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Macrophages are plastic cells of the immune system that can be broadly classified as having pro-inflammatory (M1-like) or anti-inflammatory (M2-like) phenotypes. M2-like macrophages are often associated with cancers and can promote cancer growth and create an immune-suppressive tumor microenvironment. Repolarizing macrophages from M2-like to M1-like phenotype provides a crucial strategy for anticancer immunotherapy. Imiquimod is an FDA-approved small molecule that can polarize macrophages by activating toll-like receptor 7/8 (TLR 7/8) located inside lysosomes. However, the non-specific inflammation that results from the drug has limited its systemic application. To overcome this issue, we report the use of gold nanoparticle-based bioorthogonal nanozymes for the conversion of an inactive, imiquimod-based prodrug to an active compound for macrophage re-education from anti- to pro-inflammatory phenotypes. The nanozymes were delivered to macrophages through endocytosis, where they uncaged pro-imiquimod in situ. The generation of imiquimod resulted in the expression of pro-inflammatory cytokines. The re-educated M1-like macrophages feature enhanced phagocytosis of cancer cells, leading to efficient macrophage-based tumor cell killing.
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Bioorthogonal catalysis via transition metal catalysts (TMCs) enables the generation of therapeutics locally through chemical reactions not accessible by biological systems. This localization can enhance the efficacy of anticancer treatment while minimizing off-target effects. The encapsulation of TMCs into nanomaterials generates "nanozymes" to activate imaging and therapeutic agents. Here, we report the use of cationic bioorthogonal nanozymes to create localized "drug factories" for cancer therapy in vivo. These nanozymes remained present at the tumor site at least seven days after a single injection due to the interactions between cationic surface ligands and negatively charged cell membranes and tissue components. The prodrug was then administered systemically, and the nanozymes continuously converted the non-toxic molecules into active drugs locally. This strategy substantially reduced the tumor growth in an aggressive breast cancer model, with significantly reduced liver damage compared to traditional chemotherapy.
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Neoplasias de la Mama , Nanoestructuras , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Diagnóstico por Imagen , Catálisis , Membrana CelularRESUMEN
Bioorthogonal catalysis using transition-metal catalysts (TMCs) provides a toolkit for the in situ generation of imaging and therapeutic agents in biological environments. Integrating TMCs with nanomaterials mimics key properties of natural enzymes, providing bioorthogonal "nanozymes". ZnS nanoparticles provide a platform for bioorthogonal nanozymes using ruthenium catalysts embedded in self-assembled monolayers on the particle surface. These nanozymes uncage allylated profluorophores and prodrugs. The ZnS core combines the non-toxicity and degradability with the enhancement of Ru catalysis through the release of thiolate surface ligands that accelerate the rate-determining step in the Ru-mediated deallylation catalytic cycle. The maximum rate of reaction (Vmax) increases â¼2.5-fold as compared to the non-degradable gold nanoparticle analogue. The therapeutic potential of these bioorthogonal nanozymes is demonstrated by activating a chemotherapy drug from an inactive prodrug with efficient killing of cancer cells.
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Nanopartículas del Metal , Profármacos , Rutenio , Elementos de Transición , Catálisis , Oro , Profármacos/farmacología , Sulfuros , Compuestos de ZincRESUMEN
Intracellular bacterial infections are difficult to treat, and in the case of Salmonella and related infections, can be life threatening. Antibiotic treatments for intracellular infections face challenges including cell penetration and intracellular degradation that both reduce antibiotic efficacy. Even when treatable, the increased dose of antibiotics required to counter infections can strongly impact the microbiome, compromising the native roles of beneficial non-pathogenic species. Bioorthogonal catalysis provides a new tool to combat intracellular infections. Catalysts embedded in the monolayers of gold nanoparticles (nanozymes) bioorthogonally convert inert antibiotic prodrugs (pro-antibiotics) into active species within resident macrophages. Targeted nanozyme delivery to macrophages was achieved through mannose conjugation and subsequent uptake VIA the mannose receptor (CD206). These nanozymes efficiently converted pro-ciprofloxacin to ciprofloxacin inside the macrophages, selectively killing pathogenic Salmonella enterica subsp. enterica serovar Typhimurium relative to non-pathogenic Lactobacillus sp. in a transwell co-culture model. Overall, this targeted bioorthogonal nanozyme strategy presents an effective treatment for intracellular infections, including typhoid and tuberculosis.
