A Noble AuPtAg-GOx Nanozyme for Synergistic Tumor Immunotherapy Induced by Starvation Therapy-Augmented Mild Photothermal Therapy.

Notwithstanding immune checkpoint blocking (ICB) therapy has made eminent clinical breakthroughs, overcoming immunologically "cold" tumors remains challenging. Here, a cascade potentiated nanomodulator AuPtAg-GOx is engineered for boosting immune responsiveness. Upon 1064 nm laser irradiation, AuPtAg-mediated mild photothermal therapy (PTT) activates cytotoxic T lymphocytes and reverses the immunogenic "cold" tumor microenvironment. Further, to amplify the thermal sensitivity of tumor cells, glucose oxidase (GOx) is introduced to suppress the production of heat shock proteins, thereby promoting mild photothermal therapy. Complementarily, AuPtAg nanozymes with catalase-like activity can ameliorate tumor hypoxia, significantly improving the GOx activity. As a result, the combination of AuPtAg-GOx with self-augmented photothermal ability and PD-L1 antibody can further escalate the antitumor efficacy. The AuPtAg-GOx-based synergistic starvation therapy, mild PTT, and immunotherapy cascade enhancement therapy strategy can be a favorable tool to effectively kill cancer cells.

Ferrocene and glucose oxidase-installed multifunctional hydrogel reactors for local cancer therapy.

A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical (•OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H2O2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles.

Liposomal Glucose Oxidase for Enhanced Photothermal Therapy and Photodynamic Therapy against Breast Tumors.

Organic near-infrared fluorescent dye mediated photothermal therapy (PTT) and photodynamic therapy (PDT) suffer from heat shock response, since, heat shock proteins (HSPs) are overexpressed and can repair the proteins damaged by PTT and PDT. Starvation therapy by glucose oxide (GOx) can inhibit the heat shock response by limiting the energy supply. However, the delivery of sufficient and active GOx remains a challenge. To solve this problem, we utilize liposomes as drug carriers and prepare GOx loaded liposome (GOx@Lipo) with a high drug loading content (12.0%) and high enzymatic activity. The successful delivery of GOx shows excellent inhibition of HSPs and enhances PTT and PDT. Additionally, we apply the same liposome formulation to load near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo cyanine iodide (DiR) and prepare DiR contained liposomes (DiR@Lipo) for PTT and PDT. The liposomal formulation substantially enhances the PTT and PDT properties of DiR as well as the cellular uptake and tumor accumulation. Finally, the combination therapy shows excellent tumor inhibition on 4T1 tumor-bearing mice. Interestingly, we also find that the starvation therapy can efficiently inhibit tumor metastasis, which is probably due to the immunogenic effect. Our work presents a biocompatible and effective carrier for the combination of starvation therapy and phototherapy, emphasizing the importance of auxiliary starvation therapy against tumor metastasis and offering important guidance for clinical PTT and PDT.

Construction of a Mesoporous Ceria Hollow Sphere/Enzyme Nanoreactor for Enhanced Cascade Catalytic Antibacterial Therapy.

Nanozyme has been regarded as one of the antibacterial agents to kill bacteria via a Fenton-like reaction in the presence of H2O2. However, it still suffers drawbacks such as insufficient catalytic activity in near-neutral conditions and the requirement of high H2O2 levels, which would minimize the side effects to healthy tissues. Herein, a mesoporous ceria hollow sphere/enzyme nanoreactor is constructed by loading glucose oxidase in the mesoporous ceria hollow sphere nanozyme. Due to the mesoporous framework, large internal voids, and high specific surface area, the obtained nanoreactor can effectively convert the nontoxic glucose into highly toxic hydroxyl radicals via a cascade catalytic reaction. Moreover, the generated glucose acid can decrease the localized pH value, further boosting the peroxidase-like catalytic performance of mesoporous ceria. The generated hydroxyl radicals could damage severely the cell structure of the bacteria and prevent biofilm formation. Moreover, the in vivo experiments demonstrate that the nanoreactor can efficiently eliminate 99.9% of bacteria in the wound tissues and prevent persistent inflammation without damage to normal tissues in mice. This work provides a rational design of a nanoreactor with enhanced catalytic activity, which can covert glucose to hydroxyl radicals and exhibits potential applications in antibacterial therapy.

