RESUMO
Dissolvable polymeric microneedles (DPMNs) have emerged as a powerful technology for the localized treatment of diseases, such as melanoma. Herein, we fabricated a DPMN patch containing a potent enzyme-nanozyme composite that transforms the upregulated glucose consumption of cancerous cells into lethal reactive oxygen species via a cascade reaction accelerated by endogenous chloride ions and external near-infrared (NIR) irradiation. This was accomplished by combining glucose oxidase (Gox) with a NIR-responsive chloroperoxidase-like copper sulfide (CuS) nanozyme. In contrast with subcutaneous injection, the microneedle system highly localizes the treatment, enhancing nanomedicine uptake by the tumor and reducing its systemic exposure to the kidneys and spleen. NIR irradiation further controls the potency and toxicity of the formulation by thermally disabling Gox. In a mouse melanoma model, this unique combination of photothermal, starvation, and chemodynamic therapies resulted in complete tumor eradication (99.2 ± 0.8 % reduction in tumor volume within 10 d) without producing signs of systemic toxicity. By comparison, other treatment combinations only resulted in a 42-76.5 % reduction in tumor growth. The microneedle patch design is therefore not only highly potent but also with regulated toxicity and improved safety.
Assuntos
Melanoma , Neoplasias , Animais , Camundongos , Glucose Oxidase , Transporte Biológico , Cloretos , Cobre , Modelos Animais de Doenças , Peróxido de Hidrogênio , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Boat Harbour, Nova Scotia was a tidal estuary that was converted into a wastewater treatment facility for pulp mill effluent in 1967. Treated effluent from Boat Harbour was discharged into the coastal Northumberland Strait, contributing significant nutrient and freshwater inputs into the coastal environment, potentially impacting local biogeochemistry and ecosystem structure. This study used stable isotope analysis of carbon (δ13C) and nitrogen (δ15N) of representative taxa to assess spatial variability in nutrient sources and trophic dynamics. Results identified stable isotope variation with depleted δ13C and δ15N values in taxa near Boat Harbour. Blue mussel (Mytilus edulis) and mummichog (Fundulus heteroclitus) were the most suitable bioindicators for identifying variation in nutrient sources. Stable isotope signatures in this study may be reflective of residual pulp mill effluent-derived nutrients, differences in marine versus terrestrial nutrient sources, and a pronounced coastal salinity gradient. The present study defined the baseline nutrient conditions of the Northumberland Strait and will be useful in assessing the effectiveness of remediation activities.
Assuntos
Carbono , Ecossistema , Isótopos de Carbono/análise , Isótopos de Nitrogênio/análise , Nova Escócia , Cadeia AlimentarRESUMO
Gallic acid (GA, 3,4,5-trihydroxybenzoic acid) is a widely used natural food additive of interest to food chemistry researchers, especially regarding its effects on myofibrillar protein (MP) oxidation. However, existing studies regarding MP oxidation by GA-combined with Fenton reagents are inconsistent, and the detailed mechanisms have not been fully elucidated. This work validated hydroxyl radical (HO·) as the primary oxidant for MP carbonylation; in addition, it revealed three functions of GA in the Fenton oxidation of MP. By coordination with Fe(III), GA reduces Fe(III) to generate Fe(II), which is the critical reagent for HO· generation; meanwhile, the coordination improves the availability and reactivity of Fe(III) under weakly acidic and near-neutral pH, i.e., pH 4-6. Second, the intermediates formed during GA oxidation, including semiquinone and quinone, promoted Fenton reactivity by accelerating Fe catalytic cycling. Finally, GA can scavenge HO· radicals, thus exhibiting a certain degree of antioxidant property. All three functions contribute to MP oxidation as observed in GA-containing meat.
Assuntos
Compostos Férricos , Ácido Gálico , Ácido Gálico/química , Compostos Férricos/química , Oxirredução , Antioxidantes/metabolismo , Peróxido de Hidrogênio/química , Radical HidroxilaRESUMO
As an effective antioxidant enzyme, superoxide dismutase (SOD) has been widely used as a food supplement, cosmetic additive, and therapeutic agent. However, oral delivery of SOD is challenging due to its relative instability, limited bioavailability, and low absorption efficiency in the gastrointestinal (GI) tract. We addressed these issues using a highly stable superoxide dismutase (hsSOD) generated from a hot spring microbial sample. This SOD exhibited a specific activity of 5000 IU/mg while retaining its enzymatic activity under low pH environments of an artificial GI system and in the presence of surfactants and various proteolytic enzymes. The inhibitory effects of hsSOD against skin-aging was evaluated under both in vitro and in vivo experiments using fibroblast cell and D-galactose induced aging-mouse models, respectively. Effective oral delivery of hsSOD promises wide applicability in pharmaceutical and food industries.