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Infecciones Bacterianas , Nanopartículas del Metal , Antibacterianos/farmacología , Ciprofloxacina/farmacología , Oro/farmacología , Humanos , Nanopartículas del Metal/uso terapéutico , Salmonella typhimuriumRESUMEN
Control over supramolecular recognition between proteins and nanoparticles (NPs) is of fundamental importance in therapeutic applications and sensor development. Most NP-protein binding approaches use 'tags' such as biotin or His-tags to provide high affinity; protein surface recognition provides a versatile alternative strategy. Generating high affinity NP-protein interactions is challenging however, due to dielectric screening at physiological ionic strengths. We report here the co-engineering of nanoparticles and protein to provide high affinity binding. In this strategy, 'supercharged' proteins provide enhanced interfacial electrostatic interactions with complementarily charged nanoparticles, generating high affinity complexes. Significantly, the co-engineered protein-nanoparticle assemblies feature high binding affinity even at physiologically relevant ionic strength conditions. Computational studies identify both hydrophobic and electrostatic interactions as drivers for these high affinity NP-protein complexes.
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Nanopartículas , Interacciones Hidrofóbicas e Hidrofílicas , Unión Proteica , Proteínas , Electricidad EstáticaRESUMEN
Bioorthogonal catalysis provides a promising strategy for imaging and therapeutic applications, providing controlled in situ activation of pro-dyes and prodrugs. In this work, the use of a polymeric scaffold to encapsulate transition metal catalysts (TMCs), generating bioorthogonal "polyzymes," is presented. These polyzymes enhance the stability of TMCs, protecting the catalytic centers from deactivation in biological media. The therapeutic potential of these polyzymes is demonstrated by the transformation of a nontoxic prodrug to an anticancer drug (mitoxantrone), leading to the cancer cell death in vitro.
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Antineoplásicos , Profármacos , Elementos de Transición , Catálisis , PolímerosRESUMEN
Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Nanopartículas del Metal/química , Polímeros/farmacología , Elementos de Transición/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Catálisis , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Polímeros/síntesis química , Polímeros/química , Elementos de Transición/químicaRESUMEN
Gold nanostars coated with a mesoporous silica shell and functionalized with poly(ethylene glycol) containing photolabile 2-nitrobenzyl moieties are able to release doxorubicin after NIR light irradiation at low power irradiance via a multiphoton absorption photo-dissociation process.
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Portadores de Fármacos/química , Oro/química , Nanopartículas del Metal/química , Nitrobencenos/química , Polietilenglicoles/química , Dióxido de Silicio/química , Antineoplásicos/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Células HeLa , Humanos , Rayos Infrarrojos , Nanopartículas del Metal/efectos de la radiación , Nanopartículas del Metal/toxicidad , Nitrobencenos/síntesis química , Nitrobencenos/efectos de la radiación , Nitrobencenos/toxicidad , Polietilenglicoles/síntesis química , Polietilenglicoles/toxicidad , PorosidadRESUMEN
Janus gold nanostar-mesoporous silica nanoparticle (AuNSt-MSNP) nanodevices able to release an entrapped payload upon irradiation with near infrared (NIR) light were prepared and characterized. The AuNSt surface was functionalized with a thiolated photolabile molecule (5), whereas the mesoporous silica face was loaded with a model drug (doxorubicin) and capped with proton-responsive benzimidazole-ß-cyclodextrin supramolecular gatekeepers (N 1). Upon irradiation with NIR-light, the photolabile compound 5 photodissociated, resulting in the formation of succinic acid, which induced the opening of the gatekeeper and cargo delivery. In the overall mechanism, the gold surface acts as a photochemical transducer capable of transforming the NIR-light input into a chemical messenger (succinic acid) that opens the supramolecular nanovalve. The prepared hybrid nanoparticles were non-cytotoxic to HeLa cells, until they were irradiated with a NIR laser, which led to intracellular doxorubicin release and hyperthermia. This induced a remarkable reduction in HeLa cells viability.
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Portadores de Fármacos/química , Oro/química , Rayos Infrarrojos , Nanoestructuras/química , Dióxido de Silicio/química , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Humanos , Hipertermia Inducida , Microscopía Confocal , Nanoestructuras/toxicidad , PorosidadRESUMEN
Bioorthogonal transformation of prodrugs and profluorophores using transition metal catalysts (TMCs) offers a promising strategy for therapeutic and imaging applications. Here, we report the surface engineering of nanoparticles to specifically localize gold nanoparticles (AuNPs) with encapsulated TMCs (nanozymes) to either the inside or outside of cells. The ability to control nanozyme localization and hence activity was demonstrated by the activation of pro-fluorophores and prodrugs intra- and extracellularly, establishing the potential of engineered nanozyme platforms for both diagnostic and therapeutic purposes.