A Three-in-one ZIFs-Derived CuCo(O)/GOx@PCNs Hybrid Cascade Nanozyme for Immunotherapy/Enhanced Starvation/Photothermal Therapy.

Glucose oxidase (GOx) is regarded as an ideal endogenous natural enzyme for tumor starvation therapy and photothermal therapy (PTT) is a promising strategy for the ablation of primary tumor. In this work, Cu-doped cobalt oxide and porous carbon nanocomposites (CuCo(O)@PCNs) were synthesized from double-layered ZIF-8@ZIF-67 and GOx was loaded in the porous carbon to form a CuCo(O)/GOx@PCNs hybrid nanozyme. CuCo(O) was characterized as the Cu0.3Co2.7O4 phase through X-ray diffraction analysis and it can react with H2O2 to generate O2 and alleviate tumor hypoxia, resulting in the recovered enzymatic activity of GOx and the enhanced starvation therapy. The porous nanocarbon can ablate the primary tumor because of its high photothermal conversion efficiency of 40.04%. The three-in-one functions of oxygen supply, glucose consumption, and photothermal conversion were realized in the ZIFs-derived CuCo(O)/GOx@PCNs nanozyme and the starvation therapy effect was improved by PTT and oxygen supplement. Furthermore, the inhibition effect of CuCo(O)/GOx@PCNs on metastatic tumor is similar to combined therapy of the nanozyme and the immune checkpoint-blocking antibody, α-PD-1. The related antitumor immune mechanism was studied through the analysis of immune-related proinflammatory cytokines and the activated T cells. This work may provide new ideas for the development and application of the ZIFs-derived hybrid nanozyme in tumor therapy and the CuCo(O)/GOx@PCNs nanozyme may be a promising alternative to immune checkpoint inhibitors.

A Multifunctional Cascade Bioreactor Based on Hollow-Structured Cu2 MoS4 for Synergetic Cancer Chemo-Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy.

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu2 MoS4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu1+/2+ , Mo4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H2 O2 to generate O2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H2 O2 . The regenerated H2 O2 can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O2 - ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.

Glucose oxidase and polydopamine functionalized iron oxide nanoparticles: combination of the photothermal effect and reactive oxygen species generation for dual-modality selective cancer therapy.

Cancer cells possess some inherent characteristics, such as glucose-dependence and intolerance to heat and exogenous reactive oxygen species (ROS). In this study, a strategy has been developed to target these vulnerable weaknesses of cancer cells using glucose oxidase (GOx) and polydopamine (PDA) functionalized iron oxide nanoparticles (Fe3O4@PDA/GOx NPs). PDA is first deposited on the surfaces of iron oxide NPs through self-polymerization, and then GOx is covalently linked with PDA upon mixing the enzyme and Fe3O4@PDA under alkaline conditions. In this system, the PDA layer along with iron oxide NPs serves as a photothermal transfer material converting near infrared (NIR) radiation into heat. The covalently linked GOx can competitively consume glucose and spontaneously generate ROS H2O2 that can be further converted by the iron oxide NPs into more toxic ˙OH, inducing apoptosis of cancer cells. The selective toxicity of Fe3O4@PDA/GOx NPs on cancer cells is demonstrated both in vitro and in vivo. In particular, a single injection rather than multiple doses results in significant suppression of tumors, and does not induce apparent histological lesions in the 4T1 tumor-bearing Balb/c mice. The versatility of the functionalization strategy reported in this study will contribute to developing efficient therapies for selective cancer treatment.

Engineering of a Nanosized Biocatalyst for Combined Tumor Starvation and Low-Temperature Photothermal Therapy.

Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies.

Cancer Cell Membrane Camouflaged Cascade Bioreactor for Cancer Targeted Starvation and Photodynamic Therapy.

Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal-organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (H2O2) to produce oxygen (O2), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen (1O2) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment.

A randomized clinical trial in subjects with dry mouth evaluating subjective perceptions of an experimental oral gel, an oral rinse and a mouth spray compared to water.

