticos/química , Selenio/química , Animales , Cadmio/farmacología , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fluorescencia , Glutarredoxinas/química , Glutarredoxinas/genética , Humanos , Ratones , Microscopía Fluorescente/métodos , Puntos Cuánticos/metabolismo , Selenio/farmacología , Especificidad por Sustrato/efectos de los fármacos , Tiorredoxinas/química , Tiorredoxinas/genéticaRESUMEN
Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)-block-poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin, leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro. Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance.
Asunto(s)
Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Lípidos/química , Nanopartículas/química , Profármacos/farmacología , Células A549 , Animales , Cationes , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacocinética , Ácidos Grasos Monoinsaturados/química , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Poliésteres/química , Polietilenglicoles/química , Profármacos/química , Profármacos/farmacocinética , Compuestos de Amonio Cuaternario/química , Distribución Tisular/efectos de los fármacosRESUMEN
Rationally designed PIC nanoparticles as next-generation delivery system: we have developed a core-shell-corona PIC nanoparticle (â) NP/Pt@PPC-DA as a next-generation delivery system. (â) NP/Pt@PPC-DA exhibits prolonged circulation and enhanced drug accumulation in tumors. Subsequently, tumor pH leads to the release of (â) NP/Pt, which facilitates cellular uptake followed by rapid intracellular cisplatin release. Using this delivery strategy cisplatin-resistant tumor growth in a murine xenograft model has been successfully suppressed.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Resistencia a Antineoplásicos , Nanoconjugados , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Línea Celular Tumoral , Cisplatino/sangre , Cisplatino/química , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Nanoconjugados/administración & dosificación , Nanoconjugados/química , Platino (Metal)/química , Platino (Metal)/metabolismo , Profármacos/administración & dosificación , Profármacos/química , Profármacos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel fluorescent probe for gold ions (Au(3+)/Au(+)) is reported through blocking photoinduced electron transfer, in which a boron dipyrromethene (Bodipy) derivative reveals high selectivity and sensitivity in a gold-catalyzed intramolecular hydroamination, and is successfully applied to fluorescence imaging of Au(3+) in living cells.
Asunto(s)
Compuestos de Boro/química , Colorantes Fluorescentes/química , Oro/análisis , Imagen Molecular/métodos , Fotoquímica/métodos , Aminación , Compuestos de Boro/análisis , Colorantes Fluorescentes/análisis , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Iones , Microscopía Fluorescente , Sensibilidad y Especificidad , Espectrometría de FluorescenciaRESUMEN
AA-NADase from Agkistrodon acutus venom is a unique multicatalytic enzyme with both NADase and AT(D)Pase activities. Among all identified NADases, only AA-NADase contains Cu(II) and has disulfide-bond linkages between two peptide chains. The effects of the reduction of the disulfide-bonds and Cu(II) in AA-NADase by small-molecule reductants on its NADase and ADPase activities have been investigated by polyacrylamide gel electrophoresis, high performance liquid chromatography, electron paramagnetic resonance spectroscopy and isothermal titration calorimetry. The results show that AA-NADase has six disulfide-bonds and fifteen free cysteine residues. L-ascorbate inhibits AA-NADase on both NADase and ADPase activities through the reduction of Cu(II) in AA-NADase to Cu(I), while other reductants, dithiothreitol, glutathione and tris(2-carboxyethyl)phosphine inhibit both NADase and ADPase activities through the reduction of Cu(II) to Cu(I) and the cleavage of disulfide-bonds in AA-NADase. Apo-AA-NADase can recover its NADase and ADPase activities in the presence of 1 mM Zn(II). However, apo-AA-NADase does not recover any NADase or ADPase activity in the presence of 1 mM Zn(II) and 2 mM TCEP. The multicatalytic activity relies on both disulfide-bonds and Cu(II), while Cu(I) can not activate the enzyme activities. AA-NADase is probably only active as a dimer. The inhibition curves for both ADPase and NADase activities by each reductant share a similar trend, suggesting both ADPase and NADase activities probably occur at the same site. In addition, we also find that glutathione and L-ascorbate are endogenous inhibitors to the multicatalytic activity of AA-NADase.