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Membrana Celular/metabolismo , Familia 1 del Citocromo P450/metabolismo , Nanopartículas del Metal/química , Animales , Biocatálisis , Permeabilidad de la Membrana Celular , Células , Familia 1 del Citocromo P450/administración & dosificación , Oro/química , Células HeLa , Humanos , Ratones , Células RAW 264.7RESUMEN
Bioorthogonal nanocatalysts in the form of 'nanozymes', are promising tools for generating imaging and therapeutic molecules in living systems. These systems use transformations developed by synthetic chemists to effect transformations that cannot be performed by cellular machinery. This emerging platform is rapidly evolving towards the creation of smart nanodevices featuring the capabilities of their enzyme prototypes, modulating catalytic activity through structure as well as chemical and physical signals. Here we describe different strategies to fabricate these nanocatalysts and their potential in diagnostic and therapeutic applications.
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Herein, a novel drug photorelease system based on gold nanostars (AuNSts), coated with a mesoporous silica shell and capped with paraffin as thermosensitive molecular gate, is reported. Direct measurements of the surface temperature of a single gold nanostar irradiated using a tightly focused laser beam are performed via a heat-sensitive biological matrix. The surface temperature of a AuNSt increases by hundreds of degrees (°C) even at low laser powers. AuNSts coated with a mesoporous silica shell using a surfactant-templated synthesis are used as chemotherapeutic nanocarriers. Synthetic parameters are optimized to avoid AuNSt reshaping, and thus to obtain nanoparticles with suitable and stable plasmonic properties for near-infrared (NIR) laser-triggered cargo delivery. The mesoporous silica-coated nanostars are loaded with doxorubicin (Dox) and coated with octadecyltrimethoxysilane and the paraffin heneicosane. The paraffin molecules formed a hydrophobic layer that blocks the pores, impeding the release of the cargo. This hybrid nanosystem exhibits a well-defined photodelivery profile using NIR radiation, even at low power density, whereas the nonirradiated sample shows a negligible payload release. Dox-loaded nanoparticles displayed no cytotoxicity toward HeLa cells, until they are irradiated with 808 nm laser, provoking paraffin melting and drug release. Hence, these novel, functional, and biocompatible nanoparticles display adequate plasmonic properties for NIR-triggered drug photorelease applications.
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Oro/química , Supervivencia Celular , Doxorrubicina , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Células HeLa , Humanos , Nanoestructuras , Porosidad , Dióxido de SilicioRESUMEN
The inclusion of transition metal catalysts into nanoparticle scaffolds permits the creation of catalytic nanosystems (nanozymes) able to imitate the behaviour of natural enzymes. Here we report the fabrication of a family of nanozymes comprised of bioorthogonal ruthenium catalysts inserted in the protective monolayer of gold nanoparticles. By introducing simple modifications to the functional groups at the surface of the nanozymes, we have demonstrated control over the kinetic mechanism of our system. Cationic nanozymes with hydrophobic surface functionalities tend to replicate the classical Michaelis Menten model, while those with polar groups display substrate inhibition behaviour, a key mechanism present in 20 % of natural enzymes. The structural parameters described herein can be used for creating artificial nanosystems that mimic the complexity observed in cell machinery.
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INTRODUCTION: Gold nanoparticles display a unique combination of chemical inertness, surface chemistry and size- and shape-dependent electronic and optical properties, which render them ideal for clinical applications. AREAS COVERED: The present article describes recent advancements on the application of gold nanoparticles in vaccine development and gene therapy, with augmented efficiencies in cell uptake, specific binding to bioreceptors in cells, protection of conjugated biomolecules and so forth. Additionally, we discuss how the electronic structure of the nanoparticles can be exploited for enhanced radiotherapy and X-ray tomography, while their optical properties can be used for photothermal cancer therapy or light-triggered drug delivery systems for enhanced chemotherapy. EXPERT OPINION: We analyze certain critical aspects and possible challenges that should be solved in order to use gold nanoparticle conjugates in vaccine research, as well as on the potential combination of properties to improve gene therapy and cancer treatment.