Assuntos
Envelhecimento da Pele , Animais , Camundongos , Superóxido Dismutase/farmacologia , Antioxidantes/farmacologia , Preparações Farmacêuticas , EnvelhecimentoRESUMO
A baseline survey was conducted in 2018 to characterize contaminants in American lobsters, Homarus americanus in the Northumberland Strait, Canada. Sampling included three age classes of lobsters at sites 4, 20, and 70 km from the Boat Harbour estuary, a historically contaminated site set to undergo remediation. Lobster tissues were measured for metal(loids), methylmercury, polycyclic aromatic hydrocarbons, and polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans. Contaminant concentrations were generally below the guidelines set by the Canadian Council of Ministers of the Environment and the Canadian Food Inspection Agency, except for arsenic which was elevated in all age classes from all sites (4.8-12.68 mg kg-1). Mercury and methylmercury (both ~0.04 mg kg-1) minimally exceeded one guideline in some age-classes and sites. There was also no consistent pattern of contaminant accumulation across either age classes or at particular sites. This study serves as a baseline for future monitoring following remediation of Boat Harbour.
Assuntos
Compostos de Metilmercúrio , Nephropidae , Animais , Nova Escócia , Monitoramento Ambiental , Sedimentos GeológicosRESUMO
Microneedles (MN) technology is an emerging technology for the transdermal delivery of therapeutics. When combined with photoresponsive (PR) materials, MNs can deliver therapeutics precisely and effectively with enhanced efficacy or synergistic effects. This review systematically summarizes the therapeutic applications of PRMNs in cancer therapy, wound healing, diabetes treatment, and diagnostics. Different PR approaches to activate and control the release of therapeutic agents from MNs are also discussed. Overall, PRMNs are a powerful tool for stimuli-responsive controlled-release therapeutic delivery to treat various diseases.
Assuntos
Sistemas de Liberação de Medicamentos , Pele , Agulhas , Administração Cutânea , PolímerosRESUMO
Although liposomes have demonstrated significant clinical success as drug delivery vehicles, pharmacokinetic (PK) profiling of liposomal nanomedicines remains difficult due to technical challenges accurately measuring low concentrations of free drug in complex biological matrices. Microdialysis (MD) is well established as a powerful in vivo sampling tool for PK studies, but non-volatile salts present in the microdialysate are incompatible with mass spectrometry (MS) analysis without tedious sample pre-treatment. To address this issue, a µSPE-based microfluidic chip was fabricated to interface MD with MS. By incorporating PEG 20,000 as an effective anti-foulant, the µSPE-based microfluidic chip demonstrated excellent efficiencies in drug extraction and de-salting of the microdialysate, providing a promising approach to real-time monitoring of nanomedicine PK profiles.
