Cu2WS4-PEG Nanozyme as Multifunctional Sensitizers for Enhancing Immuno-Radiotherapy by Inducing Ferroptosis.

Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu2WS4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.

Mannosylated polydopamine nanoparticles alleviate radiation- induced pulmonary fibrosis by targeting M2 macrophages and inhibiting the TGF-ß1/Smad3 signaling pathway.

Radiation-induced pulmonary fibrosis (RIPF), one type of pulmonary interstitial diseases, is frequently observed following radiation therapy for chest cancer or accidental radiation exposure. Current treatments against RIPF frequently fail to target lung effectively and the inhalation therapy is hard to penetrate airway mucus. Therefore, this study synthesized mannosylated polydopamine nanoparticles (MPDA NPs) through one-pot method to treat RIPF. Mannose was devised to target M2 macrophages in the lung through CD 206 receptor. MPDA NPs showed higher efficiency of penetrating mucus, cellular uptake and ROS-scavenging than original polydopamine nanoparticles (PDA NPs) in vitro. In RIPF mice, aerosol administration of MPDA NPs significantly alleviated the inflammatory, collagen deposition and fibrosis. The western blot analysis demonstrated that MPDA NPs inhibited TGF-ß1/Smad3 signaling pathway against pulmonary fibrosis. Taken together this study provide a novel M2 macrophages-targeting nanodrugs through aerosol delivery for the prevention and targeted treatment for RIPF.

Catalytically Active CoFe2O4 Nanoflowers for Augmented Sonodynamic and Chemodynamic Combination Therapy with Elicitation of Robust Immune Response.

A hypoxic and acidic tumor microenvironment (TME) plays a significant role in cancer development through complex cellular signaling networks, and it is thus challenging to completely eradicate tumors via monotherapy. Here, PEGylated CoFe2O4 nanoflowers (CFP) with multiple enzymatic activities, serving as bioreactors responsive to TME cues, were synthesized via a typical solvothermal method for augmented sonodynamic therapy (SDT) and chemodynamic therapy (CDT) with elicitation of robust immune response. The CFP occupying multivalent elements (Co2+/3+, Fe2+/3+) exhibited strong Fenton-like and catalase-like activity. In another aspect, CFP itself is a brand-new sonosensitizer for high-performance SDT based on ultrasound-triggered electron (e-)/hole (h+) pair separation from the energy band with promptness and high efficiency. With efficient enrichment in tumorous tissue as revealed by magnetic resonance imaging, CPF could generate •OH for CDT relying on Fenton-like reactions. Moreover, catalase-mimicking CFP could react with endogenous H2O2 to generate molecular oxygen, and high O2 level may promote the production of 1O2 for SDT. What's more, the reactive oxygen species obtained from combined SDT/CDT could efficiently trigger immunogenic cell death through a synergistic therapy based on the elicitation of antitumor immunity with the aid of an immune checkpoint blockade for the sake of suppressing primary and distant tumors as well as lung metastasis. Taken together, this paradigm delivers useful insights for developing in-coming nanocomposites based on cobalt ferrite for cancer theranostics.

Facile engineering of silk fibroin capped AuPt bimetallic nanozyme responsive to tumor microenvironmental factors for enhanced nanocatalytic therapy.

Background: Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells in situ. However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy. In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization. Methods: As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF). Antitumor effects caused by the as-synthesized AuPt@SF (APS) nanozyme were demonstrated in 4T1 tumor cells in vitro and xenograft tumor models in vivo. Results: APS nanozyme can decompose glucose to constantly supply H2O2 and deplete intracellular glutathione (GSH). APS nanozyme can simultaneously convert adsorbed O2 and endogenic H2O2 into superoxide radicals (•O2-) and hydroxyl radical (•OH), respectively, upon highly efficient catalytic reaction. Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors. Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed in vivo. Conclusion: The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics.

Biomimetic CoO@AuPt nanozyme responsive to multiple tumor microenvironmental clues for augmenting chemodynamic therapy.

