A tumor cell exosome-mimicking multifunctional nanozyme for targeted breast cancer radiotherapy.

Radiotherapy (RT) has been extensively used for the treatment of breast cancer. However, the efficacy of RT is reduced by the high content of reducing species within cells (such as glutathione (GSH)). In addition, high-dose radiotherapy is often accompanied by serious side effects. In an attempt to resolve these issues, a tumor cell exosome-mimicking multifunctional nanozyme system (CuPy-Au@EM) was developed as a radiosensitizer, which consists of an internal AuNP-embedded CuPy nanozyme core and an external tumor cell exosome membrane. The exosome membrane protein on the surface of CuPy-Au@EM leads to the accurate localization of nano-materials in the tumor site; simultaneously, the level of H2O2 will be enhanced because of the GOx-like activity of AuNPs. Then CuPy-Au@EM would continue to trigger a rapid decline in cellular GSH content and the production of a large number of hydroxyl radicals (˙OH) through its glutathione peroxidase (GPx) and peroxidase (POD) activities allows for the extension of the radiotherapeutic cascade. Studies conducted in vivo and in vitro demonstrated that the combination of CuPy-Au@EM and moderate dose RT (4 Gy) can significantly reduce tumor proliferation. These findings indicated that CuPy-Au@EM nanospheres could be plausibly developed into promising radio-sensitizers on tumors.

Self-cascade catalytic single-atom nanozyme for enhanced breast cancer low-dose radiotherapy.

Radiotherapy (RT) efficacy can be promoted with the help of nanoenzyme that can "re-programing" the tumour's micro-environment by changing the expression level of special bio-molecules. However, problems such as low reaction efficiency, limited endogenous H2O2, and/or unsatisfactory results of a single catalysis mode in treatment limit the application in the RT field. Herein, a novel Au nanoparticles (AuNPs) decorated iron SAE (FeSAE@Au) was formulated for self-cascade catalytic RT. In this dual-nanozyme system, embedded AuNPs can sever as GOx and endow FeSAE@Au with self-H2O2 supplying ability, which can elevate the H2O2 level in tumors by catalyzing cellular glucose in situ, further improving the catalytic performance of FeSAE with peroxidase-like activity. The self-cascade catalytic reaction can significantly increase cellular hydroxyl radicals (•OH) level, further promoting RT's effect. Furthermore, in vivo findings demonstrated that FeSAE can effectively limit tumor growth while causing low damage in important organs. According to our understanding, FeSAE@Au is the first description of a hybrid SAE-based nanomaterial employed in cascade catalytic RT. The research yields new and interesting insights for developing various SAE systems for anticancer therapy.

PLGA Nanoparticles Loaded with Sorafenib Combined with Thermosensitive Hydrogel System and Microwave Hyperthermia for Multiple Sensitized Radiotherapy.

Hypoxia is typically the leading cause of radiotherapy (RT) resistance in solid tumors, and glutathione (GSH) overexpression in tumor cells is a potent antioxidant mechanism that protects tumor cells from radiation damage. Herein, we developed a sorafenib (SFN) loaded-PLGA hydrogel system (SPH) in combination with microwave (MW) hyperthermia for RT sensitization. SPH with stable properties was produced by combining SFN and PLGA in a specific ratio and encapsulating the mixture in agarose hydrogel. Intratumoral injection of SPH to mice combined with MW hyperthermia can not only directly cause thermal damage to tumor cells, but also increase blood oxygen delivery to the tumor site, thus overcoming the problem of intratumoral hypoxia and achieving "first layer" RT sensitization. Moreover, high temperatures can cause the hydrogel to disintegrate and release SFN. Not only can SFN inhibit tumor growth, but it can also achieve the "second layer" of RT sensitization by inhibiting glutathione (GSH) synthesis in cells and increasing reactive oxygen species (ROS) production. Experiments, both in vitro and in vivo, have indicated that SPH and MW hyperthermia can achieve a double RT sensitization effect and a significant tumor inhibition effect. In conclusion, combining our SPH nanosystem and thermoradiotherapy is a promising anti-tumor treatment.

Injectable thermo-sensitive hydrogel loaded hollow copper sulfide nanoparticles for ROS burst in TME and effective tumor treatment.

Introduction: Lung cancer the most prevalent cause of cancer-related deaths, and current therapies lack sufficient specificity and efficacy. This study developed an injectable thermosensitive hydrogel harboring hollow copper sulfide nanoparticles and ß-lapachone (Lap) (CLH) for lung tumor treatment. Methods: The hydrogel-encapsulated CLH system can remotely control the release of copper ions (Cu2+) and drugs using photothermal effects for non-invasive controlled-release drug delivery in tumor therapy. The released Cu2+ consumes the overexpressed GSH in TME and the generated Cu+ further exploits the TME characteristics to initiate nanocatalytic reactions for generating highly toxic hydroxyl radicals. In addition, in cancer cells overexpressing Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase 1 (NQO1), Lap can catalyze the generation of hydrogen peroxide (H2O2) through futile redox cycles. H2O2 is further converted into highly toxic hydroxyl radicals via the Fenton-like reaction, leading to a burst of reactive oxygen species in TME, which further enhances the therapeutic effect of chemokines. Results: Analysis of the antitumor efficacy in a subcutaneous A549 lung tumor model mice showed a significant delay in tumor growth and no systemic toxicity was detected. Discussion: In conclusion, we have established a CLH nanodrug platform that enables efficient lung tumor therapy through combined photothermal/chemodynamic therapy (CDT) treatment and self-supplying H2O2 to achieve cascade catalysis, leading to explosive amplification of oxidative stress.

