Targeted doxorubicin-loaded core-shell copper peroxide-mesoporous silica nanoparticles for combination of ferroptosis and chemotherapy of metastatic breast cancer.

In the current study, a tumor microenvironment responsive (TME-responsive) copper peroxide-mesoporous silica core-shell structure with H2O2 self-supplying ability was fabricated for targeted ferroptosis/chemotherapy against metastatic breast cancer. At the first stage, copper peroxide nanodot was synthesized and subsequently coated with mesoporous organosilica shell. After (3-Aminopropyl) triethoxysilane (APTMS) functionalization of the organosilica shell, doxorubicin (DOX) was loaded in the mesoporous structure of the nanoparticles and then, heterofunctional COOH-PEG-Maleimide was decorated on the surface through EDC/NHS chemistry. Afterward, thiol-functionalized AS1411 aptamer was conjugated to the maleimide groups of the PEGylated nanoparticles. In vitro study illustrated ROS generation of the system in the treated 4 T1 cell. Cellular uptake and cytotoxicity experiments showed enhanced internalization and cytotoxicity of the targeted system comparing to non-targeted one. The in vivo study on ectopic 4 T1 tumor induced in Female BALB/c mice showed ideal therapeutic effect of Apt-PEG-Silica-DOT@DOX with approximately 90 % tumor suppression in comparison with 50 % and 25 % tumor suppression for PEG-Silica-DOT@DOX and PEG-Silica-DOT. Moreover, Apt-PEG-Silica-DOT@DOX provide favorable characteristics for biosafety issues concerning the rate of survival and loss of body weight. The prepared platform could serve as a multifunctional system with smart behavior in drug release, tumor accumulation and capable for ferroptosis/chemotherapy against breast cancer.

Injectable Therapeutic Hydrogel with H2O2 Self-Supplying and GSH Consumption for Synergistic Chemodynamic/Low-Temperature Photothermal Inhibition of Postoperative Tumor Recurrence and Wound Infection.

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO2@Au hydrogel system (CuO2@Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO2@Au Gel is constructed by embedding therapeutic CuO2@Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO2@Au in CuO2@Au Gel is capable of self-supplying H2O2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO2@Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery.

Portable hydrogel kit driven by bimetallic carbon dots nanozyme for H2O2-self-supplying dual-modal monitoring of atmospheric CH3SH.

Due to the typical volatility of gaseous pollutant methyl mercaptan (CH3SH), the development of a facile, reliable, and accurate onsite environmental surveillance of highly toxic CH3SH faces many challenges, but it is critical to environmental atmosphere assessment and safeguarding public health. Here, we prepared a novel bimetallic carbon dots (Fe&Cu@CDs) nanozyme with high peroxidase-mimicking activity to design a portable hydrogel kit for onsite visual H2O2-self-supplying enzymatic cascade catalytic colorimetric and photothermal signal synergistic amplification dual-modal monitoring of CH3SH in atmospheric environment. Assisted by alcohol oxidase (AOX), CH3SH could be specifically converted into H2O2 for oxidizing chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB) catalyzed by Fe&Cu@CDs to produce dark blue ox-TMB with absorption at 652 nm and photothermal characters. Consequently, a CH3SH concentration-dependent change both in naked-eye color and photothermal effect-triggered temperature were observed. By hybridizing AOX-assisted Fe&Cu@CDs + TMB with agarose, a H2O2-self-supplying colorimetric and photothermal signal synergistic amplification sensory hydrogel kit integrated with Color Picker APP-installed smartphone and 660 nm laser-equipped handheld thermal imager for CH3SH was proposed with acceptable results in atmospheric environment around wastepile (e.g., solid waste and food waste piles), which exhibited great potentials to further develop commercial onsite monitoring platforms in warning-early abnormal atmospheric CH3SH for safeguarding environmental health.

Multifunctional Fe-based coordination polymer nano-bomb modified with ß-lapachone and CaO2 for targeted tumor dual chemodynamic therapy with enhanced ferroptosis and H2O2 self-supply.

