Phase Engineered CuxS-Ag2S with Photothermoelectric Activity for Enhanced Multienzyme Activity and Dynamic Therapy.

The insufficient exposure sites and active site competition of multienzyme are the two main factors to hinder its therapeutic effect. Here, a phase-junction nanomaterial (amorphous-crystalline CuxS-Ag2S) is designed and prepared through a simple room temperature ion-exchange process. A small amount of Ag+ is added into Cu7S4 nanocrystals, which transforms Cu7S4 into amorphous phased CuxS and produces crystalline Ag2S simultaneously. In this structure, the overhanging bonds on the amorphous CuxS surface provide abundant active sites for optimizing the therapeutic activity. Meanwhile, the amorphous state enhances the photothermal effect through non-radiative relaxation, and due to its low thermal resistance, phase-junction CuxS-Ag2S forms a significant temperature gradient to unlock the optimized thermo-electrodynamic therapy. Furthermore, benefiting from the high asymmetry of the amorphous state, the material forms a spin-polarized state that can effectively inhibit electron-hole recombination. In this way, the thermoelectric effect can facilitate the enzyme-catalyzed cycle by providing electrons and holes, enabling an enhanced coupling of thermoelectric therapy with multienzyme activity, which induces excellent anti-tumor performance. More importantly, the catalytic process simulated by density-functional theory proves that Ag+ alleviates the burden on the Cu sites through favorable adsorption of O2 and prevents active site competition.

Tirapazamine-loaded UiO-66/Cu for ultrasound-mediated promotion of chemodynamic therapy cascade hypoxia-activated anticancer therapy.

Chemodynamic therapy (CDT), an emerging oncology treatment, has received considerable attention owing to its high selectivity, less aggressiveness, and endogenous stimulation. However, the complex intra-tumor environment limits the therapeutic effect. In this study, Cu+ was directly doped into the structure of the UiO-66 matrix using an in situ one-pot oil bath method. The as-formed UiO-66/Cu possessed a large surface area, making it feasible to modify folic acid (FA) and carry more chemotherapeutic agents like tirapazamine (TPZ), thus forming UiO-66/Cu-FA-TPZ nanoplatforms. For CDT, the nanoplatform catalyzed the cyclic generation of the highly oxidizing hydroxyl radical (·OH) from H2O2. Particularly, low-frequency ultrasound enhanced the curative effect. Notably, in a tumor, a severe hypoxic environment and ultrasound can activate more TPZ for safe and efficient chemotherapy, achieving synergistic and hypoxia-activated tumor treatment with a low risk of side effects. Moreover, the nanoplatform exhibits computed tomography imaging functions for combined diagnosis and treatment. Our designed nanoplatform overcomes the dilemma of insufficient efficacy from conventional therapy attributed to a hypoxic environment, expecting to guide the design of future treatment regimens for hypoxic tumors.

Dual Glutathione Depletion Enhanced Enzyme Catalytic Activity for Hyperthermia Assisted Tumor Therapy on Semi-Metallic VSe2/Mn-CS.

Semimetallic nanomaterials as photothermal agents for bioimaging and cancer therapy have attracted tremendous interest. However, the poor photothermal stability, low biocompatibility, and single component limit their therapeutic efficiency in cancer treatment. Here, manganese-doped VSe2 semimetallic nanosheets were prepared and subsequently modified with chitosan (named VSe2/Mn-CS NSs) for combined enzyme catalytic and photothermal therapy. VSe2/Mn-CS NSs show high photothermal property with a photothermal conversion efficiency of 34.61% upon 808 nm near-infrared laser irradiation. In the tumor microenvironment, VSe2/Mn-CS NSs can convert endogenous H2O2 into lethal hydroxyl radicals (•OH) to induce cancer cell apoptosis. The interaction between glutathione (GSH) and Se-Se bonds in VSe2/Mn-CS NSs results in the depletion of GSH level, and the valence states transition of manganese ions is also beneficial for the GSH consumption. This dual depletion of GSH markedly enhances the peroxidase (POD) activity, leading to the high •OH production and the improved therapeutic effect. What is more, the T1-weighted magnetic resonance and photoacoustic imaging endow VSe2/Mn-CS NSs with the ability to guide and track the treatment process. Our study provides a research strategy for the application of semimetallic nanomaterials in cancer diagnosis and treatment.

On-Demand Triggered Chemodynamic Therapy by NIR-II Light on Oxidation-Prevented Bismuth Nanodots.

As the least toxic heavy metal, monoelemental bismuth nanomaterials with several superiorities are the ideal theranostic agents. However, bismuth nanoparticles are easily oxidized by oxygen in air or media, limiting their clinical application. In contrast, the oxidization of Bi0 to Bi3+ can activate the chemodynamic therapy (CDT) by transferring endogenous H2O2 into •OH. Herein, a well-designed Bi-DMSNs@PCM nanosystem was prepared via in situ growth of Bi nanodots and a coating of phase-change material (PCM) on the surface of dendritic mesoporous silica nanoparticles (DMSNs). The coated PCM protects the Bi nanodots from oxidation by keeping them in the Bi0 state for more than 15 d. When irradiated using the near infrared-II (NIR-II) laser with a low power density (0.5 W/cm2), the heat generated from the Bi nanodots melts the PCM shell to trigger CDT through a Fenton-like reaction, accompanied by heat-induced photothermal therapy (PTT). Notably, the CDT can also compensate for the reduced PTT effect caused by the oxidation of Bi nanodots, and a satisfactory treatment effect is realized. Additionally, photoacoustic and computed tomography imaging properties were obtained. Our strategy transfers the detrimental self-oxidation of bismuth to a beneficial therapeutic mode, enhancing the potential of Bi for clinical use.

