Erythrocyte Membrane Camouflaged Nanotheranostics for Optical Molecular Imaging-Escorted Self-Oxygenation Photodynamic Therapy.

Hypoxic tumor microenvironment (TME) hampers the application of oxygen (O2 )-dependent photodynamic therapy (PDT) in solid tumors. To address this problem, a biomimetic nanotheranostics (named MMCC@EM) is developed for optical molecular imaging-escorted self-oxygenation PDT. MMCC@EM is synthesized by encapsulating chlorin e6 (Ce6) and catalase (CAT) in metal-organic framework (MOF) nanoparticles with erythrocyte membrane (EM) camouflage. Based on the biomimetic properties of EM, MMCC@EM efficiently accumulates in tumor tissues. The enriched MMCC@EM achieves TME-activatable drug release, thereby releasing CAT and Ce6, and this process can be monitored through fluorescence (FL) imaging. In addition, endogenous hydrogen peroxide (H2 O2 ) will be decomposed by CAT to produce O2 , which can be reflected by the measurement of intratumoral oxygen concentration using photoacoustic (PA) imaging. Such self-oxygenation nanotheranostics effectively mitigate tumor hypoxia and improve the generation of singlet oxygen (1 O2 ). The 1 O2 disrupts mitochondrial function and triggers caspase-3-mediated cellular apoptosis. Furthermore, MMCC@EM triggers immunogenic cell death (ICD) effect, leading to an increased infiltration of cytotoxic T lymphocytes (CTLs) into tumor tissues. As a result, MMCC@EM exhibits good therapeutic effects in 4T1-tumor bearing mice under the navigation of FL/PA duplex imaging.

Anticancer Activity of Bitter Melon-Derived Vesicles Extract against Breast Cancer.

Due to their low immunogenicity, high biocompatibility and ready availability in large quantities, plant-derived vesicles extracts have attracted considerable interest as a novel nanomaterial in tumor therapy. Bitter melon, a medicinal and edible plant, has been reported to exhibit excellent antitumor effects. It is well-documented that breast cancer gravely endangers women's health, and more effective therapeutic agents must be urgently explored. Therefore, we investigated whether bitter melon-derived vesicles extract (BMVE) has antitumor activity against breast cancer. Ultracentrifugation was used to isolate BMVE with a typical "cup-shaped" structure and an average size of approximately 147 nm from bitter melon juice. The experimental outcomes indicate that 4T1 breast cancer cells could efficiently internalize BMVE, which shows apparent anti-proliferative and migration-inhibiting effects. In addition, BMVE also possesses apoptosis-inducing effects on breast cancer cells, which were achieved by stimulating the production of reactive oxygen species (ROS) and disrupting mitochondrial function. Furthermore, BMVE could dramatically inhibit tumor growth in vivo with negligible adverse effects. In conclusion, BMVE exhibits a pronounced antitumor effect on 4T1 breast cancer cells, which has great potential for use in tumor therapy.

In Situ Sprayed Starvation/Chemodynamic Therapeutic Gel for Post-Surgical Treatment of IDH1 (R132H) Glioma.

Complete resection of isocitrate dehydrogenase 1 (IDH1) (R132H) glioma is unfeasible and the classic post-surgical chemo/radiotherapy suffers from high recurrence and low survival rate. IDH1 (R132H) cells are sensitive to low concentrations of glucose and high concentrations of reactive oxygen species (ROS) due to inherent metabolism reprograming. Hence, a starvation/chemodynamic therapeutic gel is developed to combat residual IDH1 (R132H) tumor cells after surgery. Briefly, glucose oxidase (GOx) is mineralized with manganese-doped calcium phosphate to form GOx@MnCaP nanoparticles, which are encapsulated into the fibrin gel (GOx@MnCaP@fibrin). After spraying gel in the surgical cavity, GOx catalyzes the oxidation of glucose in residual IDH1 (R132H) cells and produces H2 O2 . The generated H2 O2 is further converted into highly lethal hydroxyl radicals (•OH) by a Mn2+ -mediated Fenton-like reaction to further kill the residual IDH1 (R132H) cells. The as-prepared starvation/chemodynamic therapeutic gel shows much higher therapeutic efficacy toward IDH1 (R132H) cells than IDH1 (WT) cells, and achieves long-term survival.

A Versatile Calcium Phosphate Nanogenerator for Tumor Microenvironment-activated Cancer Synergistic Therapy.

