Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response.

Introduction: As an effective alternative choice to traditional mono-therapy, multifunctional nanoplatforms hold great promise for cancer therapy. Based on the strategies of Fenton-like reactions and reactive oxygen species (ROS)-mediated therapy, black phosphorus (BP) nanoplatform BP@Cu2O@L-Arg (BCL) co-assembly of cuprous oxide (Cu2O) and L-Arginine (L-Arg) nanoparticles was developed and evaluated for synergistic cascade breast cancer therapy. Methods: Cu2O particles were generated in situ on the surface of the BP nanosheets, followed by L-Arg incorporation through electrostatic interactions. In vitro ROS/nitric oxide (NO) generation and glutathione (GSH) depletion were evaluated. In vitro and in vivo anti-cancer activity were also assessed. Finally, immune response of BCL under ultrasound was investigated. Results: Cu2O was incorporated into BP to exhaust the overexpressed intracellular GSH in cancer cells via the Fenton reaction, thereby decreasing ROS consumption. Apart from being used as biocompatible carriers, BP nanoparticles served as sonosensitizers to produce excessive ROS under ultrasound irradiation. The enhanced ROS accumulation accelerated the oxidation of L-Arg, which further promoted NO generation for gas therapy. In vitro experiments revealed the outstanding therapeutic killing effects of BCL under ultrasound via mechanisms involving GSH deletion and excessive ROS and NO generation. In vivo studies have illustrated that the nanocomplex modified the immune response by promoting macrophage and CD8+ cell infiltration and inhibiting MDSC infiltration. Discussion: BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation, making a new multitherapy strategy for cascade breast cancer therapy.

A dual-nanozyme-loaded black phosphorus multifunctional therapeutic platform for combined photothermal/photodynamic/starvation cancer therapy.

The typical hypoxia of tumor microenvironments seriously affects the efficacy of starvation therapy (ST) and photodynamic therapy (PDT). Therefore, it is of great significance to prepare a multimodal combined therapy nanocomposite with the ability to relieve tumor hypoxia. It is an effective method to release oxygen into the tumor microenvironment using a nanoenzyme. In this work, two-dimensional black phosphorus nanosheets (BPNSs) were used as photothermal reagents and photosensitized agents due to the unique physical properties and also used as nano-carriers for the in situ reduction deposition of Au nanoparticles and fragmented MnO2 coatings. Finally, polyethylene glycol was introduced to obtain the nanocomposite BP@Au@MnO2-PEG (i.e., AMGP). In the tumor microenvironment, MnO2 can catalyze endogenous H2O2 to produce oxygen, improving the effect of ST and PDT. H2O2 generated via the catalytic oxidation of glucose by Au nanoparticles can continue to be used as the substrate catalyzed by MnO2. Meanwhile, black phosphorus nanosheets have excellent photothermal properties for photothermal treatment. The results of in vitro and in vivo experiments indicated that AMGP nanocomposites have good combined antitumor efficacies and biosafety.

ROS Generative Black Phosphorus-Tamoxifen Nanosheets for Targeted Endocrine-Sonodynamic Synergistic Breast Cancer Therapy.

Introduction: Tamoxifen (TAM) has proven to be a therapeutic breakthrough to reduce mortality and recurrence in estrogen receptor-positive (ER+) breast cancer patients. However, the application of TAM exhibits low bioavailability, off-target toxicity, instinct and acquired TAM resistance. Methods: We utilized black phosphorus (BP) as a drug carrier and sonosensitizer, integrated with TAM and tumor-targeting ligand folic acid (FA) to construct TAM@BP-FA for synergistic endocrine and sonodynamic therapy (SDT) of breast cancer. The exfoliated BP nanosheets were modified through in situ polymerization of dopamine, followed by electrostatic adsorption of TAM and FA. The anticancer effect of TAM@BP-FA was evaluated through in vitro cytotoxicity and in vivo antitumor model. RNA-sequencing (RNA-seq), quantitative real-time PCR, Western blot analysis, flow cytometry analysis and peripheral blood mononuclear cells (PBMCs) analysis were performed for mechanism investigation. Results: TAM@BP-FA had satisfactory drug loading capacity, the TAM release behavior can be controlled through pH microenvironment and ultrasonic stimulation. An amount of hydroxyl radical (∙OH) and singlet oxygen (1O2) were as expected generated under ultrasound stimulation. TAM@BP-FA nanoplatform showed excellent internalization in both TAM-sensitive MCF7 and TAM-resistant (TMR) cells. Using TMR cells, TAM@BP-FA displayed significantly enhanced antitumor ability in comparison with TAM (7.7% vs 69.6% viability at 5µg/mL), the additional SDT further caused 15% more cell death. RNA-seq unraveled the TAM@BP-FA antitumor mechanisms including effects on cell cycle, apoptosis and cell proliferation. Further analysis showed additional SDT successfully triggering reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) reduction. Moreover, PBMCs exposed to TAM@BP-FA induced an antitumor immune response by natural killer (NK) cell upregulation and immunosuppression macrophage reduction. Conclusion: The novel BP-based strategy not only delivers TAM specifically to tumor cells but also exhibits satisfactory antitumor effects through targeted therapy, SDT, and immune cell modulation. The nanoplatform may provide a superior synergistic strategy for breast cancer therapy.

