RESUMEN
Disruption of the symbiosis of extra/intratumoral metabolism is a good strategy for treating tumors that shuttle resources from the tumor microenvironment. Here, we report a precision treatment strategy for enhancing pyruvic acid and intratumoral acidosis to destroy tumoral metabolic symbiosis to eliminate tumors; this approach is based on PEGylated gold and lactate oxidase-modified aminated dendritic mesoporous silica with lonidamine and ferrous sulfide loading (PEG-Au@DMSNs/FeS/LND@LOX). In the tumor microenvironment, LOX oxidizes lactic acid to produce pyruvate, which represses tumor cell proliferation by inhibiting histone gene expression and induces ferroptosis by partial histone monoubiquitination. In acidic tumor conditions, the nanoparticles release H2S gas and Fe2+ ions, which can inhibit catalase activity to promote the Fenton reaction of Fe2+, resulting in massive ·OH production and ferroptosis via Fe3+. More interestingly, the combination of H2S and LND (a monocarboxylic acid transporter inhibitor) can cause intracellular acidosis by lactate, and protons overaccumulate in cells. Multiple intracellular acidosis is caused by lactate-pyruvate axis disorders. Moreover, H2S provides motive power to intensify the shuttling of nanoparticles in the tumor region. The findings confirm that this nanomedicine system can enable precise antitumor effects by disrupting extra/intratumoral metabolic symbiosis and inducing ferroptosis and represents a promising active drug delivery system candidate for tumor treatment.
Asunto(s)
Ferroptosis , Ácido Láctico , Ácido Pirúvico , Microambiente Tumoral , Ferroptosis/efectos de los fármacos , Humanos , Ácido Láctico/metabolismo , Animales , Ácido Pirúvico/metabolismo , Microambiente Tumoral/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/terapia , Línea Celular Tumoral , Ratones , Oro/química , Dióxido de Silicio/química , Femenino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Oxigenasas de Función Mixta , IndazolesRESUMEN
A 128-channel picoammeter system is constructed based on instrumentation amplifiers. Taking advantage of a high electric potential and narrow bandwidth in DC energetic charged beam measurements, a current resolution better than 5 fA can be achieved. Two sets of 128-channel strip electrodes are implemented on printed circuit boards and are employed for ion and electron beam current distribution measurements. Tests with 60 keV O(3+) ions and 2 keV electrons show that it can provide exact boundaries when a positive charged particle beam current distribution is measured.
RESUMEN
We have developed a real-time beam current density meter for charged particle beams. It measures the mean current density by collimating a uniform and large diameter primary beam. The suppression of the secondary electrons and the deflection of the beam were simulated, and it was tested with a 105 keV Ar(7+) ion beam.