Gas therapy is an emerging "green" cancer treatment strategy; however, its outcome often restricted by the complexity, diversity, and heterogeneity of tumor. Herein, a tumor targeting and tumor microenvironment-activated calcium phosphate nanotheranostic system (denoted as GCAH) is constructed for effective synergistic cancer starvation/gas therapy. GCAH is obtained by a facile biomineralization strategy using glucose oxidase (GOx) as a biotemplate, followed by loading of l-Arginine (L-Arg) and modification of hyaluronic acid (HA) to allow special selectivity for glycoprotien CD44 overexpressed cancer cells. This nanotheranostic system not only exhausts the glucose nutrients in tumor region by the GOx-triggered glucose oxidation, the generated H2 O2 can oxidize L-Arg into NO under acidic tumor microenvironment for enhanced gas therapy. As such, there are significant enhancement effects of starvation therapy and gas therapy through the cascade reactions of GOx and L-Arg, which yields a remarkable synergistic therapeutic effect for 4T1 tumor-bearing mice without discernible toxic side effects.

Conquering the Hypoxia Limitation for Photodynamic Therapy.

Photodynamic therapy (PDT) has aroused great research interest in recent years owing to its high spatiotemporal selectivity, minimal invasiveness, and low systemic toxicity. However, due to the hypoxic nature characteristic of many solid tumors, PDT is frequently limited in therapeutic effect. Moreover, the consumption of O2 during PDT may further aggravate the tumor hypoxic condition, which promotes tumor proliferation, metastasis, and invasion resulting in poor prognosis of treatment. Therefore, numerous efforts have been made to increase the O2 content in tumor with the goal of enhancing PDT efficacy. Herein, these strategies developed in past decade are comprehensively reviewed to alleviate tumor hypoxia, including 1) delivering exogenous O2 to tumor directly, 2) generating O2 in situ, 3) reducing tumor cellular O2 consumption by inhibiting respiration, 4) regulating the TME, (e.g., normalizing tumor vasculature or disrupting tumor extracellular matrix), and 5) inhibiting the hypoxia-inducible factor 1 (HIF-1) signaling pathway to relieve tumor hypoxia. Additionally, the O2 -independent Type-I PDT is also discussed as an alternative strategy. By reviewing recent progress, it is hoped that this review will provide innovative perspectives in new nanomaterials designed to combat hypoxia and avoid the associated limitation of PDT.

Multi-enzyme mimetic ultrasmall iridium nanozymes as reactive oxygen/nitrogen species scavengers for acute kidney injury management.

Acute kidney injury (AKI) is a kind of kidney disease with a high mortality rate, and is predominantly associated with abundant endogenous reactive oxygen/nitrogen species (RONS). However, there are no universal clinical treatment options currently. Development of antioxidants with high kidney enrichment is highly desired to prevent AKI. As a promising new artificial enzyme, nanozymes have attracted extensive attention over the past decade because of their commendable advantages over natural and traditional artificial enzymes. In this study, we reported ultrasmall polyvinylpyrrolidone-coated iridium nanoparticles (denoted as Ir NPs-PVP, 1.5 nm) as multi-enzyme mimetic to scavenge a variety of RONS, offering an efficient RONS-induced cellular protection. Meanwhile, computed tomography and inductively coupled plasma mass spectrometry demonstrated preferential renal uptake of Ir NPs-PVP following intravenous administration, leading to alleviate clinical symptoms in mice subjected to rhabdomyolysis- or cis-platinum-induced AKI. Impressively, ultrasmall Ir NPs-PVP exhibit relatively low systemic side effects in vivo due to rapid renal clearance via urine. Our work presents the clinically translatable potential of ultrasmall nanozymes for AKI management.

Nanocatalytic Theranostics with Glutathione Depletion and Enhanced Reactive Oxygen Species Generation for Efficient Cancer Therapy.

Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H2 O2 ) into highly toxic hydroxyl radicals (• OH). To overcome the current limitations of the insufficient endogenous H2 O2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC-DOX) that possesses both H2 O2 self-supply and GSH-elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one-step biomineralization method using poly(ethylene glycol)-modified glucose oxidase (GOx) as a template to form biodegradable copper-doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H2 O2 , which not only starves the tumor cells, but also supplies H2 O2 for subsequent Fenton-like reaction. Meanwhile, the redox reaction between the released Cu2+ ions and intracellular GSH will induce GSH depletion and reduce Cu2+ to Fenton agent Cu+ ions, and then trigger the H2 O2 to generate • OH by a Cu+ -mediated Fenton-like reaction, resulting in enhanced CDT efficacy. The integration of GOx-mediated starvation therapy, H2 O2 self-supply and GSH-elimination enhanced CDT, and DOX-induced chemotherapy, endow the PGC-DOX with effective tumor growth inhibition with minimal side effects in vivo.

Ultrasound-Enhanced Chemo-Photodynamic Combination Therapy by Using Albumin "Nanoglue"-Based Nanotheranostics.