Assuntos
Microfluídica , Nanomedicina , Nanomedicina/métodos , Microdiálise , Lipossomos , Sais , Espectrometria de MassasRESUMO
Simultaneous isolation of various circulating tumor cell (CTC) subtypes from whole blood is useful in cancer diagnosis and prognosis. Microfluidic affinity separation devices are promising for CTC separation because of their high throughput capacity and automatability. However, current affinity agents, such as antibodies (mAbs) and aptamers (Apts) alone, are still suboptimal for efficient, consistent, and versatile cell analysis. By introducing a hybrid affinity agent, i.e., an aptamer-antibody (Apt-mAb) conjugate, we developed a universal and regenerative microchip with high efficiency and non-invasiveness in the separation and profiling of various CTCs from blood. The Apt-mAb conjugate consists of a monoclonal antibody that specifically binds the target cell receptor and a surface-bound aptamer that recognizes the conserved Fc region of the mAb. The aptamer then indirectly links the surface functionalization of the microfluidic channels to the mAbs. This hybrid affinity agent and the microchip platform may be widely useful for various bio-particle separations in different biological matrices. Further, the regeneration capability of the microchip improves data consistency between multiple uses and minimizes plastic waste while promoting environmental sustainability. STATEMENT OF SIGNIFICANCE: A hybrid affinity agent, Apt-mAb, consisting of a universal aptamer (Apt) that binds the conserved Fc region of monoclonal antibodies (mAbs) was developed. The invented nano-biomaterial combines the strengths and overcomes the weakness of both Apts and mAbs, thus changing the paradigm of affinity separation of cell subtypes. When Apt-mAb was used to fabricate microfluidic chips using a "universal screwdriver" approach, the microchip could be easily tuned to bind any cell type, exhibiting great universality. Besides high sensitivity and selectivity, the superior regenerative capacity of the microchips makes them reusable, which provides improved consistency and repeatability in cell profiling and opens a new approach towards in vitro diagnostic point-of-care testing devices with environmental sustainability and cost-effectiveness.
Assuntos
Aptâmeros de Nucleotídeos , Técnicas Analíticas Microfluídicas , Células Neoplásicas Circulantes , Anticorpos Monoclonais , Linhagem Celular Tumoral , Separação Celular , Dimaprit/análogos & derivados , Humanos , Microfluídica , Células Neoplásicas Circulantes/patologia , PlásticosRESUMO
Nitrite is a common additive used during meat curing to prevent microbial contamination and retain an attractive red color in the product. However, the effects of nitrite on Fenton reactions catalyzed by free iron in meat products are not well understood, although such processes can induce protein oxidation and nitration, affecting the nutritional and aesthetic quality of meat products. This contribution reveals the mechanism through which nitrite affects Fenton reactions that generate reactive nitrogen and oxygen species by increasing the availability of Fe3+, facilitating its reduction and stabilizing Fe2+, and accelerating Fe3+/Fe2+ cycling, leading to exacerbated oxidative and nitrosative stress on proteins, with implications not only for meat processing but also in many biological and environmental processes due to the ubiquitous presence of iron, hydrogen peroxide, and nitrite in nature.
Assuntos
Peróxido de Hidrogênio , Nitritos , Oxirredução , Espécies Reativas de Nitrogênio , Tirosina/metabolismoRESUMO
Multimodal nanotherapeutic cancer treatments are widely studied but are often limited by their costly and complex syntheses that are not easily scaled up. Herein, a simple formulation of glucose-oxidase-coated CuS nanoparticles was demonstrated to be highly effective for melanoma treatment, acting through a synergistic combination of glucose starvation, photothermal therapy, and synergistic advanced chemodynamic therapy enabled by near-infrared irradiation coupled with Fenton-like reactions that were enhanced by endogenous chloride.
Assuntos
Antineoplásicos/uso terapêutico , Cobre/uso terapêutico , Glucose Oxidase/uso terapêutico , Melanoma/tratamento farmacológico , Nanocompostos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Cobre/química , Cobre/efeitos da radiação , Tratamento Farmacológico , Enzimas Imobilizadas/química , Enzimas Imobilizadas/uso terapêutico , Glucose/química , Glucose/metabolismo , Glucose Oxidase/química , Humanos , Luz , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocompostos/química , Nanocompostos/efeitos da radiação , Terapia FototérmicaRESUMO
Unwanted biofilms present challenges for many industries. Herein an innovative biofilm removal technology was developed based on nitrite-accelerated Fenton chemistry, where both dissolved Cu ions and nano-CuO surfaces efficiently generate reactive nitrogen species as disinfectants. This simple, efficient, and cost-effective approach for biofilm removal generates important insights into Fenton chemistry, a fundamental mechanism in nature, considering the ubiquity of copper, hydrogen peroxide, and nitrite in the environment, biological systems, and various industrial processes.
