RESUMEN
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.
Asunto(s)
Melanoma , Neoplasias , Animales , Ratones , Glucosa Oxidasa , Transporte Biológico , Cloruros , Cobre , Modelos Animales de Enfermedad , Peróxido de Hidrógeno , Línea Celular Tumoral , Microambiente TumoralRESUMEN
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.
Asunto(s)
Compuestos Férricos , Ácido Gálico , Ácido Gálico/química , Compuestos Férricos/química , Oxidación-Reducción , Antioxidantes/metabolismo , Peróxido de Hidrógeno/química , Radical HidroxiloRESUMEN
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.
Asunto(s)
Envejecimiento de la Piel , Animales , Ratones , Superóxido Dismutasa/farmacología , Antioxidantes/farmacología , Preparaciones Farmacéuticas , EnvejecimientoRESUMEN
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.
Asunto(s)
Sistemas de Liberación de Medicamentos , Piel , Agujas , Administración Cutánea , PolímerosRESUMEN
Despite their clinical success in drug delivery applications, the potential of theranostic nanomedicines is hampered by mechanistic uncertainty and a lack of science-informed regulatory guidance. Both the therapeutic efficacy and the toxicity of nanoformulations are tightly controlled by the complex interplay of the nanoparticle's physicochemical properties and the individual patient/tumor biology; however, it can be difficult to correlate such information with observed outcomes. Additionally, as nanomedicine research attempts to gradually move away from large-scale animal testing, the need for computer-assisted solutions for evaluation will increase. Such models will depend on a clear understanding of structure-activity relationships. This review provides a comprehensive overview of the field of cancer nanomedicine and provides a knowledge framework and foundational interaction maps that can facilitate future research, assessments, and regulation. By forming three complementary maps profiling nanobio interactions and pathways at different levels of biological complexity, a clear picture of a nanoparticle's journey through the body and the therapeutic and adverse consequences of each potential interaction are presented.
Asunto(s)
Nanomedicina , Neoplasias , Animales , Sistemas de Liberación de Medicamentos , Nanomedicina Teranóstica , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
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.
Asunto(s)
Aptámeros de Nucleótidos , Técnicas Analíticas Microfluídicas , Células Neoplásicas Circulantes , Anticuerpos Monoclonales , Línea Celular Tumoral , Separación Celular , Dimaprit/análogos & derivados , Humanos , Microfluídica , Células Neoplásicas Circulantes/patología , PlásticosRESUMEN
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.
Asunto(s)
Peróxido de Hidrógeno , Nitritos , Oxidación-Reducción , Especies de Nitrógeno Reactivo , Tirosina/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Cobre/uso terapéutico , Glucosa Oxidasa/uso terapéutico , Melanoma/tratamiento farmacológico , Nanocompuestos/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Terapia Combinada , Cobre/química , Cobre/efectos de la radiación , Quimioterapia , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/uso terapéutico , Glucosa/química , Glucosa/metabolismo , Glucosa Oxidasa/química , Humanos , Luz , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanocompuestos/química , Nanocompuestos/efectos de la radiación , Terapia FototérmicaRESUMEN
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.
Asunto(s)
Antibacterianos/química , Cobre/química , Nanopartículas del Metal/química , Nitritos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Cobre/farmacología , Quimioterapia Combinada , Escherichia coli , Radicales Libres/química , Peróxido de Hidrógeno/química , Nitritos/farmacología , Staphylococcus aureus , Propiedades de SuperficieRESUMEN
ß-Cyclodextrin (ß-CD) was grafted onto hyaluronic acid (HA) in a single step to generate a supramolecular biopolymer (HA-ß-CD) that was explored for targeted drug delivery applications. Along with its excellent biocompatibility, the prepared HA-ß-CD exhibits not only exceptionally high loading capacity for the model drugs doxorubicin and Rhodamine B through the formation of inclusion complexes with the ß-CD component, but also the capability of targeted drug delivery to cancerous cells with a high level of expression of CD44 receptors, attributable to its HA component. The polymer can release the drug under slightly acidic conditions. With all its attributes, HA-ß-CD may be a promising cancer-cell-targeting drug carrier.
Asunto(s)
Ácido Hialurónico , beta-Ciclodextrinas , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberación de MedicamentosRESUMEN
Hyaluronic acid (HA), a common biopolymer found in the extracellular fluid, was grafted with ß-cyclodextrin (ß-CD) to form a composite polymer that could form inclusion complexes with tocopherol (VE), enhancing its water-solubility and serving as a model drug delivery system. Herein, different copolymers were prepared with varying HA:ß-CD ratios and characterized. VE loading capacity was directly correlated with increased ß-CD composition in the polymers and morphological changes were observed upon VE binding. The host materials and their VE inclusion complexes are not cytotoxic, and are thus useful for VE and drug delivery.