A novel ROS-activable self-immolative prodrug for tumor-specific amplification of oxidative stress and enhancing chemotherapy of mitoxantrone.

Reactive oxygen species (ROS) as well-known endogenous stimuli has been widely used to activate drug delivery systems (DDSs) for tumor-specific therapy. Unfortunately, endogenous ROS in the tumor microenvironment (TME) is not enough to achieve effective therapeutic efficacy and cancer cells have adapted to high oxidative stress by upregulating glutathione (GSH) level. Herein, we devised a novel ROS-activable self-immolative prodrug CASDB with both GSH-depletion ability and ROS self-supply competence. Then, an stimuli-responsive nanoplatform integrating CASDB with clinical chemotherapeutics mitoxantrone (MTO) and PLGA was fabricated (denoted as CMPs) through nanoprecipitation method. The CMPs could achieve desired accumulation at tumor tissues through enhanced permeability and retention (EPR) effects. Then the accumulated CMPs could induce tumor cell apoptosis efficiently. Especially, ROS in tumor sites could trigger the immolation of CASDB to generate CA and quinone methide (QM). Then CA and QM cooperatively promoted damage of mitochondria due to oxidative stress and led to cancer cells more sensitive to MTO. Accordingly, MTO could perturb cellular microenvironment of cancer cells then promote the degradation of CASDB. The experiment results demonstrated that CMPs were ideal for desirable synergetic tumor-specific anticancer therapy with negligible systemic toxicity. The half-maximal inhibitory concentrations (IC50) value of CMPs was 6.53 µM, while the IC50 values of MTO was 14.76 µM. And the CMPs group showed the strongest tumor suppressor effect with the tumor sizes increased to 1.2-fold (Control group: 20.6-fold, MTO only: 3.0-fold). This study should be inspirational for designing efficient prodrugs to overcome the handicaps of traditional chemotherapy.

Hemin-loaded black phosphorus-based nanosystem for enhanced photodynamic therapy and a synergistic photothermally/photodynamically activated inflammatory immune response.

The biocompatible nanosystem integrating hemin into black phosphorus nanosheets was ingeniously constructed through the easy modified strategy. Taking advantage of the enhanced permeability and retention (EPR) effect, the designed nanosystem could accumulate into the tumor location, leading to attractive cytotoxicity through the enhanced photodynamic therapy (PDT) ascribing to the catalytic oxygen supply and GSH depletion of hemin. Simultaneously, combining PDT and photothermal therapy (PTT) showed an apparent promotion in anti-tumor effect. Moreover, inflammatory response and immune activation amplified anti-tumor effect, which could compensate limitations of exogenous therapy (i.e., limited tissue depth and intensity-dependent curation effect) and potentiate the efficiency of the endogenous immune-activating behavior. Especially, the designed nanosystem degraded followed by being metabolized in the blood circulation. By and large, this constructed nanosystem provides the new insight into designing biocompatible nanomaterials and paves the ideal way for anti-tumor therapy. STATEMENT OF SIGNIFICANCE: Biocompatible nanomaterials-based synergistic tumor therapy offers the potential application prospect. Taking advantage of degradable black phosphorus, the nanosystem integrating hemin into black phosphorus for the enhanced photodynamic therapy and synergistic photothermal-photodynamic activating inflammation-immune response was developed and the results demonstrate that tumor growth was inhibited followed by activating inflammatory factors and leading to satisfactory immune response.

Oxygen-deficient titanium dioxide-loaded black phosphorus nanosheets for synergistic photothermal and sonodynamic cancer therapy.