Chemodynamic therapy (CDT) is seriously limited by the inadequacy of exogenous catalytic ions and endogenous H2O2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO2) and ß-lapachone as donors of H2O2 and GSH-sensitive Fe-based coordination polymer as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the GSH-rich cytoplasm. Furthermore, the released CaO2 and ß-lapachone could significantly self-generated sufficient H2O2, which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H2O2, but also efficiently activates ferroptosis and initiates Ca2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H2O2.

Hyaluronic acid coated mesoporous carbon-copper peroxide for H2O2 self-supplying and near-infrared responsive multi-mode breast cancer oncotherapy.

It is challenging to develop the synergistic intelligent therapeutic nanoplatform to cure cancer. In the present study, a novel nanotherapeutic platform was constructed for H2O2 self-supplying and multimodal breast cancer therapy. In which, copper peroxide nanoparticles (CP NPs) were adsorbed on the surface of mesoporous carbon nanospheres (MCN) through electrostatic attraction, followed by loading doxorubicin (DOX) into the nanocomposite (MCN-CP) and coating hyaluronic acid (HA) on the surface, the DOX/MCN-CP-HA nanoplatform was obtained. In the system, the MCN not only possessed a high DOX loading capacity, but produced excellent photothermal therapy (PTT) effect. Importantly, the ultra-small CP NPs as the Fenton agent not only could selectively self-supplying H2O2 in acidic condition, but simultaneously release Cu2+ to catalyze the production of ·OH in the presence of H2O2. Meantime, the resulting Cu2+ possessed GSH-elimination property, which afforded enhanced chemodynamic therapy (CDT). Furthermore, the outer layer HA targeted to CD44 and achieved breast cancer cell targeting. The elevated temperature from PTT and acidic tumor microenvironment accelerated the release of DOX, which enabled DOX/MCN-CP-HA as an intelligent CDT-PTT-chemotherapy synergistic nanoplatform. In vitro and in vivo pharmacodynamic evaluations confirmed the potential of the nanoplatform for CDT-PTT-chemotherapy synergistic oncotherapy of breast cancer.

Degradable Tumor-Responsive Iron-Doped Phosphate-Based Glass Nanozyme for H2O2 Self-Supplying Cancer Therapy.

Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied both experimentally and theoretically, but the low catalytic efficiency due to insufficient H2O2 in the TME and the poor biodegradability of the nanozymes are still main challenges for clinical translation of nanozymes. Herein, we designed a H2O2 self-supplying nanozyme bearing glucose oxidase (GOX) and polyethyleneimine based on a degradable iron-doped phosphate-based glass (FePBG) nanomimic (FePBG@GOX), which can convert endogenous glucose into toxic hydroxyl radicals. The GOX loaded on the nanozyme can effectively consume glucose in tumor cells to produce a large amount of H2O2 to make up for the lack of H2O2 in the TME. Thereafter, enormous hydroxyl radicals, based on a Fenton reaction of FePBG without any exogenous H2O2, are generated to induce severe apoptosis of tumor cells. The nanozyme exhibits enhanced in vitro cytotoxicity in a high-glucose medium than in a low-glucose medium, illustrating sufficient generation of H2O2 by GOX. The excellent in vivo antitumor efficacy is manifested by a high tumor growth inhibition ratio of 94.65% in model mice. Excellent intrinsic biodegradability owing to its phosphate-based glass nature is a remarkable advantage of the prepared FePBG nanozyme over most other reported nanozymes. Big concerns about side effects caused by long-time residence in living organisms are eliminated since it degrades not only in an acid medium but also in a neutral physiological environment. Therefore, this novel strategy of the TME-responsive H2O2 self-supplying nanozyme based on an endogenous cascade catalytic reaction opens up an avenue for designing degradable nanozymes in CDT.

Synergistic H2O2 self-supplying and NIR-responsive drug delivery nanoplatform for chemodynamic-photothermal-chemotherapy.