A Class of Biocompatible Dye-Protein Complex Optical Nanoprobes.

Molecular organic dyes are classic fluorescent nanoprobes finding tremendous uses in biological and life sciences. Yet, they suffer from low brightness, poor photostability, and lack of functional groups for bioconjugation. Here, we describe a class of biocompatible dye-protein optical nanoprobes, which show long-time photostability, superbrightness, and enriched functional groups. These nanoprobes utilize apoferritin (an intracellular protein for iron stores and release) to encase appropriate molecular organic dyes to produce on-demand fluorescence in aqueous solution. A pH-driven dissociation-reconstitution process of apoferritin subunits allows substantial incorporation of hydrophilic (aggregation caused quenching, ACQ) or hydrophobic (aggregation induced enhancement, AIE) dye molecules into the protein nanocavity (8 nm), producing monodispersed dye-apoferritin nanoparticles (apo-dye-NPs, ∼12 nm). As compared with single dye monomer, single apo-dye-NPs possess hundreds of times larger molar extinction coefficient and 2 orders of magnitude higher absolute luminescence quantum yield (up to 45-fold), multiplying fluorescence brightness up to 2778-fold. We show that varying the type of incorporated dyes entails a precise control over nanoprobe emission profile tunable in a broad spectral range of 370-1300 nm. Mechanical investigations indicate that the diversified microstructures of nanocavity inner surface are able to conform ACQ dyes at reasonable space interval while providing protein-guided-stacking for AIE dyes, thus enhancing fluorescence quantum yield through confining intermolecular quenching and intramolecular rotation. Moreover, apo-dye-NPs are able to emit stable fluorescence (over 13 min) without quenching in confocal imaging of HepG2 cancer cell under ultrahigh laser irradiance (1.3 × 106 W/cm2). These superb properties make them suitable, as demonstrated in this work, for long-term super-resolved structured illumination microscopic cell imaging (spatial resolution, 117 nm) over 48 h, near-infrared (NIR) fluorescence angiography imaging of whole-body blood vessels (spatial resolution, 380 µm), and NIR photoacoustic imaging of liver in vivo.

Lack of PINK1 alters glia innate immune responses and enhances inflammation-induced, nitric oxide-mediated neuron death.

Neuroinflammation is involved in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. We show that lack of PINK1- a mitochondrial kinase linked to recessive familial PD - leads to glia type-specific abnormalities of innate immunity. PINK1 loss enhances LPS/IFN-γ stimulated pro-inflammatory phenotypes of mixed astrocytes/microglia (increased iNOS, nitric oxide and COX-2, reduced IL-10) and pure astrocytes (increased iNOS, nitric oxide, TNF-α and IL-1ß), while attenuating expression of both pro-inflammatory (TNF-α, IL-1ß) and anti-inflammatory (IL-10) cytokines in microglia. These abnormalities are associated with increased inflammation-induced NF-κB signaling in astrocytes, and cause enhanced death of neurons co-cultured with inflamed PINK1 -/- mixed glia and neuroblastoma cells exposed to conditioned medium from LPS/IFN-γ treated PINK1 -/- mixed glia. Neuroblastoma cell death is prevented with an iNOS inhibitor, implicating increased nitric oxide production as the cause for enhanced death. Finally, we show for the first time that lack of a recessive PD gene (PINK1) increases α-Synuclein-induced nitric oxide production in all glia types (mixed glia, astrocytes and microglia). Our results describe a novel pathogenic mechanism in recessive PD, where PINK1 deficiency may increase neuron death via exacerbation of inflammatory stimuli-induced nitric oxide production and abnormal innate immune responses in glia cells.

Development of metoprolol tartrate-loaded sustained-release pellets: effect of talc on the mechanism of drug release.

Talc is one of the most commonly used antiadherents in the coating film. However, the mechanism of influence of talc on drug release has yet to be fully understood. In this study, metoprolol tartrate (MT)-loaded Eudragit NE 30 D-coated sustained-release (SR) pellets were prepared using talc as an antiadherent in the layering and coating processes. Talc significantly reduced the stickiness of the layered or coated substrates, thus enhancing the process smoothness. Moreover, the incorporation of talc into the coating film significantly affected drug release. The water vapor permeability and drug permeability of free films increased as the concentration of talc increased. Importantly, talc had a dynamic effect on the drug release. The drug release rate of the pellets in the initial stage (within 2 h) increased with increasing talc concentrations, which exceeded the critical pigment volume concentration resulted in leaks formation in the coated film. However, subsequent swelling of the membrane and expansion of the copolymer network eliminated the influence of talc and the drug release was then controlled by the polymeric membrane. These results suggest that talc contributed to the reduction of the sticking of layered or coated substrates, and facilitated the manufacturing process and drug release properties.