The combination of photodynamic therapy (PDT) and chemotherapy is considered to enhance the antitumor immunity and combat multidrug resistance. Some preclinical studies have reported a positive therapeutic outcome of using ultrasound (US) irradiation to enhance chemotherapy, but the combination of these three modalities has yet to be investigated. On the basis of the discovery of a strong affinity between a photosensitizer sinoporphyrin sodium (DVDMS) and human serum albumin (HSA), a clinically used albumin-paclitaxel (HSA-PTX) nanoparticle is utilized as a "nanoglue" to load a large amount of DVDMS by simple mixing. The five conformations of HSA and DVDMS with highest affinity were calculated using AutoDock Vina. The obtained albumin "nanoglue"-based nanotheranostics, HSA-PTX-DVDMS (HPD), has better fluorescence imaging and PDT performance than free DVDMS, probably due to the reduced quenching of DVDMS after dispersion in albumin. An efficacious tumor-targeting enhancement of chemotherapy by US irradiation is verified in a bilateral subcutaneous 4T1 tumors model. With the aid of US irradiation, the combined PDT and chemotherapy mediated by HPD achieve effective tumor growth inhibition. Overall, this "nanoglue"-based nanotheranostics is composed of several clinically used elements and integrates three clinical modalities with application prospects in clinic.

Plasmon-activated nanozymes with enhanced catalytic activity by near-infrared light irradiation.

Nanozymes have attracted extensive attention due to their great potential as alternatives to natural enzymes. Optical control as an external stimulus has become the most attractive method because of its high spatial and temporal resolution. Under the action of excitation light, free electrons on the surface of gold nanorods (GNRs) will collectively oscillate, which is called localized surface plasmon resonance (LSPR). This unique LSPR effect is promising in the application of plasmon-accelerated enzyme-like catalytic reactions. Pt-tipped gold nanorod-based nanozymes (Pt-GNRs) were synthesized by the modification of Pt nanoclusters onto the tips of GNRs. The as-prepared Pt-GNRs exhibited excellent enzyme-like catalytic activity toward hydrogen peroxide. Furthermore, it was found that the enzyme-like catalytic activity of Pt-GNRs could be notably enhanced using near-infrared (NIR) light irradiation, because of the photothermal effect and hot electron effect produced by the LSPR of GNRs. Finally, the catalytic activity and cytotoxicity of Pt-GNRs were evaluated in 4T1 cells, which further demonstrated that the Pt-GNR-based nanozymes possess great potential in cancer treatment.

Janus γ-Fe2O3/SiO2-based nanotheranostics for dual-modal imaging and enhanced synergistic cancer starvation/chemodynamic therapy.

Multimodal cancer synergistic therapy exhibited remarkable advantages over monotherapy in producing an improved therapeutic efficacy. In this work, Janus-type γ-Fe2O3/SiO2 nanoparticles (JFSNs) are conjugated with glucose oxidase (GOx) for synergistic cancer starvation/chemodynamic therapy. The γ-Fe2O3 hemisphere of JFSNs can perform photoacoustic/T2 magnetic resonance dual-modal imaging of tumors. GOx on the surface of JFSNs catalyzes the decomposition of glucose and produces H2O2 for cancer starvation therapy. Subsequently, the γ-Fe2O3 hemisphere catalyzes the disproportionation of H2O2 to generate highly reactive hydroxyl radicals in an acidic tumor microenvironment. The close distance between GOx and JFSNs ensures adequate contact between the γ-Fe2O3 hemisphere and its substrate H2O2, thus enhancing the catalytic efficiency. This synergy of glucose depletion, biotoxic H2O2 and hydroxyl radicals significantly suppresses 4T1 mammary tumor growth with minimal adverse effects.

3D printing of hydrogel scaffolds for future application in photothermal therapy of breast cancer and tissue repair.

Surgical removal remains the main clinical approach to treat breast cancer, although risks including high local recurrence of cancer and loss of breast tissues are the threats for the survival and quality of life of patients after surgery. In this study, bifunctional scaffold based on dopamine-modified alginate and polydopamine (PDA) was fabricated using 3D printing with an aim to treat breast cancer and fill the cavity, thereby achieving tissue repair. The as-prepared alginate-polydopamine (Alg-PDA) scaffold exhibited favorable photothermal effect both in vitro and in vivo upon 808 nm laser irradiation. Further, the Alg-PDA scaffold showed great flexibility and similar modulus with normal breast tissues and facilitated the adhesion and proliferation of normal breast epithelial cells. Moreover, the in vivo performance of the Alg-PDA scaffold could be tracked by magnetic resonance and photoacoustic dual-modality imaging. The scaffold that was fabricated using simple and biocompatible materials with individual-designed structure and macropores, as well as outstanding photothermal effect and enhanced cell proliferation ability, might be a potential option for breast cancer treatment and tissue repair after surgery. STATEMENT OF SIGNIFICANCE: In this study, a three-dimensional porous scaffold was developed using 3D printing for the treatment of local recurrence of breast cancer and the following tissue repair after surgery. In this approach, easily available materials (dopamine-modified alginate and PDA) with excellent biocompatibility were selected and prepared as printing inks. The fabricated scaffold showed effective photothermal effects for cancer therapy, as well as matched mechanical properties with breast tissues. Furthermore, the scaffold supported attachment and proliferation of normal breast cells, which indicates its potential ability for adipose tissue repair. Together, the 3D-printed scaffold might be a promising option for the treatment of locally recurrent breast cancer cells and the following tissue repair after surgery.