Assuntos
Antibacterianos/química , Cobre/química , Nanopartículas Metálicas/química , Nitritos/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Cobre/farmacologia , Quimioterapia Combinada , Escherichia coli , Radicais Livres/química , Peróxido de Hidrogênio/química , Nitritos/farmacologia , Staphylococcus aureus , Propriedades de SuperfícieRESUMO
A bleached kraft pulp mill operating in Nova Scotia, Canada has discharged effluent into a former tidal estuary known as Boat Harbour since 1967. After treatment in Boat Harbour, effluent is discharged into Northumberland Strait. Contaminated sediments in Boat Harbour are slated for remediation following cessation of effluent discharge. A review of historical documents to identify contaminants in marine biota in Northumberland Strait found insufficient data to properly assess baseline conditions prior to remediation. This study measured metal, methylmercury, dioxin and furan concentrations in surficial sediments and American lobster (Homarus americanus), rock crabs (Cancer irroratus) and blue mussels (Mytilus edulis) in Northumberland Strait. When compared to Canadian Council of Ministers of the Environment sediment quality guidelines and Canadian Food Inspection Agency tissue guidelines results indicated limited contamination in sediments and biota, posing low risk to marine biota. Long-term monitoring is recommended to verify effectiveness of remediation.
Assuntos
Sedimentos Geológicos , Poluentes Químicos da Água/análise , Animais , Biota , Monitoramento Ambiental , Nova EscóciaRESUMO
A rapid and sensitive liquid chromatography-tandem mass spectrometric method was developed and validated for the determination of HA15, an emerging anticancer compound targeting GSPA5/BIP delivered by dissolvable polymeric microneedles. The linear range of quantification for HA15 was 2.5-1000â¯ng/ml in plasma and tissue homogenate and the limit of detection and lower limit of quantification are 1 and 2.5â¯ng/ml, respectively. The inter- and intra-day accuracy and precision were within the acceptable range. HA15 was extracted from mouse plasma and organs using protein precipitation and using dabrafenib as an internal standard and the drug was stable under relevant analytical conditions. The method was used to analyze drug loading, dissolution in vitro, and release ex vivo from dissolvable polymeric microneedles and used to compare these materials to subcutaneous injection for the tissue distribution in tumor bearing nude mice.
Assuntos
Antineoplásicos/análise , Química Farmacêutica/métodos , Melanoma Experimental/tratamento farmacológico , Sulfonamidas/análise , Tiazóis/análise , Adesivo Transdérmico , Administração Cutânea , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral/transplante , Cromatografia Líquida de Alta Pressão/métodos , Liberação Controlada de Fármacos , Feminino , Limite de Detecção , Melanoma Experimental/patologia , Camundongos , Camundongos Nus , Agulhas , Reprodutibilidade dos Testes , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Distribuição TecidualRESUMO
Dissolvable polymeric microneedles (DPMNs) are promising transdermal drug delivery systems with minimal invasiveness and improved patient compliance. Incorporation of a small amount of graphene oxide (GO) in the biocompatible polymers for microneedle fabrication results in important new DPMN properties, that is, dramatically enhanced mechanic strength (10-17 times at 500 mg/mL GO), improved moisture resistance, self-sterilization, antibacterial and anti-inflammatory properties (demonstrated in vitro), and near-infrared light-activated controlled drug release (demonstrated in vitro and in vivo), which were exploited for the transdermal delivery of the chemotherapeutic, HA15, to melanoma-bearing mouse models. These new properties improve their efficacy of transdermal drug delivery and ease of use, enhance their capability of controlled drug release, enlarge the scope of the polymers that can be used for DPMN fabrication, prevent microbial contamination during storage and transportation, and reduce infection risk in clinical applications.
Assuntos
Grafite/química , Polímeros/química , Administração Cutânea , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Isolation of specific rare cell subtypes from whole blood is critical in cellular analysis and important in basic and clinical research. Traditional immunomagnetic cell capture suffers from suboptimal sensitivity, specificity, and time- and cost-effectiveness. Mimicking the features of octopuses, a device termed a "NanoOctopus" was developed for cancer cell isolation in whole blood. The device consists of long multimerized aptamer DNA strands, or tentacle DNA, immobilized on magnetic microparticle surfaces. Their ultrahigh sensitivity and specificity are attributed to multivalent binding of the tentacle DNA to cell receptors without steric hindrance. The simple, quick, and noninvasive capture and release of the target cells allows for extensive downstream cellular and molecular analysis, and the time- and cost-effectiveness of fabrication and regeneration of the devices makes them attractive for industrial manufacture.