Chemodynamic therapy (CDT), an emerging therapeutic strategy, has been recently exploited for in situ treatment through Fenton or Fenton-like reactions to generate cytotoxic reactive oxygen species (ROS). However, current systems rely significantly on the high local oxygen levels and strongly acidic conditions (pH = 3.0-5.0). Simultaneously, the produced ROS can be rapidly consumed by intracellular glutathione (GSH) in the electron transport chain. Herein, an original and biomimetic CoO@AuPt nanocatalyst was prepared based on the assembly of Au and Pt nanoparticles (NPs) on the surface of hollow CoO nanocapsules. The as-synthesized nanozyme exhibits extremely high stability under physiological conditions, whereas it undergoes spontaneous disintegration in the unique tumor microenvironment (TME). Subsequently, the decomposition products can catalyze a cascade of biochemical reactions to produce abundant ROS without any external stimuli. Thus, the present nanoplatform can increase intracellular ROS levels through continuous supply of H2O2, relief of local hypoxia and depletion of GSH, which result in remarkable and specific tumor damage both in vitro and in vivo. The findings of this study highlight the promising potential of CoO@AuPt nanocatalyst as a TME-responsive CDT nanomagnet for highly efficient tumor therapy.

Protective effect of Polygonatum sibiricum against cadmium-induced testicular injury in mice through inhibiting oxidative stress and mitochondria-mediated apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum sibiricum (PS), the dried rhizome of the liliaceous plant including P. sibiricum Red., P. cyrtonema Hua. and P. kingianum Coll. et Hemsl., is a widely used Chinese herbal medicines. It was first published in "Special Records of Famous Doctors", in which is described to replenished Qi and nourish Yin, strengthening the spleen and nourishing the lungs and kidney. Based on the principle of kidney controlling the reproduction, kidney-tonifying therapy has traditionally been seen as most applicable to the treatment of infertility. The current investigation has focused on the protective effect of PS against cadmium-induced testicular injury in mice. AIM OF THE STUDY: To investigate the protective effect of PS against cadmium-induced testicular injury in mice via the TXNIP-NLRP3-Caspase-1 and CytC-Caspase-9-Caspase-3 pathways. MATERIALS AND METHODS: PS was processed into Polygonatum sibiricum aqueous extract (PSAE). A mouse testicular injury model was established by a single intraperitoneal (i.p.) injection of cadmium chloride (CdCl2) (2.5 mg/kg b.w.), and the mice were treated intragastrically with PSAE (10 g/kg b.w.) once daily for 35 consecutive days. At the end of the experiment blood and testicular tissue samples were collected to analyze sperm survival rate and sperm deformity rate, serum testosterone T content, testicular oxidation related indicators levels (SOD, MDA, GSH, CAT) in testicular tissue, and histopathological changes of testicular tissues. The testicular cell cycle and reactive oxygen species (ROS) levels were measured by flow cytometry, the expression levels of thioredoxin-interacting protein (TXNIP), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Caspase-1, interleukin (IL)-1ß, Cyctochrome C (CytC), Caspase-3, and Caspase-9 mRNA in testicular tissue were detected by qRT-PCR and the protein expression levels of TXNIP, NLRP3, Caspase-1, CytC, Caspase-3, and Caspase-9 were detected by Western blot and immunohistochemical method. RESULTS: The results indicated that compared with the model group, PSAE brought testicular weight to a near-normal range, improved sperm survival rate and reduced sperm abnormality rate, elevated the level of testosterone, made the damaged testis tissue recover to near normal, reduced the level of ROS, and inhibited testicular cell apoptosis. Further study showed that PSAE significantly decreased the levels of relative genes and proteins in testicular cells, such as TXNIP, NLRP3, Caspase-1, IL-1ß, CytC, Caspase-3, and Caspase-9, which suggested that PSAE could regulate oxidative stress through the TXNIP-NLRP3-Caspase-1 signaling pathway, and inhibit apoptosis in the mitochondrial pathway via CytC-Caspase-9-Caspase-3 pathway. In summary, we have confirmed that PSAE exerted a powerful protective effect on CdCl2-induced testicular injury in mice through inhibiting oxidative stress and mitochondria-mediated apoptosis.