Malignant tumors, particularly those located in deep tissues, have always been a grievous threat to human health. Sonodynamic therapy (SDT) has recently attracted great attention due to deep tissue penetration. However, the lack of effective sonosensitizers and the poor therapeutic efficacy severely limit their wider use. Herein, dual-functionalized black phosphorus nanosheets (BP@PEI-PEG, i.e., PPBP) integrating black oxygen-deficient titanium dioxide particles (B-TiO2) were successfully constructed (PPBP-B-TiO2) for synergistic photothermal (PTT)/sonodynamic therapy. In these nanocomposites, black titanium dioxide can enhance the separation of electrons (e-) and holes (h+) due to the oxygen-deficient structure and significantly improves the production of reactive oxygen species (ROS) for SDT, while the BP nanosheets endow the nanocomposites with a higher photothermal conversion capability for photothermal therapy (η = 44.1%) which can prolong the blood circulation and improve the O2 supply. In vivo experiments prove that PPBP-B-TiO2 nanocomposites exhibited outstanding tumor inhibition efficacy and excellent biocompatibility. This work provides a prospective platform for combined photothermal/sonodynamic cancer therapy.

Biodegradable L-lysine-modified amino black phosphorus/poly(l-lactide-coε-caprolactone) nanofibers with enhancements in hydrophilicity, shape recovery and osteodifferentiation properties.

Biodegradable poly-(lactide-coε-caprolactone) (PLCL) scaffolds have opened new perspectives for tissue engineering due to their nontoxic and fascinating functionality. Herein, a black phosphorus-based biodegradable material with a combination of promising enhanced hydrophilicity, shape recovery and osteodifferentiation properties was proposed. First, amino black phosphorous (BP-NH2) was prepared by a simple ball milling method. Then, L-lysine-modified black phosphorous (L-NH-BP) was formed by hydrogen bonding between L-lysine and amino BP and integrated into PLCL to form PLCL/L-NH-BP composite fibers. The scaffolds had excellent shape recovery and shape fixity properties. Moreover, based on gene expression and protein level assessment, the scaffolds could enhance the expression of alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), simultaneously improving the mineralization ability of bone mesenchymal stem cells. Specifically, this new composite material was experimentally verified to be degradable under mild conditions. This strategy provided new insight into the design of multifunctional materials for diverse applications.

Parallel Structure from Motion for Sparse Point Cloud Generation in Large-Scale Scenes.

Scene reconstruction uses images or videos as input to reconstruct a 3D model of a real scene and has important applications in smart cities, surveying and mapping, military, and other fields. Structure from motion (SFM) is a key step in scene reconstruction, which recovers sparse point clouds from image sequences. However, large-scale scenes cannot be reconstructed using a single compute node. Image matching and geometric filtering take up a lot of time in the traditional SFM problem. In this paper, we propose a novel divide-and-conquer framework to solve the distributed SFM problem. First, we use the global navigation satellite system (GNSS) information from images to calculate the GNSS neighborhood. The number of images matched is greatly reduced by matching each image to only valid GNSS neighbors. This way, a robust matching relationship can be obtained. Second, the calculated matching relationship is used as the initial camera graph, which is divided into multiple subgraphs by the clustering algorithm. The local SFM is executed on several computing nodes to register the local cameras. Finally, all of the local camera poses are integrated and optimized to complete the global camera registration. Experiments show that our system can accurately and efficiently solve the structure from motion problem in large-scale scenes.

Polypyrrole-Coated Mesoporous TiO2 Nanocomposites Simultaneously Loading DOX and Aspirin Prodrugs for a Synergistic Theranostic and Anti-Inflammatory Effect.

Although a number of therapeutic strategies have been applied in cancer therapy, treatment for cancer metastasis is challenging due to unsatisfactory cure rate and easy cancer recurrence. In our work, nanocomposites (NCs) based on polypyrrole-coated mesoporous TiO2 with a suitable size are prepared through a modified soft-templating strategy, which integrates double prodrugs (doxorubicin (DOX) prodrug and aspirin prodrug) with superior drug loading capacity. Under external stimulation of near-infrared (NIR) and ultrasound (US), the prepared nanocomposites have an excellent photothermal conversion efficiency (over 50.8%) and a satisfactory sonodynamic therapeutic effect, and simultaneous prodrug activation and drug release occur rapidly under external stimulation. Through intravenous injection, the tumor area can be clearly seen through thermal imaging, benefiting from the enhanced permeability and retention (EPR) effect. Through synergistic therapy, cancer cell toxicity and the tumor inhibition effect are significantly enhanced. Moreover, downregulated inflammatory factors also reduce the risk of cancer recurrence. In general, the designed NCs provide a potential alternative for synergistic therapy as well as downregulation of inflammatory cytokines.