Asunto(s)
Sistemas de Liberación de Medicamentos , Ácido Hialurónico/química , Tocoferoles/administración & dosificación , beta-Ciclodextrinas/química , Antioxidantes/administración & dosificación , Antioxidantes/química , Células HeLa , Humanos , Polímeros/química , Solubilidad , Tocoferoles/química , Agua/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos/análisis , Química Farmacéutica/métodos , Melanoma Experimental/tratamiento farmacológico , Sulfonamidas/análisis , Tiazoles/análisis , Parche Transdérmico , Administración Cutánea , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Línea Celular Tumoral/trasplante , Cromatografía Líquida de Alta Presión/métodos , Liberación de Fármacos , Femenino , Límite de Detección , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Agujas , Reproducibilidad de los Resultados , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Distribución TisularRESUMEN
Polymeric microneedles (MNs) are attractive transdermal drug delivery systems because of their efficient drug delivery and minimal invasiveness. Master template fabrication is the most time-consuming and costly step in producing polymeric MNs using a micromoulding approach. Herein, this issue is addressed by modifying tattoo needle cartridges by adjusting the volume of a PDMS spacer, thus streamlining polymeric MN fabrication and significantly reducing its manufacturing cost. Using the fabricated master template, dissolvable polymeric MN systems containing poly(vinyl pyrrolidone) (PVP) and poly(vinyl alcohol) (PVA) were developed. This MN system exhibits several advantages, including controllable MN length, uniform distribution of each needle, and controllable drug release profiles. Overall, polymeric MN fabrication using this method is inexpensive, simple, and yields controllable and effective transdermal drug delivery.
RESUMEN
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.
Asunto(s)
Grafito/química , Polímeros/química , Administración Cutánea , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Polymeric microneedle (MN) systems are interesting transdermal drug delivery systems because of their controlled drug delivery, tunable properties, and ease of patient self-administration. They are biocompatible and can easily and painlessly penetrate the stratum corneum, delivering their contents into the dermis where they can be adsorbed into systemic circulation. Polymeric MNs can facilitate appropriate therapeutic dosing by controlling the release kinetics of pre-loaded drugs, targeting specific tissues, or responding to changing physiological conditions. This can be accomplished by modifying the degradation and swelling profiles of the host polymer and the diffusion profiles of the encapsulated drugs. In this review various mechanisms of controlled drug delivery using polymeric MNs, including new strategies, applications, and their future outlook are summarized and evaluated.
Asunto(s)
Sistemas de Liberación de Medicamentos , Polímeros/química , Piel/metabolismo , Animales , Preparaciones de Acción Retardada , Liberación de Fármacos , Humanos , Agujas , Absorción CutáneaRESUMEN
Circulating tumor cells (CTCs) are indicative for cancer diagnosis and prognosis. However, conventional immuno-magnetic cell capture technologies using antibody- and aptamer-functionalized magnetic particles generate increased intracellular oxidative stress through endocytosis. Herein, we efficiently, selectively, and non-invasively isolate CTCs from whole blood by mimicking double-sided tape using DNA.
Asunto(s)
Aptámeros de Nucleótidos/química , Separación Celular/métodos , Células Neoplásicas Circulantes/metabolismo , Línea Celular Tumoral , ADN/química , Humanos , Nanopartículas de Magnetita/química , Microscopía Confocal , Células Neoplásicas Circulantes/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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.
Asunto(s)
Aptámeros de Nucleótidos/química , Proteínas Sanguíneas/aislamiento & purificación , Proteínas Sanguíneas/metabolismo , Separación Celular/métodos , Nanotecnología/métodos , Células Neoplásicas Circulantes/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Sanguíneas/análisis , Estudios de Casos y Controles , Humanos , Fenómenos Magnéticos , Microesferas , Células Neoplásicas Circulantes/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
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.
Asunto(s)
Hidróxido de Aluminio/química , Hidróxido de Magnesio/química , Nanopartículas/química , Oligodesoxirribonucleótidos/química , Adsorción , Técnicas de Transferencia de Gen , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Fluorescent pyrene-polyethersulfone (Py-PES) nanofibers were prepared through electrospinning technique using mixed solvents. The effects of mixed solvent ratio and polymer/fluorophore concentrations on electrospun nanofiber's morphology and its sensing performance were systematically investigated and optimized. The Py-PES nanofibers prepared under optimized conditions were further applied for highly sensitive detection of explosives, such as picric acid (PA), 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), and 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) in aqueous phase with limits of detection (S/N = 3) of 23, 160, 400, and 980 nM, respectively. The Stern-Volmer (S-V) plot for Py excimer fluorescence quenching by PA shows two linear regions at low (0-1 µM) and high concentration range (>1 µM) with a quenching constant of 1.263 × 10(6) M(-1) and 5.08 × 10(4) M(-1), respectively. On the contrary, S-V plots for Py excimer fluorescence quenching by TNT, DNT, and RDX display an overall linearity in the entire tested concentration range. The fluorescence quenching by PA can be attributed to the fact that both photoinduced electron transfer and energy transfer are involved in the quenching process. In addition, pyrene monomer fluorescence is also quenched and exhibits different trends for different explosives. Fluorescence lifetime studies have revealed a dominant static quenching mechanism of the current fluorescent sensors for explosives in aqueous solution. Selectivity study demonstrates that common interferents have an insignificant effect on the emission intensity of the fluorescent nanofibers in aqueous phase, while reusability study indicates that the fluorescent nanofibers can be regenerated. Spiked real river water sample was also tested, and negligible matrix effect on explosives detection was observed. This research provides new insights into the development of fluorescent explosive sensor with high performance.