Structural effect of Fe3O4 nanoparticles on peroxidase-like activity for cancer therapy.

Ferromagnetic nanoparticles (Fe3O4 NPs) have been proven to have the intrinsic peroxidase-like activity. This property has been used for analyte detection, tumor tissue visualization, and cancer therapy, etc. However, the effect of particle structure and morphology on its peroxidase-like activity has been rarely reported. In this work, we fabricated Fe3O4 nanoparticles with different structures (nanoclusters, nanoflowers, and nanodiamonds) by facilely tuning the pH values in the hydrothermal reaction. Their in vitro peroxidase-like activity was evaluated via chromogenic reaction of 3,3',5,5'-tetramethylbenzidine (TMB) by the reduction of H2O2 to H2O. It was found the nanostructures had a great influence on their peroxidase-like activity, following the order of nanoclusters>nanoflowers>nanodiamonds. With this activity, the peroxidase-like activity of Fe3O4 NPs was used for cancer therapy with the addition of low-concentration H2O2. The cancer cell-killing activity was due to the intracellular generated reactive oxygen species (ROS) after endocytosis of Fe3O4 NPs into the Hela cells. It was interesting that the cell killing ability of these three kinds of Fe3O4 NPs was not consistent with the in vitro enzyme-like activity. It was deduced that the cell endocytosis of the nanoparticles along with their enzyme-like activity co-determined their cancer cell-killing performance.

Microenvironment-Driven Bioelimination of Magnetoplasmonic Nanoassemblies and Their Multimodal Imaging-Guided Tumor Photothermal Therapy.

Biocompatibility and bioelimination are basic requirements for systematically administered nanomaterials for biomedical purposes. Gold-based plasmonic nanomaterials have shown potential applications in photothermal cancer therapy. However, their inability to biodegrade has impeded practical biomedical application. In this study, a kind of bioeliminable magnetoplasmonic nanoassembly (MPNA), assembled from an Fe3O4 nanocluster and gold nanoshell, was elaborately designed for computed tomography, photoacoustic tomography, and magnetic resonance trimodal imaging-guided tumor photothermal therapy. A single dose of photothermal therapy under near-infrared light induced a complete tumor regression in mice. Importantly, MPNAs could respond to the local microenvironment with acidic pH and enzymes where they accumulated including tumors, liver, spleen, etc., collapse into small molecules and discrete nanoparticles, and finally be cleared from the body. With the bioelimination ability from the body, a high dose of 400 mg kg(-1) MPNAs had good biocompatibility. The MPNAs for cancer theranostics pave a way toward biodegradable bio-nanomaterials for biomedical applications.

Hollow ZrO2/PPy nanoplatform for improved drug delivery and real-time CT monitoring in synergistic photothermal-chemo cancer therapy.

With the aim of fabricating multifunctional nanoplatforms for cancer diagnosis and therapy, we design hollow ZrO2 nanospheres as novel nanocarriers with enhanced CT imaging properties to integrate NIR light absorbing agents and anti-cancer drugs into one nanosystem. Polypyrrole (PPy) is encapsulated into the hollow ZrO2 nanospheres to endow the nanosystem with strong photothermal transfer capability via an oxidative polymerization method. The anti-cancer drug, doxorubicin (DOX), was loaded into the hollow ZrO2 nanospheres with a high loading content and Dox could be released from the carrier by NIR photothermal stimulus. The hollow ZrO2 nanoplatform has been successfully demonstrated for synergistic photothermal-chemo therapy, both in vitro and in vivo. Due to the excellent X-ray attenuation ability of Zr, the biodistribution of this nanosystem was real-time monitored via CT imaging technology using mini swine as animal models. ICP-OES analysis of tissues obtained from the biopsy also confirms the biodistribution. The in vitro and in vivo toxicity evaluation shows that this nanosystem has good biocompatibility and has great prospects for imaging-guided photothermal-chemo cancer therapy.