PURPOSE: This multicenter, randomized, parallel group study analyzed the effectiveness of an experimental oral gel, a commercially available oral rinse and a commercially available mouth spray versus water alone at relieving self-reported symptoms of dry mouth over a 28-day home use treatment period. The effects of the study treatments on dry mouth-related quality of life (QoL) were also investigated. METHODS: Eligible subjects were stratified by dry mouth severity (mild, moderate or severe) and randomized to receive one of the study treatments. Prior to first use they completed a questionnaire designed to assess their baseline dry mouth-related QoL. Following first use and on Day 8 (2 hours post-treatment only) and Day 29, subjects completed the modified Product Performance and Attributes Questionnaire (PPAQ) I at 0.5, 1, 2 and 4 hours post-treatment. Subjects further assessed treatment performance using the PPAQ II questionnaire on Days 8 and 29 and the dry mouth-related QoL questionnaire on Day 29. RESULTS: In 396 randomized subjects almost all comparisons of responses to PPAQ I, including those for the primary endpoint (response to PPAQ I Question 1 'Relieving the discomfort of dry mouth' after 2 hours on Day 29), were statistically significant in favor of active treatment groups versus water (P < 0.05). All comparisons of responses to PPAQ II on Days 8 and 29 were statistically significant in favor of active treatments versus water (P < 0.05). Moreover, nearly all comparisons for dry mouth-related QoL scores on Day 29 were statistically significant in favor of the active treatments versus water. All the dry mouth management strategies in this trial were well tolerated.

Oral care may reduce pneumonia in the tube-fed elderly: a preliminary study.

Pneumonia is one of the most important diseases in terms of mortality in the elderly. In particular, bedridden patients who are forbidden oral ingestion during enteral nutrition may have a poor outcome resulting from a respiratory infection. Oral hygiene can play a positive role in preventing aspiration pneumonia in the elderly. The aim of this study was to investigate the effectiveness of oral hygiene for bedridden and tube-fed patients at an increased risk of pneumonia. This retrospective study was conducted from July 2011 to June 2013 on a long-term-care hospital unit. The oral care protocol (OCP) intervention commenced in July 2012, during the study period. The subjects of this study were 63 elderly patients with a mean age of 81.7 years. Thirty-one patients were enrolled in the OCP intervention group, and the mean observation length was 130.4 days; the mean observation length for the 32 patients in the control group was 128.4 days. The incidence of pneumonia and the numbers of days with a recorded fever, antibiotics administration, blood tests, and radiological examinations were reduced from 1.20 to 0.45, 24.57 to 17.48, 25.52 to 10.12, 10.91 to 6.54, and 6.33 to 3.09 %, respectively. These reductions were significantly less in the OCP intervention group. In conclusion, the results of the present study suggest that daily oral care for tube-fed patients who do not receive nutrition by mouth reduced the incidence of pneumonia. In addition to patients consuming food by mouth, all tube-fed patients require dedicated oral care to maintain healthy oral conditions.

Reduction of erosion by protein-containing toothpastes.

AIM: To assess the effect of protein-containing toothpastes on the progression of dental erosion in situ (with pellicle) and in vitro (without pellicle). METHODS: A combined split-mouth (extraoral water or toothpaste brushing) and crossover (type of toothpaste) setup was used. Two protein-containing (high/low concentrations of colostrum) and one nonprotein (placebo) toothpaste were investigated. Sixteen volunteers wore intraoral appliances containing 2 human enamel samples on 3 afternoons for pellicle growth during 90 min. One enamel sample was brushed for 5 s with one of the three toothpastes and subsequently exposed to a slurry of the corresponding toothpaste for 2 min. The other sample was exposed to water. Both samples were subsequently exposed to citric acid (extraorally). Loss of calcium and inorganic phosphate were determined. The same sequence of exposures was applied to 16 enamel samples in an in vitro setup without pellicle. RESULTS: With the in situ-formed pellicle, all toothpastes significantly reduced calcium loss compared to water brushing, although no significant differences were found among toothpastes (p = 0.073). For the loss of phosphate, a significant reduction could be found with the use of the high-protein toothpaste compared to the nonprotein toothpaste. Overall there were only slight differences between the toothpastes. Toothpaste effects were less clear in the in vitro experiment. CONCLUSION: The addition of proteins to toothpaste shows some promise for the prevention of erosion. Further research is needed to investigate the performance of the protein-containing toothpastes in longer in situ studies with regard to erosive wear.