Assuntos
Aptâmeros de Nucleotídeos/química , Proteínas Sanguíneas/isolamento & purificação , Proteínas Sanguíneas/metabolismo , Separação Celular/métodos , Nanotecnologia/métodos , Células Neoplásicas Circulantes/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Sanguíneas/análise , Estudos de Casos e Controles , Humanos , Fenômenos Magnéticos , Microesferas , Células Neoplásicas Circulantes/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
A highly regenerative multifunctional nanobot system, using Fe3O4@SiO2@MgFe-LDH nanoparticles, is developed for efficient removal of waterborne azo dyes and pharmaceuticals. Efficient capture of pollutants, powerful Fenton degradation, and superior materials regeneration lead to a simple and cost-effective wastewater remediation solution.
RESUMO
Biofilms present challenges to numerous industries. Herein, a simple approach was developed based on chloride-accelerated Fenton chemistry, where copper oxide nanoparticles facilitate efficient generation of reactive chlorine species for biofilm removal.
Assuntos
Biofilmes , Cloretos/química , Cobre/química , Peróxido de Hidrogênio/química , Ferro/química , Nanopartículas/químicaRESUMO
Magnesium aluminum-layered double-hydroxide nanoparticles (LDH NPs) are promising drug-delivery vehicles for gene therapy, particularly for siRNA interference; however, the interactions between oligo-DNA and LDH surfaces have not been adequately elucidated. Through a mechanistic study, oligo-DNA initially appears to rapidly bind strongly to the LDH outer surfaces through interactions with their phosphate backbones via ligand exchange with OH- on Mg2+ centers and electrostatic forces with Al3+. These initial interactions might precede diffusion into interlayer spaces, and this knowledge can be used to design better gene therapy delivery systems.
Assuntos
Hidróxido de Alumínio/química , Hidróxido de Magnésio/química , Nanopartículas/química , Oligodesoxirribonucleotídeos/química , Adsorção , Técnicas de Transferência de Genes , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Polycyclic aromatic hydrocarbons (PAHs) were assessed spatially and temporally within and adjacent to a former coking and steel manufacturing facility in Sydney, Nova Scotia, Canada. Concentrations of PAHs were measured in surface soils, marine and estuary sediments prior to and during remediation of the Sydney Tar Ponds (STPs) site which was contaminated by nearly a century of coking and steel production. Previous studies identified PAHs in surficial marine sediments within Sydney Harbour, which were considered to be derived from STP discharges. Numerous PAH fingerprint techniques (diagnostic ratios, principal component analysis, quantitative and qualitative analysis) were applied to soil and sediment samples from the STPs and surrounding area to identify common source apportionment of PAHs. Results indicate coal combustion (from historical residential, commercial and industrial uses) and coal handling (from historic on-site stockpiling and current coal transfer and shipment facilities) are likely the principal source of PAHs found in urban soils and marine sediments, consistent with current and historical activities near these sites. However, PAH fingerprints associated with STP sediments correlated poorly with those of urban soils and marine sediments, but were similar to coal tar, historically consistent with by-products produced by the former coking operations. This study suggests PAH contamination of Sydney Harbour sediments and urban soils is largely unrelated to historic coking operations or recent remediation of the STPs site, but rather a legacy of extensive use of coal for a variety of activities.
Assuntos
Alcatrão/análise , Monitoramento Ambiental/métodos , Poluentes Ambientais/química , Hidrocarbonetos Policíclicos Aromáticos/química , Carvão Mineral/análise , Coque , Estuários , Resíduos Industriais/análise , Nova Escócia , Solo/químicaRESUMO
Layered double hydroxide nanoparticles (LDH NPs) have attracted interest as an effective gene delivery vehicle in biomedicine. Recent advances in clinic trials have demonstrated the efficacy of Mg/Fe LDHs for hyperphosphatemia treatment, but their feasibility for gene delivery has not been systematically evaluated. As a starting point, we aimed to study the interaction between oligo-DNA and Mg/Fe LDH NPs. Our investigation revealed the chemisorption mechanism of DNA on Mg/Fe LDH surfaces, wherein the phosphate backbone of the DNA polymer coordinates with the metal cations of the LDH lattice via the ligand-exchange process. This mechanistic insight may facilitate future gene delivery applications using Mg/Fe LDH NPs.