Developing effectively synergistic multi-mode drug delivery nanoplatform for cancer treatment is of great significance but still challenging. Here, we construct core-shell (CaO2@Au nanoshells) nanoparticles coated with doxorubicin-loaded hyaluronic acid. The developed platform can be used as synergistic H2O2 self-supplying and near-infrared-enhanced reactive oxygen species producer for chemodynamic-photothermal-chemotherapy multi-mode drug delivery. In this platform, the CaO2 possesses a high capacity of self-supplying H2O2 in acidic conditions, while retains desired stability under physiological conditions. The in-situ deposited Au nanoshells not only provide a remarkable photothermal therapy, but function as peroxidase mimics to catalyze H2O2 to produce hydroxyl radical to afford highly efficient chemodynamic therapy. Furthermore, the outer layer hyaluronic acid can load doxorubicin and target overexpressed receptor CD44 of cancer cell, meanwhile, trigger release of DOX in photothermal condition and acidic tumor microenvironment. The results of in vitro cell viability and in vivo tumor inhibition indicate that the developed synergistic nanoplatform hold the potential as an efficient strategy for chemodynamic-photothermal-chemotherapy combination therapy of cancer.

Pomegranate-Like CuO2@SiO2 Nanospheres as H2O2 Self-Supplying and Robust Oxygen Generators for Enhanced Antibacterial Activity.

Reactive oxygen species (ROS)-induced nanosystems represent one of the most essential, efficient, and encouraging nanobactericides for eliminating bacterial infection concerning the increasing resistance threats of existing antibiotics. Among them, Fenton-type metal peroxide nanoparticles are exciting nanomaterials with intriguing physiochemical properties, yet the study of this antimicrobial agent is still in its infancy. Herein, a robust pH-responsive Fenton nanosystem is constructed by the assembly of copper peroxide nanodots in pomegranate-like mesoporous silica nanoshells (CuO2@SiO2) that are capable of self-supplying H2O2 and sustainably generating O2. The enhanced antimicrobial performance is attributed to the pH responsiveness and excellent Fenton catalytic activity through either the Cu2+-catalyzed conversion of H2O2 to detrimental ROS under acid treatment or in situ O2 evolution in neutral media. Moreover, in vitro and in vivo investigations demonstrate that this nanocomposite can exhibit boosted antimicrobial capabilities and can significantly accelerate skin wound closure, while retaining outstanding cytocompatibility and hemocompatibility. Given its excellent physicochemical and antimicrobial properties, the broad application of this nanocomposite in bacteria-associated wound management is anticipated.

Engineering H2O2 Self-Supplying Nanotheranostic Platform for Targeted and Imaging-Guided Chemodynamic Therapy.

Developing highly efficient chemodynamic therapy (CDT)-based theranostic technology for cancer treatment is highly desired but still challenging. A novel nanotheranostic platform is constructed for enhanced CDT by engineering hybrid CaO2 and Fe3O4 nanoparticles with a hyaluronate acid (HA) stabilizer and NIR fluorophore label. This design not only enables the nanotheranostic agent to afford highly efficient CDT against tumor cells but also confers NIR fluorescence (NIRF) and magnetic resonance (MR) bimodal imaging for in vivo visualization of CDT. Moreover, the use of the HA stabilizer allows for the facile synthesis of the nanotheranostic agent with excellent biocompatibility and active targetability. The nanotheranaostic agent possesses a high capacity of self-supplying H2O2 and producing •OH in acidic conditions, while retaining the desired stability under physiological conditions. It also demonstrates high selectivity to tumor cells via CDT with minimized toxicity to normal cells. In vivo studies reveal that our nanotheranaostic agent exhibits efficacious tumor growth inhibition via a CDT mechanism with favorable biosafety. Moreover, in vivo visualization of the CDT progress via NIRF and MR bimodal imaging demonstrates specific targeting and treatment of tumors. The developed H2O2 self-supplying, active targeting, and bimodal imaging nanotheranostic platform holds the potential as a highly efficient strategy for CDT of cancer.