Ultrasound Triggered Tumor Metabolism Suppressor Induces Tumor Starvation for Enhanced Sonodynamic Immunotherapy of Breast Cancer.

Introduction: Sonodynamic therapy (SDT) as an emerging tumor treatment gained wide attention. However, tumor vascular destruction and oxygen depletion in SDT process may lead to further hypoxia. This may lead to enhanced glycolysis, lactate accumulation, and immunosuppression. Methods: A glycolysis inhibitor (3PO) loaded and PEG modified black phosphorus nanosheets (BO) is constructed for potent starvation therapy and efficient immune activation. Results: Under ultrasound irradiation, the BO can produce ROS to destroy tumors and tumor blood vessels and lead to further hypoxia and nutrients block. Then, the released 3PO inhibits tumor glycolysis and prevents the hypoxia-induced glycolysis and lactate accumulation. Both SDT and 3PO can cut off the source of lactic acid, as well as achieve antitumor starvation therapy through the blockade of the adenosine triphosphate (ATP) supply. In addition, the combination of starvation treatment and SDT further facilitates dendritic cells (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity and inhibition of abscopal tumor growth. Conclusion: This is the first time that combines SDT with inhibition of glycolysis, achieving admirable tumor treatment and decreasing adverse events caused by SDT process and that has caused good immune activation. Our system provides a new idea for the future design of anti-tumor nanomedicines.

Glutathione-depleting nanoplatelets for enhanced sonodynamic cancer therapy.

In combating cancer, ultrasound (US)-triggered sonodynamic therapy (SDT) manifests a wide range of promising applications as a noninvasive treatment modality, thus showing potential to overcome the shortcomings and disadvantages of conventional photodynamic therapy (PDT). Reactive oxygen species (ROS)-based therapy is practically destroyed by the high concentration of glutathione (GSH) inside tumors, and depleting GSH to improve the outcome of SDT is indeed a great challenge. Herein, we designed GSH-depleting nanoplatelets for enhanced sonodynamic cancer therapy. A platelet membrane coated nanosystem (PSCI) has been designed and tested comprising mesoporous silica nanoparticles (MSNs) which have been loaded with cinnamaldehyde (CA) as an oxidative stress amplifier. The inner layer comprises the sonosensitizer IR780 and the oxidative stress amplifier CA, whereas the platelet membranes (PM) were designed and utilized as an outer layer that can target tumors, thereby enhancing the effectiveness of SDT by attenuating the capability of tumor cells for scavenging ROS with GSH. SDT and cinnamaldehyde amplify oxidative stress by acting synergistically, leading to the preferential destruction of cancer cells in vitro and in vivo. It is hoped that next-generation tumor SDT treatments will find their way with the help of this strategy.

Novel Engineered Bacterium/Black Phosphorus Quantum Dot Hybrid System for Hypoxic Tumor Targeting and Efficient Photodynamic Therapy.

Intratumoral hypoxia significantly constrains the susceptibility of solid tumors to oxygen-dependent photodynamic therapy (PDT), and effort to reverse such hypoxia has achieved limited success to date. Herein, we developed a novel engineered bacterial system capable of targeting hypoxic tumor tissues and efficiently mediating the photodynamic treatment of these tumors. For this system, we genetically engineered Escherichia coli to express catalase, after which we explored an electrostatic adsorption approach to link black phosphorus quantum dots (BPQDs) to the surface of these bacteria, thereby generating an engineered E. coli/BPQDs (EB) system. Following intravenous injection, EB was able to target hypoxic tumor tissues. Subsequent 660 nm laser irradiation drove EB to generate reactive oxygen species (ROS) and destroy the membranes of these bacteria, leading to the release of catalase that subsequently degrades hydrogen peroxide to yield oxygen. Increased oxygen levels alleviate intratumoral hypoxia, thereby enhancing BPQD-mediated photodynamic therapy. This system was able to efficiently kill tumor cells in vivo, exhibiting good therapeutic efficacy. In summary, this study is the first to report the utilization of engineered bacteria to facilitate PDT, and our results highlight new avenues for BPQD-mediated cancer treatment.

Glutathione-Depleting Nanoenzyme and Glucose Oxidase Combination for Hypoxia Modulation and Radiotherapy Enhancement.

Nanoenzymes perceive the properties of enzyme-like catalytic activity, thereby offering significant cancer therapy potential. In this study, Fe3 O4 @MnO2 , a magnetic field (MF) targeting nanoenzyme with a core-shell structure, is synthesized and applied to radiation enhancement with using glucose oxidase (GOX) for combination therapy. The glucose is oxidized by the GOX to produce excess H2 O2 in an acidic extracellular microenvironment, following which the MnO2 shell reacts with H2 O2 to generate O2 and overcome hypoxia. Concurrently, intracellular glutathione (GSH)-which limits the effects of radiotherapy (RT)-can be oxidized by the MnO2 shell while the latter is reduced to Mn2+ for T1 -weighed MRI. The core Fe3 O4 , with its good magnetic targeting ability, can be utilized for T2 -weighed MRI. In summary, the work demonstrates that Fe3 O4 @MnO2 , as a dual T1 - and T2 -weighed MRI contrast agent with strong biocompatibility, exhibits striking potential for radiation enhancement under magnetic targeting.