Effect of different mucosal and acrylic resin surface treatments in a denture retention model for patients with radiotherapy-induced xerostomia.

The purpose of this study was to determine the effect of oral moisturizing agents, denture adhesives, and surface treatments on the retention of an acrylic resin test base dislodged from the maxillary alveolar ridges of xerostomic radiotherapy patients. Acrylic resin test bases prepared for 10 edentulous xerostomia patients were subjected to 8 surface treatment methods: method 1 = untreated dry surface; method 2 = use of Biotène oral moisturizer; method 3 = use of Protefix denture adhesive; method 4 = combination of Biotène and Protefix; method 5 = sandblasting of test bases; method 6 = use of Biotène on sandblasted surface; method 7 = use of Protefix on sandblasted surface; method 8 = combination of Protefix and Biotène on sandblasted surface. After each treatment, a tensile testing apparatus was used to dislodge the inserted test bases, and force values (N) were recorded. A significant difference in retentive force was observed between the 4 Protefix groups and those that did not use denture adhesive (P < .001). There were no differences among the 4 combinations of denture adhesive treatments (P > .05). Sandblasting the denture surfaces did not increase retentive forces alone or in combination with any other treatments. Biotène oral moisturizing agent was used in 4 treatment methods, but only had a significant effect on increasing retentive force when used with a nonsandblasted surface (P < .05). Biotène had no effect on retentive force compared to a nonsandblasted surface without moisturizer or when it was used in combination with any other methods. Protefix denture adhesive offered the greatest improvement in retentive force. Sandblasting the intaglio surface did not improve retentive force. Biotène was reported to improve patient comfort but had minimal effect on retentive force; however, Biotène can be assumed to be a more advantageous method of increasing retention compared to sandblasting (P < .05).

An in vitro study of antimicrobial activity and efficacy of iodine-generating hydrogel dressings.

OBJECTIVE: To determine the antimicrobial activity and efficacy of different formulations of novel bioxygenating hydrogel dressings (which deliver both iodine and oxygen into the wound) against various target organisms by means of an in vitro test system that more effectively mimics the conditions encountered when dressings are in contact with wounds. METHOD: Three bioxygenating hydrogels were tested: Oxyzyme, which releases low levels of iodine into the wound, and Iodozyme 402 and Iodozyme 401, which release higher levels of iodine, with Iodozyme 402 releasing twice the amount of 401. Cellulose filter disks (n = 32) were inoculated with indicator species and placed equidistant from each other as a matrix onto agar test beds. Cut squares of control or test dressings were placed on top of each disk. Kill curves were constructed from determinations of the numbers of survivors (log cfu per disk) over time by removing disk samples at various time points. RESULTS: Significant differences (p < 0.05) were observed between the controls and test samples. The order of sensitivity for Oxyzyme was Fusobacterium nucleatum, Bacteroides fragilis, Propionibacterium acnes, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans and Pseudomonas aeruginosa. The order of efficacy of the three hydrogel dressings (Iodozyme 402, followed by Iodozyme 401 and then Oxyzyme) was the same regardless of the target species. CONCLUSION: The novel hydrogel skin surface wound dressings are broad-spectrum in activity, encompassing antibiotic-resistant organisms, anaerobes and yeasts; their antimicrobial function appears to be rapidly effective.

Clinical applications of antimicrobial host proteins lactoperoxidase, lysozyme and lactoferrin in xerostomia: efficacy and safety.

Innate human salivary defence proteins, lysozyme, lactoferrin and peroxidase, are known to exert a wide antimicrobial activity against a number of bacterial, viral and fungal pathogens in vitro. Therefore, these proteins, alone or in combinations, have been incorporated as preservatives in foods and pharmaceuticals as well as in oral health care products to restore salivas' own antimicrobial capacity in patients with dry mouth. These antimicrobials used in oral health care products, such as dentifrices, mouth-rinses, moisturizing gels and chewing gums, have been purified from bovine colostrum. In this review I critically evaluate the clinical efficacy and safety of this kind of preventive approach against various oral diseases and symptoms.