ABSTRACT
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.
Subject(s)
Ferroptosis , Lactic Acid , Pyruvic Acid , Tumor Microenvironment , Ferroptosis/drug effects , Humans , Lactic Acid/metabolism , Animals , Pyruvic Acid/metabolism , Tumor Microenvironment/drug effects , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/therapy , Cell Line, Tumor , Mice , Gold/chemistry , Silicon Dioxide/chemistry , Female , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Mice, Inbred BALB C , Cell Proliferation/drug effects , Mixed Function Oxygenases , IndazolesABSTRACT
As emerging nanosystems, nanomotors have been applied in the active treatment of many diseases. In this paper, Pt@chitosan-loaded melatonin asymmetrical nanomaterials embedded with L-serine (S, kidney injury molecule 1-targeting agent) were constructed to alleviate acute kidney injury (AKI). The Janus nanocarriers arrived at the renal injury site via the bloodstream and exhibited high permeability. Because of melatonin distribution in the kidneys combined with H2O2-stimulated O2 release, the administration of the Janus nanosystem resulted in active treatment through the motion of nanomotors by asymmetrical O2 release.