A Versatile Theranostic Nanoemulsion for Architecture-Dependent Multimodal Imaging and Dually Augmented Photodynamic Therapy.

To design a clinically translatable nanomedicine for photodynamic theranostics, the ingredients should be carefully considered. A high content of nanocarriers may cause extra toxicity in metabolism, and multiple theranostic agents would complicate the preparation process. These issues would be of less concern if the nanocarrier itself has most of the theranostic functions. In this work, a poly(ethylene glycol)-boron dipyrromethene amphiphile (PEG-F54 -BODIPY) with 54 fluorine-19 (19 F) is synthesized and employed to emulsify perfluorohexane (PFH) into a theranostic nanoemulsion (PFH@PEG-F54 -BODIPY). The as-prepared PFH@PEG-F54 -BODIPY can perform architecture-dependent fluorescence/photoacoustic/19 F magnetic resonance multimodal imaging, providing more information about the in vivo structure evolution of nanomedicine. Importantly, this nanoemulsion significantly enhances the therapeutic effect of BODIPY through both the high oxygen dissolving capability and less self-quenching of BODIPY molecules. More interestingly, PFH@PEG-F54 -BODIPY shows high level of tumor accumulation and long tumor retention time, allowing a repeated light irradiation after a single-dose intravenous injection. The "all-in-one" photodynamic theranostic nanoemulsion has simple composition, remarkable theranostic efficacy, and novel treatment pattern, and thus presents an intriguing avenue to developing clinically translatable theranostic agents.

[Effects of Straw in Combination with Reducing Fertilization Rate on Soil Nutrients and Enzyme Activity in the Paddy-Vegetable Rotation Soils].

The effects of straw returning combined the reducing application of chemical fertilizer for crop yield, soil nutrients and enzyme activity were studied in a typical southwestern hilly area of China in a rice-vegetable (Brassica juncea var. gemmifera Lin.) cropping system. The purple soil was selected as the target type of soil, and the Pioneer Town, Jiangjin District, Chongqing, China was selected as the typical southwestern hilly area during 2013 and 2014.Scientific basis based on the optimized fertilization strategy and the recyclable utilization of straw was provided through a field in-situ experiment in this study. There were five treatments in the field experiment: F (conventional fertilizer), 90% F+AS (100% straw with 90% conventional fertilizer), 80% F+AS (100% straw with 80% conventional fertilizer), 70% F+AS (100% straw with 70% conventional fertilizer), 50% F+DS (200% straw with 50% conventional fertilizer), and the 100% straw was 7500 kg·hm-2. The results showed that the yields of rice and vegetable were all increased in straw with reduced fertilizer treatments (3.0%-17.9% in rice yield and 12.2%-36.4% in vegetable yield) compared with conventional fertilizer (F) treatment. Moreover, the yield of rice in the second season was also increased by 820-1240 kg·hm-2. Soil pH values in straw with reduced fertilizer treatments raised by 0.06-0.55 compared with F treatment, especially in straw with 70% and 80% of conventional fertilizer dosage which increased by 6.74-6.88 and 6.52-6.84, respectively. The highest content of soil organic matter was 41.01 g·kg-1 in straw with 80% of conventional fertilizer treatment. For the aspect of soil available nutrients, straw with 80% of conventional fertilizer treatment increased 110-178 mg·kg-1 content of soil available nitrogen and 31.3-64.0 mg·kg-1 content of soil available phosphorus. However, the excessive application of straw had negative effect on the accumulation of soil available phosphorus. In the same cultivation period, the contents of soil urease increased significantly in straw with 70% and 80% of conventional fertilizer treatments, which increased by 13.6%-76.4% and 20.1%-75.0% compared with F treatment. The contents of soil catalase in straw with reduced fertilizer treatments were significantly higher than F treatment; in first two seasons, soil catalase contents increased by 0.37 and 0.31 mL·(h·g)-1 relative to F treatment in straw with reduced fertilizer treatment (80% of conventional fertilizer). With the increasing time of planting, the soil phosphatase content in the third season was higher than those in first two seasons. Straw with 70% and 80% of fertilizer treatments increased the activity of soil phosphatase by 45.2% and 48.2% compared with F treatment. It was concluded that straw application with 70% or 80% dosage of conventional fertilizer could benefit the rice-vegetable rotation in the southwest hilly area of China.