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1.
Small ; 18(38): e2203080, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35989099

RESUMO

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO2- x . Compared to 3.09 eV of nano-ZrO2- x , the bandgap of ZrO2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e- /h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (• R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives.


Assuntos
Neoplasias , Terapia por Ultrassom , Animais , Catalase/metabolismo , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico , Neoplasias/terapia , Estresse Oxidativo , Oxigênio , Platina , Propano , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete , Termodinâmica , Microambiente Tumoral
2.
ACS Nano ; 18(11): 8083-8098, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38456744

RESUMO

Active polymetallic atomic clusters can initiate heterogeneous catalytic reactions in the tumor microenvironment, and the products tend to cause manifold damage to cell metabolic functions. Herein, bimetallic PtPd atomic clusters (BAC) are constructed by the stripping of Pt and Pd nanoparticles on nitrogen-doped carbon and follow-up surface PEGylation, aiming at efficacious antineoplastic therapy through heterogeneous catalytic processes. After endocytosed by tumor cells, BAC with catalase-mimic activity can facilitate the decomposition of endogenous H2O2 into O2. The local oxygenation not only alleviates hypoxia to reduce the invasion ability of cancer cells but also enhances the yield of •O2- from O2 catalyzed by BAC. Meanwhile, BAC also exhibit peroxidase-mimic activity for •OH production from H2O2. The enrichment of reactive oxygen species (ROS), including the radicals of •OH and •O2-, causes significant oxidative cellular damage and triggers severe apoptosis. In another aspect, intrinsic glutathione (GSH) peroxidase-like activity of BAC can indirectly upregulate the level of lipid peroxides and promote ferroptosis. Such deleterious redox dyshomeostasis caused by ROS accumulation and GSH consumption also results in immunogenic cell death to stimulate antitumor immunity for metastasis suppression. Collectively, this paradigm is expected to inspire more facile designs of polymetallic atomic clusters in disease therapy.


Assuntos
Antineoplásicos , Ferroptose , Neoplasias , Humanos , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Apoptose , Peroxidases , Antineoplásicos/farmacologia , Catálise , Glutationa , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Microambiente Tumoral
3.
Biomaterials ; 302: 122340, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37774552

RESUMO

Ion homeostasis distortion through exogenous overload or underload of intracellular ion species has become an arresting therapeutic approach against malignant tumor. Nevertheless, treatment outcomes of such ion interference are always compromised by the intrinsic ion homeostasis maintenance systems in cancer cells. Herein, an ion homeostasis perturbator (CTC) is facilely designed by co-encapsulation of carvacrol (CAR) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) into pH-sensitive nano-CaCO3, aiming to disrupt the self-defense mechanism during the process of ion imbalance. Upon the endocytosis of CTC into tumor cells, lysosomal acidity can render the decomposition of CaCO3, resulting in the instant Ca2+ overload and CO2 generation in cytoplasm. Simultaneously, CaCO3 disintegration triggers the release of CAR and TCPP, which are devoted to TRPM7 inhibition and sonosensitization, respectively. The malfunction of TRPM7 can impede the influx of Mg2+ and allow unrestricted influx of Ca2+ based on the antagonism relationship between Mg2+ and Ca2+, leading to an aggravated Ca2+/Mg2+ dyshomeostasis through ion channel deactivation. In another aspect, US-triggered cavitation can be significantly enhanced by the presence of inert CO2 microbubbles, further amplifying the generation of reactive oxygen species. Such oxidative damage-augmented Ca2+/Mg2+ interference therapy effectively impairs the mitochondrial function of tumor, which may provide useful insights in cancer therapy.


Assuntos
Canais de Cátion TRPM , Dióxido de Carbono , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Homeostase , Carbonato de Cálcio , Cálcio/metabolismo
4.
Biomaterials ; 286: 121572, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35580473

RESUMO

Endogenous H2O2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H2O2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H2O2-rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn2+/3+. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O2 replenishment through Pt-catalyzed decomposition of H2O2. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H2O2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H2O2 balance during H2O2-depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.


Assuntos
Peróxido de Hidrogênio , Neoplasias , Linhagem Celular Tumoral , Glucose/metabolismo , Glucose Oxidase/metabolismo , Homeostase , Humanos , Peróxido de Hidrogênio/metabolismo , Manganês/uso terapêutico , Mitocôndrias/metabolismo , Neoplasias/terapia , Platina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral
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